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    SSA lists the income and resource http://www.amisdepasteur.fr/buy-lasix-without-prescription/ limits for Extra Help on their website, where you can also file an get lasix prescription application online and get more information about the program. You can also find out information about Extra Help in many different languages. See Medicare Rights Center chart on Extra Help Income and Asset Limits - updated annually You can apply for Extra Help and MSP at the same time through SSA. SSA will forward your Extra Help application get lasix prescription data to the New York State Department of Health, who will use that data to assess your eligibility for MSP.

    Individuals who apply for LIS through SSA and those who are deemed into LIS should receive written confirmation of their Extra Help status through SSA. Of course, individuals who apply for LIS through SSA and are found ineligible are also entitled to a written notice and have appeal rights. Benefits of Extra Help 1) Assistance with Part D cost-sharing The Extra Help get lasix prescription program provides a subsidy which covers most (but not all) of beneficiary’s cost sharing obligations. Extra Help beneficiaries do not have to worry about hitting the “donut hole” – the LIS subsidy continues to cover them through the donut hole and into catastrophic coverage.

    Full Extra Help. LIS beneficiaries with incomes up to 135% FPL are generally eligible for "full" Extra Help -- meaning they pay no Part D deductible, no charge for get lasix prescription monthly premiums up to the benchmark amount, and fixed, relatively low co-pays (between $1.30 and $8.95 for 2020 depending on the person's income level and the tier category of the drug. Medicaid beneficiaries in nursing homes, waiver programs, or managed long term care have $0 co-pays). Full Extra Help beneficiaries who hit the catastrophic coverage limit have $0 co-pays.

    See current co-pay levels here get lasix prescription. Partial Extra Help. Beneficiaries between 135%-150% FPL receive "partial" Extra Help, which limits the Part D deductible to $89 (2020 figure - click here for updated chart). Sets sliding get lasix prescription scale fees for monthly premiums.

    And limits co-pays to 15%, until the beneficiary reaches the catastrophic coverage limit, at which point co-pays are limited to a $8.95 maximum (2020 or see current amount here) or 5% of the drug cost, whichever is greater. 2) Facilitated enrollment into a Part D plan Extra Help recipients who aren’t already enrolled in a Part D plan and don’t want to choose one on their own will be automatically enrolled into a benchmark plan by CMS. This facilitated enrollment ensures that Extra Help recipients have Part get lasix prescription D coverage. However, the downside to facilitated enrollment is that the plan may not be the best “fit” for the beneficiary, if it doesn’t cover all his/her drugs, assesses a higher tier level for covered drugs than other comparable plans, and/or requires the beneficiary to go through administrative hoops like prior authorization, quantity limits and/or step therapy.

    Fortunately, Extra Help recipients can always enroll in a new plan … see #3 below. 3) Continuous special enrollment period Extra Help recipients have a continuous get lasix prescription special enrollment period, meaning that they can switch plans at any time. They are not “locked into” the annual open enrollment period (October 15-December 7). NOTE.

    This changed in get lasix prescription 2019. Starting in 2019, those with Extra Help will no longer have a continuous enrollment period. Instead, Extra Help recipients will be eligible to enroll no more than once per quarter for each of the first three quarters of the year. 4) No late enrollment penalty Non LIS beneficiaries generally face a premium penalty (higher monthly premium) if they delayed their enrollment into Part D, meaning that they didn’t enroll when they were initially eligible and didn’t have “creditable coverage.” Extra Help recipients do not get lasix prescription have to worry about this problem – the late enrollment penalty provision does not apply to LIS beneficiaries.

    1) For “deemed” beneficiaries (Medicaid/Medicare Savings Program recipients). Extra Help status lasts at least until the end of the current calendar year, even if the individual loses their Medicaid or Medicare Savings Program coverage during that year. Individuals who receive Medicaid or get lasix prescription a Medicare Savings Program any month between July and December keep their LIS status for the remainder of that calendar year and the following year. Getting Medicaid coverage for even just a short period of time (ie, meeting a spenddown for just one month) can help ensure that the individual obtains Extra Help coverage for at least 6 months, and possibly as long as 18 months.

    TIP. People get lasix prescription with a high spend-down who want to receive Medicaid for just one month in order to get Extra Help for 6-18 months can use past medical bills to meet their spend-down for that one month. There are different rules for using past paid medical bills verses past unpaid medical bills. For information see Spend down training materials.

    Individuals who are losing their deemed status at the end of a calendar year because they are no longer receiving Medicaid or the Medicare Savings Program should be notified in advance by get lasix prescription SSA, and given an opportunity to file an Extra Help application through SSA. 2) For “non-deemed” beneficiaries (those who filed their LIS applications through SSA) Non-deemed beneficiaries retain their LIS status until/unless SSA does a redetermination and finds the individual ineligible for Extra Help. There are no reporting requirements per se in the Extra Help program, but beneficiaries must respond to SSA’s redetermination request. What to do if the Part D plan doesn't know that someone has Extra get lasix prescription Help Sometimes there are lengthy delays between the date that someone is approved for Medicaid or a Medicare Savings Program and when that information is formally conveyed to the Part D plan by CMS.

    As a practical matter, this often results in beneficiaries being charged co-pays, premiums and/or deductibles that they can't afford and shouldn't have to pay. To protect LIS beneficiaries, CMS has a "Best Available Evidence" policy which requires plans to accept alternative forms of proof of someone's LIS status and adjust the person's cost-sharing obligation accordingly. LIS beneficiaries who are being charged improperly should get lasix prescription be sure to contact their plan and provide proof of their LIS status. If the plan still won't recognize their LIS status, the person or their advocate should file a complaint with the CMS regional office.

    The federal regulations governing the Low Income Subsidy program can be found at 42 CFR Subpart P (sections 423.771 through 423.800). Also, CMS provides detailed guidance on the LIS provisions in chapter 13 of its Medicare Prescription Drug get lasix prescription Benefit Manual. This article was authored by the Empire Justice Center.Medicare Savings Programs (MSPs) pay for the monthly Medicare Part B premium for low-income Medicare beneficiaries and qualify enrollees for the "Extra Help" subsidy for Part D prescription drugs. There are three separate MSP programs, the Qualified Medicare Beneficiary (QMB) Program, the Specified Low Income Medicare Beneficiary (SLMB) Program and the Qualified Individual (QI) Program, each of which is discussed below.

    Those in get lasix prescription QMB receive additional subsidies for Medicare costs. See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH State law. N.Y. Soc.

    Serv. L. § 367-a(3)(a), (b), and (d). 2020 Medicare 101 Basics for New York State - 1.5 hour webinar by Eric Hausman, sponsored by NYS Office of the Aging TOPICS COVERED IN THIS ARTICLE 1.

    No Asset Limit 1A. Summary Chart of MSP Programs 2. Income Limits &. Rules and Household Size 3.

    The Three MSP Programs - What are they and how are they Different?. 4. FOUR Special Benefits of MSP Programs. Back Door to Extra Help with Part D MSPs Automatically Waive Late Enrollment Penalties for Part B - and allow enrollment in Part B year-round outside of the short Annual Enrollment Period No Medicaid Lien on Estate to Recover Payment of Expenses Paid by MSP Food Stamps/SNAP not reduced by Decreased Medical Expenses when Enroll in MSP - at least temporarily 5.

    Enrolling in an MSP - Automatic Enrollment &. Applications for People who Have Medicare What is Application Process?. 6. Enrolling in an MSP for People age 65+ who Do Not Qualify for Free Medicare Part A - the "Part A Buy-In Program" 7.

    What Happens After MSP Approved - How Part B Premium is Paid 8 Special Rules for QMBs - How Medicare Cost-Sharing Works 1. NO ASSET LIMIT!. Since April 1, 2008, none of the three MSP programs have resource limits in New York -- which means many Medicare beneficiaries who might not qualify for Medicaid because of excess resources can qualify for an MSP. 1.A.

    SUMMARY CHART OF MSP BENEFITS QMB SLIMB QI-1 Eligibility ASSET LIMIT NO LIMIT IN NEW YORK STATE INCOME LIMIT (2020) Single Couple Single Couple Single Couple $1,064 $1,437 $1,276 $1,724 $1,436 $1,940 Federal Poverty Level 100% FPL 100 – 120% FPL 120 – 135% FPL Benefits Pays Monthly Part B premium?. YES, and also Part A premium if did not have enough work quarters and meets citizenship requirement. See “Part A Buy-In” YES YES Pays Part A &. B deductibles &.

    Co-insurance YES - with limitations NO NO Retroactive to Filing of Application?. Yes - Benefits begin the month after the month of the MSP application. 18 NYCRR §360-7.8(b)(5) Yes – Retroactive to 3rd month before month of application, if eligible in prior months Yes – may be retroactive to 3rd month before month of applica-tion, but only within the current calendar year. (No retro for January application).

    See GIS 07 MA 027. Can Enroll in MSP and Medicaid at Same Time?. YES YES NO!. Must choose between QI-1 and Medicaid.

    Cannot have both, not even Medicaid with a spend-down. 2. INCOME LIMITS and RULES Each of the three MSP programs has different income eligibility requirements and provides different benefits. The income limits are tied to the Federal Poverty Level (FPL).

    2019 FPL levels were released by NYS DOH in GIS 20 MA/02 - 2020 Federal Poverty Levels -- Attachment II and have been posted by Medicaid.gov and the National Council on Aging and are in the chart below. NOTE. There is usually a lag in time of several weeks, or even months, from January 1st of each year until the new FPLs are release, and then before the new MSP income limits are officially implemented. During this lag period, local Medicaid offices should continue to use the previous year's FPLs AND count the person's Social Security benefit amount from the previous year - do NOT factor in the Social Security COLA (cost of living adjustment).

    Once the updated guidelines are released, districts will use the new FPLs and go ahead and factor in any COLA. See 2019 Fact Sheet on MSP in NYS by Medicare Rights Center ENGLISH SPANISH Income is determined by the same methodology as is used for determining in eligibility for SSI The rules for counting income for SSI-related (Aged 65+, Blind, or Disabled) Medicaid recipients, borrowed from the SSI program, apply to the MSP program, except for the new rules about counting household size for married couples. N.Y. Soc.

    Serv. L. 367-a(3)(c)(2), NYS DOH 2000-ADM-7, 89-ADM-7 p.7. Gross income is counted, although there are certain types of income that are disregarded.

    The most common income disregards, also known as deductions, include. (a) The first $20 of your &. Your spouse's monthly income, earned or unearned ($20 per couple max). (b) SSI EARNED INCOME DISREGARDS.

    * The first $65 of monthly wages of you and your spouse, * One-half of the remaining monthly wages (after the $65 is deducted). * Other work incentives including PASS plans, impairment related work expenses (IRWEs), blind work expenses, etc. For information on these deductions, see The Medicaid Buy-In for Working People with Disabilities (MBI-WPD) and other guides in this article -- though written for the MBI-WPD, the work incentives apply to all Medicaid programs, including MSP, for people age 65+, disabled or blind. (c) monthly cost of any health insurance premiums but NOT the Part B premium, since Medicaid will now pay this premium (may deduct Medigap supplemental policies, vision, dental, or long term care insurance premiums, and the Part D premium but only to the extent the premium exceeds the Extra Help benchmark amount) (d) Food stamps not counted.

    You can get a more comprehensive listing of the SSI-related income disregards on the Medicaid income disregards chart. As for all benefit programs based on financial need, it is usually advantageous to be considered a larger household, because the income limit is higher. The above chart shows that Households of TWO have a higher income limit than households of ONE. The MSP programs use the same rules as Medicaid does for the Disabled, Aged and Blind (DAB) which are borrowed from the SSI program for Medicaid recipients in the “SSI-related category.” Under these rules, a household can be only ONE or TWO.

    18 NYCRR 360-4.2. See DAB Household Size Chart. Married persons can sometimes be ONE or TWO depending on arcane rules, which can force a Medicare beneficiary to be limited to the income limit for ONE person even though his spouse who is under 65 and not disabled has no income, and is supported by the client applying for an MSP. EXAMPLE.

    Bob's Social Security is $1300/month. He is age 67 and has Medicare. His wife, Nancy, is age 62 and is not disabled and does not work. Under the old rule, Bob was not eligible for an MSP because his income was above the Income limit for One, even though it was well under the Couple limit.

    In 2010, NYS DOH modified its rules so that all married individuals will be considered a household size of TWO. DOH GIS 10 MA 10 Medicare Savings Program Household Size, June 4, 2010. This rule for household size is an exception to the rule applying SSI budgeting rules to the MSP program. Under these rules, Bob is now eligible for an MSP.

    When is One Better than Two?. Of course, there may be couples where the non-applying spouse's income is too high, and disqualifies the applying spouse from an MSP. In such cases, "spousal refusal" may be used SSL 366.3(a). (Link is to NYC HRA form, can be adapted for other counties).

    3. The Three Medicare Savings Programs - what are they and how are they different?. 1. Qualified Medicare Beneficiary (QMB).

    The QMB program provides the most comprehensive benefits. Available to those with incomes at or below 100% of the Federal Poverty Level (FPL), the QMB program covers virtually all Medicare cost-sharing obligations. Part B premiums, Part A premiums, if there are any, and any and all deductibles and co-insurance. QMB coverage is not retroactive.

    The program’s benefits will begin the month after the month in which your client is found eligible. ** See special rules about cost-sharing for QMBs below - updated with new CMS directive issued January 2012 ** See NYC HRA QMB Recertification form ** Even if you do not have Part A automatically, because you did not have enough wages, you may be able to enroll in the Part A Buy-In Program, in which people eligible for QMB who do not otherwise have Medicare Part A may enroll, with Medicaid paying the Part A premium (Materials by the Medicare Rights Center). 2. Specifiedl Low-Income Medicare Beneficiary (SLMB).

    For those with incomes between 100% and 120% FPL, the SLMB program will cover Part B premiums only. SLMB is retroactive, however, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. 3. Qualified Individual (QI-1).

    For those with incomes between 120% and 135% FPL, and not receiving Medicaid, the QI-1 program will cover Medicare Part B premiums only. QI-1 is also retroactive, providing coverage for three months prior to the month of application, as long as your client was eligible during those months. However, QI-1 retroactive coverage can only be provided within the current calendar year. (GIS 07 MA 027) So if you apply in January, you get no retroactive coverage.

    Q-I-1 recipients would be eligible for Medicaid with a spend-down, but if they want the Part B premium paid, they must choose between enrolling in QI-1 or Medicaid. They cannot be in both. It is their choice. DOH MRG p.

    19. In contrast, one may receive Medicaid and either QMB or SLIMB. 4. Four Special Benefits of MSPs (in addition to NO ASSET TEST).

    Benefit 1. Back Door to Medicare Part D "Extra Help" or Low Income Subsidy -- All MSP recipients are automatically enrolled in Extra Help, the subsidy that makes Part D affordable. They have no Part D deductible or doughnut hole, the premium is subsidized, and they pay very low copayments. Once they are enrolled in Extra Help by virtue of enrollment in an MSP, they retain Extra Help for the entire calendar year, even if they lose MSP eligibility during that year.

    The "Full" Extra Help subsidy has the same income limit as QI-1 - 135% FPL. However, many people may be eligible for QI-1 but not Extra Help because QI-1 and the other MSPs have no asset limit. People applying to the Social Security Administration for Extra Help might be rejected for this reason. Recent (2009-10) changes to federal law called "MIPPA" requires the Social Security Administration (SSA) to share eligibility data with NYSDOH on all persons who apply for Extra Help/ the Low Income Subsidy.

    Data sent to NYSDOH from SSA will enable NYSDOH to open MSP cases on many clients. The effective date of the MSP application must be the same date as the Extra Help application. Signatures will not be required from clients. In cases where the SSA data is incomplete, NYSDOH will forward what is collected to the local district for completion of an MSP application.

    The State implementing procedures are in DOH 2010 ADM-03. Also see CMS "Dear State Medicaid Director" letter dated Feb. 18, 2010 Benefit 2. MSPs Automatically Waive Late Enrollment Penalties for Part B Generally one must enroll in Part B within the strict enrollment periods after turning age 65 or after 24 months of Social Security Disability.

    An exception is if you or your spouse are still working and insured under an employer sponsored group health plan, or if you have End Stage Renal Disease, and other factors, see this from Medicare Rights Center. If you fail to enroll within those short periods, you might have to pay higher Part B premiums for life as a Late Enrollment Penalty (LEP). Also, you may only enroll in Part B during the Annual Enrollment Period from January 1 - March 31st each year, with Part B not effective until the following July. Enrollment in an MSP automatically eliminates such penalties...

    For life.. Even if one later ceases to be eligible for the MSP. AND enrolling in an MSP will automatically result in becoming enrolled in Part B if you didn't already have it and only had Part A. See Medicare Rights Center flyer.

    Benefit 3. No Medicaid Lien on Estate to Recover MSP Benefits Paid Generally speaking, states may place liens on the Estates of deceased Medicaid recipients to recover the cost of Medicaid services that were provided after the recipient reached the age of 55. Since 2002, states have not been allowed to recover the cost of Medicare premiums paid under MSPs. In 2010, Congress expanded protection for MSP benefits.

    Beginning on January 1, 2010, states may not place liens on the Estates of Medicaid recipients who died after January 1, 2010 to recover costs for co-insurance paid under the QMB MSP program for services rendered after January 1, 2010. The federal government made this change in order to eliminate barriers to enrollment in MSPs. See NYS DOH GIS 10-MA-008 - Medicare Savings Program Changes in Estate Recovery The GIS clarifies that a client who receives both QMB and full Medicaid is exempt from estate recovery for these Medicare cost-sharing expenses. Benefit 4.

    SNAP (Food Stamp) benefits not reduced despite increased income from MSP - at least temporarily Many people receive both SNAP (Food Stamp) benefits and MSP. Income for purposes of SNAP/Food Stamps is reduced by a deduction for medical expenses, which includes payment of the Part B premium. Since approval for an MSP means that the client no longer pays for the Part B premium, his/her SNAP/Food Stamps income goes up, so their SNAP/Food Stamps go down. Here are some protections.

    Do these individuals have to report to their SNAP worker that their out of pocket medical costs have decreased?. And will the household see a reduction in their SNAP benefits, since the decrease in medical expenses will increase their countable income?. The good news is that MSP households do NOT have to report the decrease in their medical expenses to the SNAP/Food Stamp office until their next SNAP/Food Stamp recertification. Even if they do report the change, or the local district finds out because the same worker is handling both the MSP and SNAP case, there should be no reduction in the household’s benefit until the next recertification.

    New York’s SNAP policy per administrative directive 02 ADM-07 is to “freeze” the deduction for medical expenses between certification periods. Increases in medical expenses can be budgeted at the household’s request, but NYS never decreases a household’s medical expense deduction until the next recertification. Most elderly and disabled households have 24-month SNAP certification periods. Eventually, though, the decrease in medical expenses will need to be reported when the household recertifies for SNAP, and the household should expect to see a decrease in their monthly SNAP benefit.

    It is really important to stress that the loss in SNAP benefits is NOT dollar for dollar. A $100 decrease in out of pocket medical expenses would translate roughly into a $30 drop in SNAP benefits. See more info on SNAP/Food Stamp benefits by the Empire Justice Center, and on the State OTDA website. Some clients will be automatically enrolled in an MSP by the New York State Department of Health (NYSDOH) shortly after attaining eligibility for Medicare.

    Others need to apply. The 2010 "MIPPA" law introduced some improvements to increase MSP enrollment. See 3rd bullet below. Also, some people who had Medicaid through the Affordable Care Act before they became eligible for Medicare have special procedures to have their Part B premium paid before they enroll in an MSP.

    See below. WHO IS AUTOMATICALLY ENROLLED IN AN MSP. Clients receiving even $1.00 of Supplemental Security Income should be automatically enrolled into a Medicare Savings Program (most often QMB) under New York State’s Medicare Savings Program Buy-in Agreement with the federal government once they become eligible for Medicare. They should receive Medicare Parts A and B.

    Clients who are already eligible for Medicare when they apply for Medicaid should be automatically assessed for MSP eligibility when they apply for Medicaid. (NYS DOH 2000-ADM-7 and GIS 05 MA 033). Clients who apply to the Social Security Administration for Extra Help, but are rejected, should be contacted &. Enrolled into an MSP by the Medicaid program directly under new MIPPA procedures that require data sharing.

    Strategy TIP. Since the Extra Help filing date will be assigned to the MSP application, it may help the client to apply online for Extra Help with the SSA, even knowing that this application will be rejected because of excess assets or other reason. SSA processes these requests quickly, and it will be routed to the State for MSP processing. Since MSP applications take a while, at least the filing date will be retroactive.

    Note. The above strategy does not work as well for QMB, because the effective date of QMB is the month after the month of application. As a result, the retroactive effective date of Extra Help will be the month after the failed Extra Help application for those with QMB rather than SLMB/QI-1. Applying for MSP Directly with Local Medicaid Program.

    Those who do not have Medicaid already must apply for an MSP through their local social services district. (See more in Section D. Below re those who already have Medicaid through the Affordable Care Act before they became eligible for Medicare. If you are applying for MSP only (not also Medicaid), you can use the simplified MSP application form (theDOH-4328(Rev.

    8/2017-- English) (2017 Spanish version not yet available). Either application form can be mailed in -- there is no interview requirement anymore for MSP or Medicaid. See 10 ADM-04. Applicants will need to submit proof of income, a copy of their Medicare card (front &.

    Back), and proof of residency/address. See the application form for other instructions. One who is only eligible for QI-1 because of higher income may ONLY apply for an MSP, not for Medicaid too. One may not receive Medicaid and QI-1 at the same time.

    If someone only eligible for QI-1 wants Medicaid, s/he may enroll in and deposit excess income into a pooled Supplemental Needs Trust, to bring her countable income down to the Medicaid level, which also qualifies him or her for SLIMB or QMB instead of QI-1. Advocates in NYC can sign up for a half-day "Deputization Training" conducted by the Medicare Rights Center, at which you'll be trained and authorized to complete an MSP application and to submit it via the Medicare Rights Center, which submits it to HRA without the client having to apply in person. Enrolling in an MSP if you already have Medicaid, but just become eligible for Medicare Those who, prior to becoming enrolled in Medicare, had Medicaid through Affordable Care Act are eligible to have their Part B premiums paid by Medicaid (or the cost reimbursed) during the time it takes for them to transition to a Medicare Savings Program. In 2018, DOH clarified that reimbursement of the Part B premium will be made regardless of whether the individual is still in a Medicaid managed care (MMC) plan.

    GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare ( PDF) provides, "Due to efforts to transition individuals who gain Medicare eligibility and who require LTSS, individuals may not be disenrolled from MMC upon receipt of Medicare. To facilitate the transition and not disadvantage the recipient, the Medicaid program is approving reimbursement of Part B premiums for enrollees in MMC." The procedure for getting the Part B premium paid is different for those whose Medicaid was administered by the NYS of Health Exchange (Marketplace), as opposed to their local social services district. The procedure is also different for those who obtain Medicare because they turn 65, as opposed to obtaining Medicare based on disability. Either way, Medicaid recipients who transition onto Medicare should be automatically evaluated for MSP eligibility at their next Medicaid recertification.

    NYS DOH 2000-ADM-7 Individuals can also affirmatively ask to be enrolled in MSP in between recertification periods. IF CLIENT HAD MEDICAID ON THE MARKETPLACE (NYS of Health Exchange) before obtaining Medicare. IF they obtain Medicare because they turn age 65, they will receive a letter from their local district asking them to "renew" Medicaid through their local district. See 2014 LCM-02.

    Now, their Medicaid income limit will be lower than the MAGI limits ($842/ mo reduced from $1387/month) and they now will have an asset test. For this reason, some individuals may lose full Medicaid eligibility when they begin receiving Medicare. People over age 65 who obtain Medicare do NOT keep "Marketplace Medicaid" for 12 months (continuous eligibility) See GIS 15 MA/022 - Continuous Coverage for MAGI Individuals. Since MSP has NO ASSET limit.

    Some individuals may be enrolled in the MSP even if they lose Medicaid, or if they now have a Medicaid spend-down. If a Medicare/Medicaid recipient reports income that exceeds the Medicaid level, districts must evaluate the person’s eligibility for MSP. 08 OHIP/ADM-4 ​If you became eligible for Medicare based on disability and you are UNDER AGE 65, you are entitled to keep MAGI Medicaid for 12 months from the month it was last authorized, even if you now have income normally above the MAGI limit, and even though you now have Medicare. This is called Continuous Eligibility.

    EXAMPLE. Sam, age 60, was last authorized for Medicaid on the Marketplace in June 2016. He became enrolled in Medicare based on disability in August 2016, and started receiving Social Security in the same month (he won a hearing approving Social Security disability benefits retroactively, after first being denied disability). Even though his Social Security is too high, he can keep Medicaid for 12 months beginning June 2016.

    Sam has to pay for his Part B premium - it is deducted from his Social Security check. He may call the Marketplace and request a refund. This will continue until the end of his 12 months of continues MAGI Medicaid eligibility. He will be reimbursed regardless of whether he is in a Medicaid managed care plan.

    See GIS 18 MA/001 Medicaid Managed Care Transition for Enrollees Gaining Medicare (PDF) When that ends, he will renew Medicaid and apply for MSP with his local district. Individuals who are eligible for Medicaid with a spenddown can opt whether or not to receive MSP. (Medicaid Reference Guide (MRG) p. 19).

    Obtaining MSP may increase their spenddown. MIPPA - Outreach by Social Security Administration -- Under MIPPA, the SSA sends a form letter to people who may be eligible for a Medicare Savings Program or Extra Help (Low Income Subsidy - LIS) that they may apply. The letters are. · Beneficiary has Extra Help (LIS), but not MSP · Beneficiary has no Extra Help (LIS) or MSP 6.

    Enrolling in MSP for People Age 65+ who do Not have Free Medicare Part A - the "Part A Buy-In Program" Seniors WITHOUT MEDICARE PART A or B -- They may be able to enroll in the Part A Buy-In program, in which people eligible for QMB who are age 65+ who do not otherwise have Medicare Part A may enroll in Part A, with Medicaid paying the Part A premium. See Step-by-Step Guide by the Medicare Rights Center). This guide explains the various steps in "conditionally enrolling" in Part A at the SSA office, which must be done before applying for QMB at the Medicaid office, which will then pay the Part A premium. See also GIS 04 MA/013.

    In June, 2018, the SSA revised the POMS manual procedures for the Part A Buy-In to to address inconsistencies and confusion in SSA field offices and help smooth the path for QMB enrollment. The procedures are in the POMS Section HI 00801.140 "Premium-Free Part A Enrollments for Qualified Medicare BenefiIaries." It includes important clarifications, such as. SSA Field Offices should explain the QMB program and conditional enrollment process if an individual lacks premium-free Part A and appears to meet QMB requirements. SSA field offices can add notes to the “Remarks” section of the application and provide a screen shot to the individual so the individual can provide proof of conditional Part A enrollment when applying for QMB through the state Medicaid program.

    Beneficiaries are allowed to complete the conditional application even if they owe Medicare premiums. In Part A Buy-in states like NYS, SSA should process conditional applications on a rolling basis (without regard to enrollment periods), even if the application coincides with the General Enrollment Period. (The General Enrollment Period is from Jan 1 to March 31st every year, in which anyone eligible may enroll in Medicare Part A or Part B to be effective on July 1st). 7.

    What happens after the MSP approval - How is Part B premium paid For all three MSP programs, the Medicaid program is now responsible for paying the Part B premiums, even though the MSP enrollee is not necessarily a recipient of Medicaid. The local Medicaid office (DSS/HRA) transmits the MSP approval to the NYS Department of Health – that information gets shared w/ SSA and CMS SSA stops deducting the Part B premiums out of the beneficiary’s Social Security check. SSA also refunds any amounts owed to the recipient. (Note.

    This process can take awhile!. !. !. ) CMS “deems” the MSP recipient eligible for Part D Extra Help/ Low Income Subsidy (LIS).

    ​Can the MSP be retroactive like Medicaid, back to 3 months before the application?. ​The answer is different for the 3 MSP programs. QMB -No Retroactive Eligibility – Benefits begin the month after the month of the MSP application. 18 NYCRR § 360-7.8(b)(5) SLIMB - YES - Retroactive Eligibility up to 3 months before the application, if was eligible This means applicant may be reimbursed for the 3 months of Part B benefits prior to the month of application.

    QI-1 - YES up to 3 months but only in the same calendar year.

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    } } Latest Updates. The Coronavirus Outbreak Updated 2020-08-31T10:20:43.431Z The U.S. Has more than 6 million cases as President Trump retweets fringe theories on the virus. India now has the third-highest death rate from the virus.

    €˜Not completely benign’. Why children are not as safe from infection as commonly believed. See more updates More live coverage. Markets And yet.

    I kept getting the emails about this race, in a year flooded with bad news that had come very close to home. In March, four members of my family were sick with Covid-19. In June, my brother was in the hospital for weeks after a driver struck him while he was on a bike ride.I’ve spent five months trying to find glimpses of joy in small, simple things, like the sight of a bird on the tree I planted last year, or the feel of my dog’s very soft ear. But the idea of a big, outlandish thing that might bump me out of my gloom had a certain draw.Ron Horn, the event’s organizer.

    €œNot enough of us do things outside the box anymore, particularly as we get older,” he said.Credit...Michelle Gustafson for The New York TimesWhen a friend who lives in upstate New York said she was 90 percent willing to commit to making the trip to participate in this race, I thought maybe I should go, if for nothing else than to see her.“What else do you have to do?. € she asked.Sunny Rest was founded as a nudist resort in 1945 and, except for the lack of clothing, looks like a lot of other campgrounds, with mobile homes, cabins, tents and RVs. There’s a pool, spa, volleyball and tennis courts, hot tub, and hiking and biking trails. Most people go about their daily activities wearing nothing but shoes or sandals, maybe a hat.

    It’s private property, so laws against public nudity are not an issue. Pretzel City has been putting on races there for 13 years.The events are meant to be fun, but the race organizers recognize that there is something of a taboo around nudity, so it anonymizes race results when posting them online, listing participants only by first name, last initial and home state. Knowing the privacy concerns, Pretzel City’s race director announced before the race that a photographer and I would be covering the event, and that we would include only those runners who consented to being photographed and interviewed.Several runners were eager to talk to me, including Bruce Freeburger, 69, who drove from Detroit to run this race. He operates the website naked5k.com.

    Its slogan. €œI did wear shoes!. €â€œIt’s not ‘Girls Gone Wild,’” he said of naked runs. He believes that those who run nude tend to be “unselfish, and more sportsmanlike.”As soon as I pulled into Sunny Rest (after showing my ID and having the license plate of my car recorded by security), I saw a man in a wide-brimmed sun hat and no pants walking toward the pool.Runners in various states of undress on the course.

    The more experienced runners knew to carry towels to wipe away sweat.Credit...Michelle Gustafson for The New York TimesBy the time I parked near the race start, I felt prim. Some runners were clothed, but most were in some state of undress. A woman breastfed her child while she checked in. A man waited to run in just sneakers and a Viking helmet — he hung his mask from one of the horns when he wasn’t near other people.

    I saw my friend, already stripped down. She fit right in. I gave her an elbow bump and took off my shorts. It didn’t feel weird, at all.To prepare for the experience, I’d tried running completely naked on the treadmill in my basement, and determined that going braless was impractical for me.

    So I took the Donald Duck approach and wore a hat and sports bra but no bottoms. When I checked in, I was handed a race bib and a T-shirt, but then a staffer — naked except for mask and gloves — wrote my race number with a marker on my leg. Where was I going to pin a bib anyway?. .css-1wxds7f{margin-bottom:10px;font-family:nyt-franklin,helvetica,arial,sans-serif;font-weight:700;font-size:0.875rem;line-height:1.25rem;color:#333 !.

    Important;}.css-2al2sh{font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:0.9375rem;line-height:1.25rem;color:#333;margin-bottom:0.78125rem;margin-top:20px;margin-bottom:5px;font-weight:700;}@media (min-width:740px){.css-2al2sh{font-size:1.0625rem;line-height:1.5rem;margin-bottom:0.9375rem;}}@media (min-width:740px){.css-2al2sh{margin-bottom:10px;}}.css-1yyoic1{font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:0.9375rem;line-height:1.25rem;color:#333;margin-bottom:0.78125rem;}@media (min-width:740px){.css-1yyoic1{font-size:1.0625rem;line-height:1.5rem;margin-bottom:0.9375rem;}}.css-zkk2wn{margin-bottom:20px;font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:0.875rem;line-height:1.5625rem;color:#333;}.css-1dvfdxo{margin:10px auto 0px;font-family:nyt-franklin,helvetica,arial,sans-serif;font-weight:700;font-size:1.125rem;line-height:1.5625rem;color:#121212;}@media (min-width:740px){.css-1dvfdxo{font-size:1.25rem;line-height:1.875rem;}}.css-16ed7iq{width:100%;display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;-webkit-box-pack:center;-webkit-justify-content:center;-ms-flex-pack:center;justify-content:center;padding:10px 0;background-color:white;}.css-pmm6ed{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;}.css-pmm6ed > :not(:first-child){margin-left:5px;}.css-5gimkt{font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:0.8125rem;font-weight:700;-webkit-letter-spacing:0.03em;-moz-letter-spacing:0.03em;-ms-letter-spacing:0.03em;letter-spacing:0.03em;text-transform:uppercase;color:#333;}.css-5gimkt:after{content:'Collapse';}.css-rdoyk0{-webkit-transition:all 0.5s ease;transition:all 0.5s ease;-webkit-transform:rotate(180deg);-ms-transform:rotate(180deg);transform:rotate(180deg);}.css-eb027h{max-height:5000px;-webkit-transition:max-height 0.5s ease;transition:max-height 0.5s ease;}.css-6mllg9{-webkit-transition:all 0.5s ease;transition:all 0.5s ease;position:relative;opacity:0;}.css-6mllg9:before{content:'';background-image:linear-gradient(180deg,transparent,#ffffff);background-image:-webkit-linear-gradient(270deg,rgba(255,255,255,0),#ffffff);height:80px;width:100%;position:absolute;bottom:0px;pointer-events:none;}#masthead-bar-one{display:none;}#masthead-bar-one{display:none;}.css-19mumt8{background-color:white;margin:30px 0;padding:0 20px;max-width:510px;}@media (min-width:740px){.css-19mumt8{margin:40px auto;}}.css-19mumt8:focus{outline:1px solid #e2e2e2;}.css-19mumt8 a{color:#326891;-webkit-text-decoration:none;text-decoration:none;border-bottom:2px solid #ccd9e3;}.css-19mumt8 a:visited{color:#333;-webkit-text-decoration:none;text-decoration:none;border-bottom:2px solid #ddd;}.css-19mumt8 a:hover{border-bottom:none;}.css-19mumt8[data-truncated] .css-rdoyk0{-webkit-transform:rotate(0deg);-ms-transform:rotate(0deg);transform:rotate(0deg);}.css-19mumt8[data-truncated] .css-eb027h{max-height:300px;overflow:hidden;-webkit-transition:none;transition:none;}.css-19mumt8[data-truncated] .css-5gimkt:after{content:'See more';}.css-19mumt8[data-truncated] .css-6mllg9{opacity:1;}.css-a8d9oz{border-top:5px solid #121212;border-bottom:2px solid #121212;margin:0 auto;padding:5px 0 0;overflow:hidden;}The Coronavirus Outbreak ›Frequently Asked QuestionsUpdated August 27, 2020What should I consider when choosing a mask?. There are a few basic things to consider. Does it have at least two layers?. Good.

    If you hold it up to the light, can you see through it?. Bad. Can you blow a candle out through your mask?. Bad.

    Do you feel mostly OK wearing it for hours at a time?. Good. The most important thing, after finding a mask that fits well without gapping, is to find a mask that you will wear. Spend some time picking out your mask, and find something that works with your personal style.

    You should be wearing it whenever you’re out in public for the foreseeable future. Read more. What’s the Best Material for a Mask?. What are the symptoms of coronavirus?.

    In the beginning, the coronavirus seemed like it was primarily a respiratory illness — many patients had fever and chills, were weak and tired, and coughed a lot, though some people don’t show many symptoms at all. Those who seemed sickest had pneumonia or acute respiratory distress syndrome and received supplemental oxygen. By now, doctors have identified many more symptoms and syndromes. In April, the C.D.C.

    Added to the list of early signs sore throat, fever, chills and muscle aches. Gastrointestinal upset, such as diarrhea and nausea, has also been observed. Another telltale sign of infection may be a sudden, profound diminution of one’s sense of smell and taste. Teenagers and young adults in some cases have developed painful red and purple lesions on their fingers and toes — nicknamed “Covid toe” — but few other serious symptoms.Why does standing six feet away from others help?.

    The coronavirus spreads primarily through droplets from your mouth and nose, especially when you cough or sneeze. The C.D.C., one of the organizations using that measure, bases its recommendation of six feet on the idea that most large droplets that people expel when they cough or sneeze will fall to the ground within six feet. But six feet has never been a magic number that guarantees complete protection. Sneezes, for instance, can launch droplets a lot farther than six feet, according to a recent study.

    It's a rule of thumb. You should be safest standing six feet apart outside, especially when it's windy. But keep a mask on at all times, even when you think you’re far enough apart.I have antibodies. Am I now immune?.

    As of right now, that seems likely, for at least several months. There have been frightening accounts of people suffering what seems to be a second bout of Covid-19. But experts say these patients may have a drawn-out course of infection, with the virus taking a slow toll weeks to months after initial exposure. People infected with the coronavirus typically produce immune molecules called antibodies, which are protective proteins made in response to an infection.

    These antibodies may last in the body only two to three months, which may seem worrisome, but that’s perfectly normal after an acute infection subsides, said Dr. Michael Mina, an immunologist at Harvard University. It may be possible to get the coronavirus again, but it’s highly unlikely that it would be possible in a short window of time from initial infection or make people sicker the second time.I’m a small-business owner. Can I get relief?.

    The stimulus bills enacted in March offer help for the millions of American small businesses. Those eligible for aid are businesses and nonprofit organizations with fewer than 500 workers, including sole proprietorships, independent contractors and freelancers. Some larger companies in some industries are also eligible. The help being offered, which is being managed by the Small Business Administration, includes the Paycheck Protection Program and the Economic Injury Disaster Loan program.

    But lots of folks have not yet seen payouts. Even those who have received help are confused. The rules are draconian, and some are stuck sitting on money they don’t know how to use. Many small-business owners are getting less than they expected or not hearing anything at all.What are my rights if I am worried about going back to work?.

    Employers have to provide a safe workplace with policies that protect everyone equally. And if one of your co-workers tests positive for the coronavirus, the C.D.C. Has said that employers should tell their employees -- without giving you the sick employee’s name -- that they may have been exposed to the virus.I lined up near the start, a body in a sea of 115 bodies, ages 9 through 78, all standing six feet apart. The energy felt zippier here than at a normal race — almost giddy.

    While most of the runners were from Pennsylvania, only a handful were also members of the Sunny Rest Resort. That meant almost everyone had traveled to this place — from places as far away as Ohio, Delaware and West Virginia — for the opportunity to do something unusual.Runners were required to wear masks to pick up their packets, and asked to wear them when near other people. Pretzel City also moved the start and finish area away from the more crowded part of the resort toward the camping sites, so we had more space to spread out. Over a bullhorn, Horn asked us to put our arms straight out by our sides and said, “If you are touching someone you are not sleeping with, you are standing too close.”After the initial newness of being aware of my butt bouncing around, everything felt pretty much the same as in a clothed race.

    We started at 10:15 a.m., and I’m usually done running by 8 a.m. In the summer, so it was hot. I was grateful for my hat, and the sunblock and anti-chafing balm I’d applied all over my body. By the first mile, I was coated in sweat.“I don’t have a shirt to wipe off my face!.

    € another runner shouted. The more experienced naked runners had thought to carry little towels.Part of the course was an out and back, so I saw the leaders coming back as I went out. With a full view of their entire, naked forms in motion, I felt appreciation, in the same way I’d look at a nice painting.I didn’t worry about anyone else appreciating my body — from the naked ladies cheering from their trailer’s outdoor bar to the gentleman doing naked squats on his deck. The race didn’t feel sexualized at all, and I didn’t worry about which parts of my body were not perfectly flat and smooth, about what parts of my body shook with every step.

    I was just another body in motion.Michael Lyons of Douglassville, Pa. €œI’m not a nudist type,” he said. €œI’m just a goofball who likes to do fun things.”Credit...Michelle Gustafson for The New York TimesI was feeling what many runners had told me before the start of the race — that this was freeing. Richard Whalen, 43, of Folcroft, Pa., said that for him it’s also a celebration of who he is now.

    He’s a recovering alcoholic who took up running after he stopped being too hung over to run in the morning. €œThere’s a sense of freedom here to show off your beautiful body.”That’s also why Jim and Susan Fiordeliso of Yardley, Pa., came too. Last year, Mr. Fiordeliso, 53, had heart surgery, after which they vowed to take better care of their bodies.

    That included moving to a plant-based diet, as well as lots of walking and running. They’ve lost 210 pounds between them. It was their first time at a nude race, and they treated it as a celebration of their new lives. €œI loved it and I would do it again,” he said.And then there’s just the fun of it.

    €œI’m not a nudist type. I’m not an exhibitionist type,” said Michael Lyons, 35, of Douglassville, Pa., who has done both naked road races and bike rides. €œI’m just a goofball who likes to do fun things.”I finished in 30 minutes, 26 seconds, good enough for fifth place in my category. My award.

    A medal that I wore at around my neck with nothing but my sandals, bandanna and a fresh coating of sun block.Jen A. Miller, the author of “Running. A Love Story,” writes The Times’s weekly running newsletter.Buying a short-term health plan in Kansas As the name indicates, short-term health insurance is designed to fill short gaps in coverage. It’s not as comprehensive as regular major medical health insurance, and it’s not suitable to serve as a person’s only coverage for a significant length of time.

    But there are a variety of reasons a person might need short-term health insurance. Who can buy short-term health insurance in Kansas?. Short-term health insurance plans are available in Kansas to anyone who can meet the underwriting guidelines that the insurers impose. In general, this means being under 65 years old (some insurers put the age limit at 64 years) and in fairly good health — defined as being able to answer “no” to several questions that ask about major health conditions, obesity, mental health/substance abuse issues, etc.It’s important to understand, however, that short-term health insurance plans generally come with blanket exclusions for pre-existing conditions.

    So they would not provide suitable coverage for a person who is currently in need of medical care and seeking a policy that will cover those needs. Short-term health insurance in Kansas should only be thought of as a means of covering unexpected future medical needs that fall within the coverage guidelines the plan offers.If you’re in need of health insurance coverage in Kansas, you’ll want to check first to see if you’re eligible for a special enrollment period that would allow you to enroll in an ACA-compliant major medical plan. Special enrollment periods are triggered by a variety of qualifying events, including losing another health insurance policy. Special enrollment periods are available through the health insurance exchange in Kansas, and most are also available outside the exchange.So for example, if you’re turning 26 and aging off a parent’s policy, or losing a plan offered by your former employer, you have an opportunity to enroll in an ACA-compliant plan at that point, even if it’s not during the annual open enrollment period in the fall.

    If you’re eligible for premium subsidies or cost-sharing reductions, you can get them through the exchange when you enroll.And you can enroll in an ACA-compliant policy even if you know you’re only going to need it for a short time. ACA-compliant individual market plans are purchased on a month-to-month basis. You can cancel at any time. So if you’re losing a plan from your former employer at the end of July and you know that you’ll have coverage under a new employer starting in October, you can still sign up for an ACA-compliant plan to cover you for August and September (with a premium subsidy if you’re eligible), and then cancel it before your new plan takes effect in October.When should I consider short-term health insurance?.

    With that said, there are times when a short-term health insurance plan might be the only option, or the most realistic option. Kansas short-term health insurance regulationsShort-term health insurance plans in Kansas are defined in Kansas Statute 40-2, 193.Kansas has a minimum loss ratio requirement of 60 percent. But under the terms of Kansas Statute 40-2, 193, this only applies to Kansas short-term plans if any monthly administrative fees are excluded from the medical loss ratio calculation.Short-term plan duration in KansasThe state law limits short-term plans to terms of “six months or 12 months, based upon policy design.” (The Kansas Insurance Department has clarified that the distinction between six-month and 12-month plans is up to the insurer. From a regulatory standpoint, the maximum term is 12 months).Kansas statute also limits short-term plans to no more than one renewal period, regardless of whether the insurer uses medical underwriting for the renewal.Under federal rules that took effect in 2018, short-term health insurance plans can have initial terms up to 364 days, and total duration, including renewals, of up to 36 months.

    The regulations are clear, however, in noting that states may continue to impose tighter regulations than the new federal rules. Since Kansas statute only allows for a maximum term of 12 months and no more than one renewal, the maximum total duration of a short-term plan in Kansas is 24 months.And insurers can impose shorter duration limits. They can, for example, limit their initial policy terms, and can offer plans that are not renewable at all (the state limits Kansas short-term plans to one renewal, but does not require an insurer to make short-term plans renewable).Which insurance companies offer short-term plans in Kansas?. As of early 2020, the Kansas Insurance Department reported that five insurers were offering short-term plans in Kansas.

    BCBSKC, Independence American Insurance Company, Freedom Life, Golden Rule, and United States Fire Insurance Company.As of mid-2020, however, there were also Kansas short-term health insurance plans for sale from National General. So short-term insurance providers in Kansas as of 2020 include:Blue Cross Blue Shield of Kansas CityIndependence American Insurance CompanyNational GeneralUnited Healthcare (Golden Rule)Freedom LifeUnited States Fire Insurance CompanyAn agent or broker can help you compare the available options for short-term health insurance in Kansas and determine which will best fit your needs. Some things to keep in mind are the allowable plan durations (some insurers cap their plans at shorter durations than the maximum the state allows), whether the insurer offers guaranteed renewability, and the specific benefits the plan covers. Pay attention to things such as whether the plan covers outpatient drugs (most short-term health insurance plans do not, but some do), and whether it imposes specific dollar limits on services such as inpatient care, surgery, etc.

    (in addition to the plan’s overall benefit maximum).Louise Norris is an individual health insurance broker who has been writing about health insurance and health reform since 2006. She has written dozens of opinions and educational pieces about the Affordable Care Act for healthinsurance.org. Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts..

    I heard the “Rocky” theme twice along the course.Except the lasix 500mg tablet spectators were get lasix prescription naked. And I was, too.That’s because the race was the Bouncing Buns Clothing Optional 5K, held at the Sunny Rest Resort, a nudist resort in Palmerton, Pa.“Not enough of us do things outside the box anymore, particularly as we get older,” said Ron Horn, race director and co-owner of Pretzel City Sports, which put on the race.I’ve run a handful of Pretzel City’s clothed (or as naked runners call them, “textile”) races, but the nude events never appealed to me, not when there were a zillion other races to run.But this year, it caught my attention in part because almost all other races have been canceled because of the coronavirus. In this pandemic season of covering our faces in public, why not uncover everything else?. What a fun way to experience some freedom in a time of pressing fear, get lasix prescription grief, restrictions and disappointments.But I hesitated.

    I’ve been to “toptional” pools in Las Vegas, so nudity wasn’t that much of an obstacle. But running naked?. It seemed get lasix prescription so — uncomfortable. #styln-briefing-block { font-family.

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    The Coronavirus Outbreak Updated 2020-08-31T10:20:43.431Z The U.S. Has more than 6 million cases as President Trump retweets fringe theories on the virus. India now has the third-highest death rate from the virus. €˜Not completely benign’.

    Why children are not as safe from infection as commonly believed. See more updates More live coverage. Markets And yet. I kept getting the emails about this race, in a year flooded with bad news that had come very close to home.

    In March, four members of my family were sick with Covid-19. In June, my brother was in the hospital for weeks after a driver struck him while he was on a bike ride.I’ve spent five months trying to find glimpses of joy in small, simple things, like the sight of a bird on the tree I planted last year, or the feel of my dog’s very soft ear. But the idea of a big, outlandish thing that might bump me out of my gloom had a certain draw.Ron Horn, the event’s organizer. €œNot enough of us do things outside the box anymore, particularly as we get older,” he said.Credit...Michelle Gustafson for The New York TimesWhen a friend who lives in upstate New York said she was 90 percent willing to commit to making the trip to participate in this race, I thought maybe I should go, if for nothing else than to see her.“What else do you have to do?.

    € she asked.Sunny Rest was founded as a nudist resort in 1945 and, except for the lack of clothing, looks like a lot of other campgrounds, with mobile homes, cabins, tents and RVs. There’s a pool, spa, volleyball and tennis courts, hot tub, and hiking and biking trails. Most people go about their daily activities wearing nothing but shoes or sandals, maybe a hat. It’s private property, so laws against public nudity are not an issue.

    Pretzel City has been putting on races there for 13 years.The events are meant to be fun, but the race organizers recognize that there is something of a taboo around nudity, so it anonymizes race results when posting them online, listing participants only by first name, last initial and home state. Knowing the privacy concerns, Pretzel City’s race director announced before the race that a photographer and I would be covering the event, and that we would include only those runners who consented to being photographed and interviewed.Several runners were eager to talk to me, including Bruce Freeburger, 69, who drove from Detroit to run this race. He operates the website naked5k.com. Its slogan.

    €œI did wear shoes!. €â€œIt’s not ‘Girls Gone Wild,’” he said of naked runs. He believes that those who run nude tend to be “unselfish, and more sportsmanlike.”As soon as I pulled into Sunny Rest (after showing my ID and having the license plate of my car recorded by security), I saw a man in a wide-brimmed sun hat and no pants walking toward the pool.Runners in various states of undress on the course. The more experienced runners knew to carry towels to wipe away sweat.Credit...Michelle Gustafson for The New York TimesBy the time I parked near the race start, I felt prim.

    Some runners were clothed, but most were in some state of undress. A woman breastfed her child while she checked in. A man waited to run in just sneakers and a Viking helmet — he hung his mask from one of the horns when he wasn’t near other people. I saw my friend, already stripped down.

    She fit right in. I gave her an elbow bump and took off my shorts. It didn’t feel weird, at all.To prepare for the experience, I’d tried running completely naked on the treadmill in my basement, and determined that going braless was impractical for me. So I took the Donald Duck approach and wore a hat and sports bra but no bottoms.

    When I checked in, I was handed a race bib and a T-shirt, but then a staffer — naked except for mask and gloves — wrote my race number with a marker on my leg. Where was I going to pin a bib anyway?. .css-1wxds7f{margin-bottom:10px;font-family:nyt-franklin,helvetica,arial,sans-serif;font-weight:700;font-size:0.875rem;line-height:1.25rem;color:#333 !. Important;}.css-2al2sh{font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:0.9375rem;line-height:1.25rem;color:#333;margin-bottom:0.78125rem;margin-top:20px;margin-bottom:5px;font-weight:700;}@media (min-width:740px){.css-2al2sh{font-size:1.0625rem;line-height:1.5rem;margin-bottom:0.9375rem;}}@media (min-width:740px){.css-2al2sh{margin-bottom:10px;}}.css-1yyoic1{font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:0.9375rem;line-height:1.25rem;color:#333;margin-bottom:0.78125rem;}@media (min-width:740px){.css-1yyoic1{font-size:1.0625rem;line-height:1.5rem;margin-bottom:0.9375rem;}}.css-zkk2wn{margin-bottom:20px;font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:0.875rem;line-height:1.5625rem;color:#333;}.css-1dvfdxo{margin:10px auto 0px;font-family:nyt-franklin,helvetica,arial,sans-serif;font-weight:700;font-size:1.125rem;line-height:1.5625rem;color:#121212;}@media (min-width:740px){.css-1dvfdxo{font-size:1.25rem;line-height:1.875rem;}}.css-16ed7iq{width:100%;display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;-webkit-box-pack:center;-webkit-justify-content:center;-ms-flex-pack:center;justify-content:center;padding:10px 0;background-color:white;}.css-pmm6ed{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;}.css-pmm6ed > :not(:first-child){margin-left:5px;}.css-5gimkt{font-family:nyt-franklin,helvetica,arial,sans-serif;font-size:0.8125rem;font-weight:700;-webkit-letter-spacing:0.03em;-moz-letter-spacing:0.03em;-ms-letter-spacing:0.03em;letter-spacing:0.03em;text-transform:uppercase;color:#333;}.css-5gimkt:after{content:'Collapse';}.css-rdoyk0{-webkit-transition:all 0.5s ease;transition:all 0.5s ease;-webkit-transform:rotate(180deg);-ms-transform:rotate(180deg);transform:rotate(180deg);}.css-eb027h{max-height:5000px;-webkit-transition:max-height 0.5s ease;transition:max-height 0.5s ease;}.css-6mllg9{-webkit-transition:all 0.5s ease;transition:all 0.5s ease;position:relative;opacity:0;}.css-6mllg9:before{content:'';background-image:linear-gradient(180deg,transparent,#ffffff);background-image:-webkit-linear-gradient(270deg,rgba(255,255,255,0),#ffffff);height:80px;width:100%;position:absolute;bottom:0px;pointer-events:none;}#masthead-bar-one{display:none;}#masthead-bar-one{display:none;}.css-19mumt8{background-color:white;margin:30px 0;padding:0 20px;max-width:510px;}@media (min-width:740px){.css-19mumt8{margin:40px auto;}}.css-19mumt8:focus{outline:1px solid #e2e2e2;}.css-19mumt8 a{color:#326891;-webkit-text-decoration:none;text-decoration:none;border-bottom:2px solid #ccd9e3;}.css-19mumt8 a:visited{color:#333;-webkit-text-decoration:none;text-decoration:none;border-bottom:2px solid #ddd;}.css-19mumt8 a:hover{border-bottom:none;}.css-19mumt8[data-truncated] .css-rdoyk0{-webkit-transform:rotate(0deg);-ms-transform:rotate(0deg);transform:rotate(0deg);}.css-19mumt8[data-truncated] .css-eb027h{max-height:300px;overflow:hidden;-webkit-transition:none;transition:none;}.css-19mumt8[data-truncated] .css-5gimkt:after{content:'See more';}.css-19mumt8[data-truncated] .css-6mllg9{opacity:1;}.css-a8d9oz{border-top:5px solid #121212;border-bottom:2px solid #121212;margin:0 auto;padding:5px 0 0;overflow:hidden;}The Coronavirus Outbreak ›Frequently Asked QuestionsUpdated August 27, 2020What should I consider when choosing a mask?.

    There are a few basic things to consider. Does it have at least two layers?. Good. If you hold it up to the light, can you see through it?.

    Bad. Can you blow a candle out through your mask?. Bad. Do you feel mostly OK wearing it for hours at a time?.

    Good. The most important thing, after finding a mask that fits well without gapping, is to find a mask that you will wear. Spend some time picking out your mask, and find something that works with your personal style. You should be wearing it whenever you’re out in public for the foreseeable future.

    Read more. What’s the Best Material for a Mask?. What are the symptoms of coronavirus?. In the beginning, the coronavirus seemed like it was primarily a respiratory illness — many patients had fever and chills, were weak and tired, and coughed a lot, though some people don’t show many symptoms at all.

    Those who seemed sickest had pneumonia or acute respiratory distress syndrome and received supplemental oxygen. By now, doctors have identified many more symptoms and syndromes. In April, the C.D.C. Added to the list of early signs sore throat, fever, chills and muscle aches.

    Gastrointestinal upset, such as diarrhea and nausea, has also been observed. Another telltale sign of infection may be a sudden, profound diminution of one’s sense of smell and taste. Teenagers and young adults in some cases have developed painful red and purple lesions on their fingers and toes — nicknamed “Covid toe” — but few other serious symptoms.Why does standing six feet away from others help?. The coronavirus spreads primarily through droplets from your mouth and nose, especially when you cough or sneeze.

    The C.D.C., one of the organizations using that measure, bases its recommendation of six feet on the idea that most large droplets that people expel when they cough or sneeze will fall to the ground within six feet. But six feet has never been a magic number that guarantees complete protection. Sneezes, for instance, can launch droplets a lot farther than six feet, according to a recent study. It's a rule of thumb.

    You should be safest standing six feet apart outside, especially when it's windy. But keep a mask on at all times, even when you think you’re far enough apart.I have antibodies. Am I now immune?. As of right now, that seems likely, for at least several months.

    There have been frightening accounts of people suffering what seems to be a second bout of Covid-19. But experts say these patients may have a drawn-out course of infection, with the virus taking a slow toll weeks to months after initial exposure. People infected with the coronavirus typically produce immune molecules called antibodies, which are protective proteins made in response to an infection. These antibodies may last in the body only two to three months, which may seem worrisome, but that’s perfectly normal after an acute infection subsides, said Dr.

    Michael Mina, an immunologist at Harvard University. It may be possible to get the coronavirus again, but it’s highly unlikely that it would be possible in a short window of time from initial infection or make people sicker the second time.I’m a small-business owner. Can I get relief?. The stimulus bills enacted in March offer help for the millions of American small businesses.

    Those eligible for aid are businesses and nonprofit organizations with fewer than 500 workers, including sole proprietorships, independent contractors and freelancers. Some larger companies in some industries are also eligible. The help being offered, which is being managed by the Small Business Administration, includes the Paycheck Protection Program and the Economic Injury Disaster Loan program. But lots of folks have not yet seen payouts.

    Even those who have received help are confused. The rules are draconian, and some are stuck sitting on money they don’t know how to use. Many small-business owners are getting less than they expected or not hearing anything at all.What are my rights if I am worried about going back to work?. Employers have to provide a safe workplace with policies that protect everyone equally.

    And if one of your co-workers tests positive for the coronavirus, the C.D.C. Has said that employers should tell their employees -- without giving you the sick employee’s name -- that they may have been exposed to the virus.I lined up near the start, a body in a sea of 115 bodies, ages 9 through 78, all standing six feet apart. The energy felt zippier here than at a normal race — almost giddy. While most of the runners were from Pennsylvania, only a handful were also members of the Sunny Rest Resort.

    That meant almost everyone had traveled to this place — from places as far away as Ohio, Delaware and West Virginia — for the opportunity to do something unusual.Runners were required to wear masks to pick up their packets, and asked to wear them when near other people. Pretzel City also moved the start and finish area away from the more crowded part of the resort toward the camping sites, so we had more space to spread out. Over a bullhorn, Horn asked us to put our arms straight out by our sides and said, “If you are touching someone you are not sleeping with, you are standing too close.”After the initial newness of being aware of my butt bouncing around, everything felt pretty much the same as in a clothed race. We started at 10:15 a.m., and I’m usually done running by 8 a.m.

    In the summer, so it was hot. I was grateful for my hat, and the sunblock and anti-chafing balm I’d applied all over my body. By the first mile, I was coated in sweat.“I don’t have a shirt to wipe off my face!. € another runner shouted.

    The more experienced naked runners had thought to carry little towels.Part of the course was an out and back, so I saw the leaders coming back as I went out. With a full view of their entire, naked forms in motion, I felt appreciation, in the same way I’d look at a nice painting.I didn’t worry about anyone else appreciating my body — from the naked ladies cheering from their trailer’s outdoor bar to the gentleman doing naked squats on his deck. The race didn’t feel sexualized at all, and I didn’t worry about which parts of my body were not perfectly flat and smooth, about what parts of my body shook with every step. I was just another body in motion.Michael Lyons of Douglassville, Pa.

    €œI’m not a nudist type,” he said. €œI’m just a goofball who likes to do fun things.”Credit...Michelle Gustafson for The New York TimesI was feeling what many runners had told me before the start of the race — that this was freeing. Richard Whalen, 43, of Folcroft, Pa., said that for him it’s also a celebration of who he is now. He’s a recovering alcoholic who took up running after he stopped being too hung over to run in the morning.

    €œThere’s a sense of freedom here to show off your beautiful body.”That’s also why Jim and Susan Fiordeliso of Yardley, Pa., came too. Last year, Mr. Fiordeliso, 53, had heart surgery, after which they vowed to take better care of their bodies. That included moving to a plant-based diet, as well as lots of walking and running.

    They’ve lost 210 pounds between them. It was their first time at a nude race, and they treated it as a celebration of their new lives. €œI loved it and I would do it again,” he said.And then there’s just the fun of it. €œI’m not a nudist type.

    I’m not an exhibitionist type,” said Michael Lyons, 35, of Douglassville, Pa., who has done both naked road races and bike rides. €œI’m just a goofball who likes to do fun things.”I finished in 30 minutes, 26 seconds, good enough for fifth place in my category. My award. A medal that I wore at around my neck with nothing but my sandals, bandanna and a fresh coating of sun block.Jen A.

    Miller, the author of “Running. A Love Story,” writes The Times’s weekly running newsletter.Buying a short-term health plan in Kansas As the name indicates, short-term health insurance is designed to fill short gaps in coverage. It’s not as comprehensive as regular major medical health insurance, and it’s not suitable to serve as a person’s only coverage for a significant length of time. But there are a variety of reasons a person might need short-term health insurance.

    Who can buy short-term health insurance in Kansas?. Short-term health insurance plans are available in Kansas to anyone who can meet the underwriting guidelines that the insurers impose. In general, this means being under 65 years old (some insurers put the age limit at 64 years) and in fairly good health — defined as being able to answer “no” to several questions that ask about major health conditions, obesity, mental health/substance abuse issues, etc.It’s important to understand, however, that short-term health insurance plans generally come with blanket exclusions for pre-existing conditions. So they would not provide suitable coverage for a person who is currently in need of medical care and seeking a policy that will cover those needs.

    Short-term health insurance in Kansas should only be thought of as a means of covering unexpected future medical needs that fall within the coverage guidelines the plan offers.If you’re in need of health insurance coverage in Kansas, you’ll want to check first to see if you’re eligible for a special enrollment period that would allow you to enroll in an ACA-compliant major medical plan. Special enrollment periods are triggered by a variety of qualifying events, including losing another health insurance policy. Special enrollment periods are available through the health insurance exchange in Kansas, and most are also available outside the exchange.So for example, if you’re turning 26 and aging off a parent’s policy, or losing a plan offered by your former employer, you have an opportunity to enroll in an ACA-compliant plan at that point, even if it’s not during the annual open enrollment period in the fall. If you’re eligible for premium subsidies or cost-sharing reductions, you can get them through the exchange when you enroll.And you can enroll in an ACA-compliant policy even if you know you’re only going to need it for a short time.

    ACA-compliant individual market plans are purchased on a month-to-month basis. You can cancel at any time. So if you’re losing a plan from your former employer at the end of July and you know that you’ll have coverage under a new employer starting in October, you can still sign up for an ACA-compliant plan to cover you for August and September (with a premium subsidy if you’re eligible), and then cancel it before your new plan takes effect in October.When should I consider short-term health insurance?. With that said, there are times when a short-term health insurance plan might be the only option, or the most realistic option.

    Kansas short-term health insurance regulationsShort-term health insurance plans in Kansas are defined in Kansas Statute 40-2, 193.Kansas has a minimum loss ratio requirement of 60 percent. But under the terms of Kansas Statute 40-2, 193, this only applies to Kansas short-term plans if any monthly administrative fees are excluded from the medical loss ratio calculation.Short-term plan duration in KansasThe state law limits short-term plans to terms of “six months or 12 months, based upon policy design.” (The Kansas Insurance Department has clarified that the distinction between six-month and 12-month plans is up to the insurer. From a regulatory standpoint, the maximum term is 12 months).Kansas statute also limits short-term plans to no more than one renewal period, regardless of whether the insurer uses medical underwriting for the renewal.Under federal rules that took effect in 2018, short-term health insurance plans can have initial terms up to 364 days, and total duration, including renewals, of up to 36 months.

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    €‹15 full-time equivalent specialist counsellors will be deployed across rural NSW to help prevent suicide, with lasix online in canada the first two counsellors starting in the Eurobodalla and Snowy Mountains regions.NSW Mental Health Minister Bronnie Taylor said the relatively high rates of suicide in rural areas are lasix iv push devastating families and communities, and the $6.75 million investment will add another layer of help.“Many factors can contribute to suicide, from domestic violence, to relationship issues or unemployment, to stress and hardship,” Mrs Taylor said. €œThese specialist mental health counsellors are there on the ground to support people thinking of suicide or impacted by suicide, and I encourage communities across the state to lean on them for support.”Director Mental Health Drug and Alcohol for Southern NSW Local Health District Damien Eggleton said he wants more people to ask for help when they need it. €œOur rural communities have proven beyond a doubt they’re resilient and fearless when faced with adversity, whether that be geographic isolation, searing drought lasix iv push or the impact of the current pandemic – but they don’t need to go it alone,” Mr Eggleton said.

    €œThe support provided by these counsellors will complement the peer work and drought support provided by our Farm Gate Counsellors and Drought Counsellors.”Rural counsellor Samara Byrne said she wants young people to know there are people you can turn to when feeling overwhelmed with life or feeling like a burden on others. €œWe are here for you and here to listen if you are feeling distressed, anxious or a burden to loved lasix iv push ones. The service is easily accessible through the Mental Health Line.

    Just ask for the Rural Counsellor.”“Having moved from Sydney in 2016 to our beautiful farm in SNSW, I am so pleased to be able to do what I lasix iv push am most passionate about, supporting people’s wellbeing in Rural Australia and building on the natural local community resilience”.Minister Taylor urges people in the bush to get help by contacting these rural counsellors. €œSupport is available, all you need to do is pick up the phone and make an appointment by calling the NSW Mental Health Line on 1800 011 511.”The 15 rural counselling positions are part of the Towards Zero Suicides. A $87 million investment over three years in new suicide lasix iv push prevention initiatives.

    A NSW Premier’s Priority, this is a whole-of-government commitment to transforming the way we identify and support anyone impacted by suicide.If you, or someone you know, is thinking about suicide or experiencing a personal crisis or distress, please seek help immediately in a life-threatening situation by calling 000 or seek support though one of these services:Lifeline 13 11 14Suicide Call Back Service 1300 659 467NSW Mental Health Line 1800 011 511Minister for Mental Health Bronnie Taylor and Minister for Police and Emergency Services David Elliott today announced the expansion of the Police Ambulance and Clinical Early Response (PACER) pilot program.“This ground breaking collaboration embeds mental health experts with first responders to support them to appropriately recognise, assess, and respond to mental health emergencies live at the scene,” Mrs Taylor said. €œThe pilot program has had incredible results with lasix iv push significant reductions in emergency department presentations, police and ambulance time on scene. €œThis approach has enormous potential to change lives, with the community getting more appropriate care at the time when they need it most.” Mr Elliott welcomed the support for the police officers who are deeply committed to serving and protecting the people of NSW “During the pilot program, police time-on-scene was reduced by an average of 45 minutes, not only supporting first responders to appropriately recognise and respond to psychiatric incidents in the community, but also freeing up officers to serve thecommunity in other areas,” Mr Elliott said.

    €œThe presence and availability of a PACER clinician in a police station increases the knowledge and understanding of mental health issues amongst officers This initiative is crucial, now more than ever, following the devastating ‘Black Summer’ bushfires and the COVID-19 pandemic, lasix iv push which have affected us all.” NSW Police Force Deputy Commissioner, Malcolm Lanyon APM, said the PACER model has been a success at the trial site in St George Police Area Command. €œDuring the trial we saw a significant reduction in time taken for police to respond to these matters. It translated to a better outcome for both our officers and the individuals in need of assistance,” Mr Lanyon said lasix iv push.

    The PACER program will expand to Campbelltown, Nepean, Northern Beaches, Sutherland Shire, Blacktown, Eastern Beaches, Kuring-gai, Metro Combined consisting of Kings Cross/Surry Hills/City of Sydney, South Sydney and Bankstown Police Area Commands with recruitment underway for the specialist mental health clinicians from July 2020. This investment is part of the $73 million suite of mental lasix iv push health measures recently announced by the NSW Government. This includes 216 new mental health staff, additional funding for the NSW Mental Health Line, extra support for Telehealth, funding for extra therapeutic programs to aid recovery in mental health units and a $6 million investment in Lifeline to expand their invaluable service..

    €‹15 full-time equivalent specialist counsellors will be deployed across rural NSW to help prevent suicide, with the first two counsellors starting in the Eurobodalla and Snowy Mountains regions.NSW Mental Health Minister Bronnie Taylor said the relatively high rates of suicide in rural areas are devastating families and communities, and the $6.75 million investment will add another layer of get lasix prescription help.“Many factors can contribute to suicide, from domestic violence, to relationship issues or unemployment, to stress and hardship,” Mrs Taylor said. €œThese specialist mental health counsellors are there on the ground to support people thinking of suicide or impacted by suicide, and I encourage communities across the state to lean on them for support.”Director Mental Health Drug and Alcohol for Southern NSW Local Health District Damien Eggleton said he wants more people to ask for help when they need it. €œOur rural communities have proven beyond a doubt they’re resilient and fearless when faced with adversity, whether that be geographic isolation, searing drought or the impact of the current pandemic – but they don’t need to go it alone,” Mr Eggleton said get lasix prescription. €œThe support provided by these counsellors will complement the peer work and drought support provided by our Farm Gate Counsellors and Drought Counsellors.”Rural counsellor Samara Byrne said she wants young people to know there are people you can turn to when feeling overwhelmed with life or feeling like a burden on others. €œWe are here for you and here get lasix prescription to listen if you are feeling distressed, anxious or a burden to loved ones.

    The service is easily accessible through the Mental Health Line. Just ask for the Rural Counsellor.”“Having moved from Sydney in 2016 to our beautiful farm in SNSW, I am so pleased to be able to do what I am most passionate about, supporting people’s wellbeing in Rural Australia and building on the natural local community resilience”.Minister Taylor urges people in the bush to get help by get lasix prescription contacting these rural counsellors. €œSupport is available, all you need to do is pick up the phone and make an appointment by calling the NSW Mental Health Line on 1800 011 511.”The 15 rural counselling positions are part of the Towards Zero Suicides. A $87 million investment over three years get lasix prescription in new suicide prevention initiatives. A NSW Premier’s Priority, this is a whole-of-government commitment to transforming the way we identify and support anyone impacted by suicide.If you, or someone you know, is thinking about suicide or experiencing a personal crisis or distress, please seek help immediately in a life-threatening situation by calling 000 or seek support though one of these services:Lifeline 13 11 14Suicide Call Back Service 1300 659 467NSW Mental Health Line 1800 011 511Minister for Mental Health Bronnie Taylor and Minister for Police and Emergency Services David Elliott today announced the expansion of the Police Ambulance and Clinical Early Response (PACER) pilot program.“This ground breaking collaboration embeds mental health experts with first responders to support them to appropriately recognise, assess, and respond to mental health emergencies live at the scene,” Mrs Taylor said.

    €œThe pilot program has had incredible results with significant get lasix prescription reductions in emergency department presentations, police and ambulance time on scene. €œThis approach has enormous potential to change lives, with the community getting more appropriate care at the time when they need it most.” Mr Elliott welcomed the support for the police officers who are deeply committed to serving and protecting the people of NSW “During the pilot program, police time-on-scene was reduced by an average of 45 minutes, not only supporting first responders to appropriately recognise and respond to psychiatric incidents in the community, but also freeing up officers to serve thecommunity in other areas,” Mr Elliott said. €œThe presence and availability of a PACER clinician in a police station increases the get lasix prescription knowledge and understanding of mental health issues amongst officers This initiative is crucial, now more than ever, following the devastating ‘Black Summer’ bushfires and the COVID-19 pandemic, which have affected us all.” NSW Police Force Deputy Commissioner, Malcolm Lanyon APM, said the PACER model has been a success at the trial site in St George Police Area Command. €œDuring the trial we saw a significant reduction in time taken for police to respond to these matters. It translated to a better outcome for both our officers and the individuals in need of get lasix prescription assistance,” Mr Lanyon said.

    The PACER program will expand to Campbelltown, Nepean, Northern Beaches, Sutherland Shire, Blacktown, Eastern Beaches, Kuring-gai, Metro Combined consisting of Kings Cross/Surry Hills/City of Sydney, South Sydney and Bankstown Police Area Commands with recruitment underway for the specialist mental health clinicians from July 2020. This investment is part of the $73 million suite of mental get lasix prescription health measures recently announced by the NSW Government. This includes 216 new mental health staff, additional funding for the NSW Mental Health Line, extra support for Telehealth, funding for extra therapeutic programs to aid recovery in mental health units and a $6 million investment in Lifeline to expand their invaluable service..

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    IntroductionThere has been considerable interest in elucidating the contribution of genetic where to buy cheap lasix factors to the development of common diseases and using this information for better prediction of disease risk. The common disease common variant hypothesis predicts that variants that are common in the population play a role in disease susceptibility.1 Genome-wide association studies where to buy cheap lasix (GWAS) using single nucleotide polymorphism (SNP) arrays were developed as a mechanism by which to investigate these genetic factors and it was hoped this would lead to identification of variants associated with disease risk and subsequent development of predictive tests. Variants identified as associated with particular traits by these studies, for the large part, are SNPs that individually have a minor effect on disease risk and hence, by themselves, cannot be reliably used in disease prediction. Looking at the aggregate impact of these SNPs in the form of a polygenic score (PGS) appeared to be one possible means of using this information to predict disease.2 It is thought this will be of benefit as our genetic make-up where to buy cheap lasix is largely stable from birth and dictates a ‘baseline risk’ on which external influences act and modulate.

    Therefore, PGS are a potential mechanism to act as a risk predictor by capturing information on this genetic liability.The use of PGS as a predictive biomarker is being explored in a number of different disease areas, including cancer,3 4 psychiatric disorders,5–7 metabolic disorders (diabetes,8 obesity9) and coronary artery disease (CAD).10 The proposed applications range from aiding disease diagnosis, informing selection of therapeutic interventions, improvement of risk prediction, informing disease screening and, on a personal level, informing life planning. Therefore, genetic risk information in the form of a PGS is considered to have potential in informing both clinical where to buy cheap lasix and individual-level decision-making.Recent advances in statistical techniques, improved computational power and the availability of large data sets have led to rapid developments in this area over the past few years. This has resulted in a variety of approaches to construction of models for score calculation and the investigation of these scores for prediction of common diseases.11 Several review articles aimed at researchers with a working knowledge of this field have been produced.6 11–17 In this article, we provide an overview of the key aspects of PGS construction to assist clinicians and researchers in other areas of academia to gain an understanding of the processes involved in score construction. We also consider the implications of evolving methodologies for the development of applications of PGS in healthcare.Evolution in polygenic model construction methodologiesTerminology with where to buy cheap lasix respect to PGS has evolved over time, reflecting evolving approaches and methodology.

    Other terms include PGS, polygenic risk score, polygenic load, genotype score, genetic burden, polygenic hazard score, genetic risk score (GRS), metaGRS and allelic risk score. Throughout this article we use the terms polygenic models to refer to the method used to where to buy cheap lasix calculate an output in the form of a PGS. Different polygenic models can be used to calculate a PGS and analysis of these scores can be used to examine associations with particular markers or to predict an individuals risk of diseases.12Usual practice in calculating PGS is as a weighted sum of a number of risk alleles carried by an individual, where the risk alleles and their weights are defined by SNPs and their measured effects (figure 1).11 Polygenic models have been constructed using a few, hundreds or thousands of SNPs, and more recently SNPs across the whole genome. Consequently, determining which SNPs to include and the disease-associated weighting to assign to SNPs are important aspects of model construction (figure 2).18 These aspects are influenced by available genotype data and effect size estimates where to buy cheap lasix as well as the methodology employed in turning this information into model parameters (ie, weighted SNPs).Polygenic score calculation.

    This calculation aggregates the SNPs and their weights selected for a polygenic score. Common diseases where to buy cheap lasix are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score." data-icon-position data-hide-link-title="0">Figure 1 Polygenic score calculation. This calculation aggregates where to buy cheap lasix the SNPs and their weights selected for a polygenic score.

    Common diseases where to buy cheap lasix are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score.Construction of a polygenic score. In the process of developing a polygenic score, numerous models are tested and where to buy cheap lasix then compared. The model that performs best (as determined by one or more measures) is then selected for validation in the external data set.

    GWAS, genome-wide association studies." data-icon-position data-hide-link-title="0">Figure where to buy cheap lasix 2 Construction of a polygenic score. In the process of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one or more measures) where to buy cheap lasix is then selected for validation in the external data set. GWAS, genome-wide association studies.Changes in data availability over time have had an impact on the approach taken in SNP selection and weighting.

    Early studies to identify variants associated with common diseases took the form of candidate gene where to buy cheap lasix studies. The small size of candidate gene studies, the limitation of technologies available for genotyping and stringent significance thresholds meant that these studies investigated fewer variants and those that were identified with disease associations had relatively large effect sizes.19 Taken together, this meant that a relatively small number of variants were available for consideration for inclusion in a polygenic model.20 21 Furthermore, weighting parameters for these few variants were often simplistic, such as counts of the number of risk alleles carried, ignoring their individual effect sizes.16The advent of GWAS enabled assessment of SNPs across the genome, leading to the identification of a larger number of disease-associated variants and therefore more variants suitable for inclusion in a polygenic model. In addition, the increasing number of individuals in the association studies meant that the power of these studies increased, allowing for more precise estimates of effect sizes.19 Furthermore, some theorised that lowering stringent significance thresholds set for SNP–trait associations could also identify SNPs that might play a part in disease risk.11 16 This resulted in more options with respect to polygenic model parameters of SNPs to include and weights to assign to where to buy cheap lasix them. However, the inclusion of more SNPs and direct application of GWAS effect sizes as a weighting parameter does not always equate to better predictive performance.4 16 This is because GWAS do not provide perfect information with respect to the causal SNP, the effect sizes or the number of SNPs that contribute to the trait.

    Therefore, different methods have been developed to address these issues and optimise predictive performance where to buy cheap lasix of the score. Current common practice is to construct models with different iterations of SNPs and weighting, with assessment of the performance of each to identify the optimum configuration of SNPs and their weights (figure 2).Methods used in SNP selection and weighting assignmentSome methods of model development will initially involve selection of SNPs followed by optimisation of weighting, whereas others may involve optimisation of weightings for all SNPs that have been genotyped using their overall GWAS effect sizes, the linkage disequilibrium (LD) and an estimate of the proportion of SNPs that are expected to contribute to the risk.22LD is the phenomenon where some SNPs are coinherited more frequently with other SNPs due to their close proximity on the genome. Segments with where to buy cheap lasix strong LD between SNPs are referred to as haplotype blocks. This phenomenon means that GWAS often identify multiple SNPs in the same haplotype block associated with disease and the true causal SNP is not known.

    As models have where to buy cheap lasix started to assess more SNPs, careful consideration is required to take into account possible correlation between SNPs as a result of this phenomenon. Correlation between SNPs can lead to double counting of SNPs and association redundancy, where multiple SNPs in a region of LD are identified as being where to buy cheap lasix associated with the outcome. This can lead to reduction in the predictive performance of the model. Therefore, processes for filtering SNPs and using one SNP (tag SNP) to act as a marker in an area of high LD, through LD thinning, were developed where to buy cheap lasix.

    Through these processes SNPs correlated with other SNPs in a block are removed, by either pruning or clumping. Pruning ignores p value thresholds and ‘eliminates’ SNPs by a process of iterative comparison between where to buy cheap lasix a pair of SNPs to assess if they are correlated, and subsequently could remove SNPs that are deemed to have evidence of association. Clumping (also known as informed pruning) is guided by GWAS p values and chooses the most significant SNP, therefore keeping the most significant SNP within a block.23 This is all done with the aim of pinpointing relatively small areas of the genome that contribute to risk of the trait. Different significance thresholds may be used to select SNPs from this subgroup for inclusion in models.Poor performance of a model can result from imperfect tagging with the underlying causal SNP.16 This is because the causal SNP that is associated with disease might not be in LD with the tag SNP where to buy cheap lasix that is in the model but is in LD with another SNP which is not in the model.

    This particularly occurs where the LD and variant frequency differs between population groups.24 An alternate approach to filter SNPs is stepwise regression where SNPs are selected based on how much the SNPs improve the model’s performance. This is a statistical approach and does where to buy cheap lasix not consider the impact of LD or effect size.As described above, early studies used simple weighting approaches or directly applied effect sizes from GWAS as weighting parameters for SNPs. However, application of effect sizes as a weighting parameter directly from a GWAS may not be optimal, due to differences in the population that the GWAS was conducted in and the target population. Also as described above, LD and the fact that where to buy cheap lasix not all SNPs may contribute to the trait mean that these effect sizes from GWAS are imperfect estimates.

    Therefore, methods have been developed that adjust effect size estimates from GWAS using statistical techniques which make assumptions about factors such as the number of causal SNPs, level of LD between SNPs or knowledge of their potential function to better reflect their impact on a trait. Numerous statistical methodologies have been developed to improve weighting with a view to enhancing the discriminative power of a PGS.25 26 Examples of some methodological approaches where to buy cheap lasix are LDpred,22 winner’s curse correction,23 empirical Bayes estimation,27 shrinkage regression (Lasso),28 linear mixed models,29 with more being developed or tested. An additional improvement on the methods is to embed non-genetic information (eg, age-specific ORs).6 Determination of which methodology or hybrid of methodologies is most appropriate for various settings and conditions is continuously being explored and is evolving with new statistical approaches developing at a rapid pace.In summary, model development has evolved in an attempt to gain the most from available GWAS data and address some of the issues that arise due to working with data sets which cannot be directly translated into parameters for prediction models. The different approaches taken in SNP selection and weighting, and the impact on the predictive performance of a where to buy cheap lasix model are important to consider when assessing different models.

    This is because different approaches to PGS modelling can achieve the same or a similar level of prediction. From a health system implementation perspective, particular approaches may be preferred following practical considerations and trade-offs between obtaining genotype data, processes for score construction and model performance where to buy cheap lasix. In addition, the degree to which these parameters need to be optimised will also be impacted by the input data and validation data set, where to buy cheap lasix and the quality control procedures that need to be applied to these data sets.12Sources of input data for score constructionKey to the development of a polygenic model is the availability of data sets that can provide input parameters for model construction. Genotype data used in model construction can either be available as raw GWAS data or provided as GWAS summary statistics.

    Data in the raw format are individual-level data from a SNP array and may not have undergone basic quality control such as assessment of missingness, sex discrepancy checks, deviation from Hardy-Weinberg equilibrium, heterozygosity where to buy cheap lasix rate, relatedness or assessment for outliers.30 31 Availability of raw GWAS data allows for different polygenic models to be developed because of the richness of the data, however computational issues arise because of the size of the data sets. Data based on genome sequencing, as opposed to SNP arrays, could also be used in model construction. There have been limited studies of PGS developed from this form of data due to limitations in data availability, which is mainly due to cost restraints.15 32 Individual-level genomic data are also often not available to researchers due to privacy concerns.Due to these issues, the focus where to buy cheap lasix of polygenic model development has therefore been on using well-powered GWAS summary statistics.33 These are available from open access repositories and contain summary information such as the allele positions, ORs, CIs and allele frequency, without containing confidential information on individuals. These data sets have usually been through the basic quality control measures mentioned above.

    There are, however, no standards for publicly available files, meaning some further processing steps may be required, in particular when where to buy cheap lasix various data sets are combined for a meta-analysis. Quality control on summary statistics is only possible if information such as missing genotype rate, minor allele frequency, Hardy-Weinberg equilibrium failures and non-Mendelian transmission rates is provided.12Processing of GWAS data may include additional quality control steps, imputation and filtering of the SNP information, which can be done at the level of genotype or summary statistics data. SNP arrays used in GWAS only have common SNPs represented on them where to buy cheap lasix as they rely on LD between SNPs to cover the entire genome. As described above, one tag SNP on the array can represent many other SNPs.

    Imputation of SNPs is common in GWAS and describes the process of predicting genotypes that have not been directly genotyped but where to buy cheap lasix are statistically inferred (imputed) based on haplotype blocks from a reference sequence.33–35 Often association tests between the imputed SNPs and trait are repeated. As genotype imputation requires individual-level data, researchers have proposed summary statistics imputation as a mechanism to infer the association between untyped SNPs and a trait. The performance of imputation has been evaluated and shown that, with certain limitations, summary statistics imputation is an efficient and cost-effective methodology to identify loci associated with traits when compared with imputation done on genotypes.36An alternative source of input data for the selection of SNPs and their weightings is where to buy cheap lasix through literature or in existing databases, where already known trait-associated SNPs and their effect sizes are used as the input parameters in model development. A number of studies have taken this approach37 38 and it is possible to use multiple sources when developing various polygenic models and establishing the preferred parameters to use.Currently, there does not appear to be one methodology that works across all contexts and traits, each trait will need to be assessed to determine which method is the most suitable for the trait being evaluated.

    For example, four different polygenic model construction strategies were explored for three skin cancer subtypes4 by using data on SNPs and their effect sizes from different sources, such as the latest GWAS meta-analysis results, the National Human where to buy cheap lasix Genome Research Institute (NHGRI) EBI GWAS catalogue, UK Biobank GWAS summary statistics with different thresholds and GWAS summary statistics with LDpred. In this setting for basal cell carcinoma and melanoma, the meta-analysis and catalogue-derived models were found to perform similarly but that the latter was ultimately used as it included more SNPs. For squamous cell carcinoma the meta-analysis-derived model performed better than where to buy cheap lasix the catalogue-derived model. This demonstrates how each disease subtype, model construction strategy and data set can have their own limitations and advantages.Knowledge where to buy cheap lasix of the sources of input data and its subsequent use in model development is important in understanding the limitations of available models.

    Models that are developed using data sets that reflect the population in which prediction is to be carried out will perform better. For example, data collected from a symptomatic or high-risk population may not be suitable as an input data set for the development of a polygenic model that will where to buy cheap lasix be used for disease prediction in the general population. Large GWAS studies were previously focused on high-risk individuals, such as patients with breast cancer with a strong family history or known pathogenic variants in BRCA1 or BRCA2. These studies would not be suitable for the development of PGS for use in the general population but can where to buy cheap lasix inform risk assessment in high-risk individuals.

    The source of the data for SNP selection and weighting also has implications for downstream uses and validation. For example, variant frequency and LD patterns can vary between populations and this can translate to poor performance of the polygenic model if the external validation population is different from that of the input data set.39–41 Furthermore, the power and validity of polygenic analyses are influenced by the input data sources.12 42From a where to buy cheap lasix model to a scorePGS can be calculated using one of the methodologies discussed above. The resulting PGS units of measurement depend on which measurement is used for the weighting.12 For example, the weightings may have been calculated based on logOR for discrete traits or linear regression coefficient (β/beta) in continuous traits from univariate regression tests carried out in the GWAS. The resulting scores are then usually transformed to a standard normal distribution to give scores ranging from −1 to 1, or 0 to 100 where to buy cheap lasix for ease of interpretation.

    This enables further examination of the association between the score and a trait and the predictive ability of different scores generated by different models. Similar to other where to buy cheap lasix biomarker analyses, this involves using the PGS as a predictor of a trait with other covariates (eg, age, smoking, and so on) added, if appropriate, in a target sample. Examination of differences in the distribution of scores in cases and controls, or by examining differences in traits between different strata of PGS can enable assessment of predictive ability (figure 3). Common practice is for individual-level PGS values to be where to buy cheap lasix used to stratify populations into distinct groups of risk based on percentile cut-off or threshold values (eg, the top 1%).Example distribution of polygenic scores across a population.

    Thresholds can be set to stratify risk as low (some), average (most) and high (some)." data-icon-position data-hide-link-title="0">Figure 3 Example distribution of polygenic scores across a population. Thresholds can be set to stratify risk as low (some), average (most) and high (some).Model validationPolygenic model development is reliant on further data sets for model testing and validation and the composition of these where to buy cheap lasix data sets is important in ensuring that the models are appropriate for a particular purpose. The development of where to buy cheap lasix a model to calculate a PGS involves refinement of the previously discussed input parameters, and selection of the ‘best’ of several models based on performance (figure 2). Therefore, a testing/training data set is often required to assess the model’s ability to accurately predict the trait of interest.

    This is often a data where to buy cheap lasix set that is independent of the base/input/discovery data set. It may comprise a subset of the discovery data set that is only used for testing and was not included in the initial development of the model but should ideally be a separate independent data set.Genotype and phenotype data are needed in these data sets. Polygenic models are used to calculate PGS for individuals in the training data set and regression analysis is performed with the where to buy cheap lasix PGS as a predictor of a trait. Other covariates may also be included, if appropriate.

    This testing phase can be considered a process for where to buy cheap lasix identifying models with better overall performance and/or informing refinements needed. Hence, this phase often involves comparison of different models that are developed using the same input data set to identify those models that have optimal performance.The primary purpose is to determine which model best discriminates between cases and controls. The area where to buy cheap lasix under the curve (AUC) or the C-statistic is the most commonly used measure in assessing discriminative ability. It has been criticised as being an insensitive measure that is not able to fully capture all aspects of predictive ability.

    For instance, in some instances, AUC can remain unchanged between models but the individuals within are categorised into a different risk group.43 Alternative metrics that have been used to evaluate model performance include increase in risk difference, integrated discrimination improvement, R2 (estimate of variance explained by the PGS after covariate adjustment), net classification where to buy cheap lasix index and the relative risk (highest percentile vs lowest percentile). A clear understanding on how to interpret the performance within various settings is important in determining which model is most suitable.44As per normal practice when developing any prediction model, polygenic models with the optimal performance in a testing/training data set should be further validated in external data sets. External data sets are critical in where to buy cheap lasix validation of models and assessment of generalisability, hence must also conform to the desired situations in which a model is to be used. The goal is to find a model with suitable parameters of predictive performance in data sets outside of those in which it was developed.

    Ideally, external validation where to buy cheap lasix requires replication in independent data sets. Few existing polygenic models have been validated to this extent, the focus being rather on the development of new models rather than evaluation of existing ones. One example where replication has been carried out where to buy cheap lasix is in the field of CAD, where the GPSCAD45 and metaGRSCAD10 polygenic models (both developed using UK Biobank data) were evaluated in a Finnish population cohort.46 Predictive ability was found to be lower in the Finnish population. This is likely to be due to the differences in genetic structure of this population and the population of the data set used for polygenic model where to buy cheap lasix development.

    Research is ongoing to evaluate polygenic models in other populations and strategies are being developed to ensure the same performance when used more widely, possibly through reweighting and adjustment of the scores.47Moving towards clinical applicationsPGS are thought to be useful information that could improve risk estimation and provide an avenue for disease prevention and deciding treatment strategies. There are indications from a number of fields that genetic information in the form of PGS can act as independent biomarkers and aid stratification.11 16 48 However, the clinical benefits of stratification using a PGS and where to buy cheap lasix the implications for clinical practice are only just beginning to be examined. The use of PGS as part of existing risk prediction tools or as a stand-alone predictor has been suggested. This latter option may be true for diseases where knowledge or predictive ability with other risk factors is limited, such as in prostate cancer.49 In either case, polygenic models need to be individually examined to determine suitability and applicability for the specific clinical question.50 Despite some commercial companies developing PGS,51 52 where to buy cheap lasix currently PGS are not an established part of clinical practice.Integration into clinical practice requires evaluation of a PGS-based test.

    An important concept to consider in this regard is the distinction between an assay and a test. This has been previously discussed with respect to genetic test evaluation.53 54 It is worth examining this concept as applied to PGS, where to buy cheap lasix as their evaluation is reliant on a clear understanding of the test to be offered. As outlined by Zimmern and Kroese,54 the method used to analyse a substance in a sample is considered the assay, whereas a test is the use of an assay within a specific context. With respect to PGS, the process of developing a model to derive a score can be considered the assay, while the use of this model for a particular where to buy cheap lasix disease, population and purpose can be considered the test.

    This distinction is important when assessing if studies are reporting on assay performance as opposed to test performance. It is our where to buy cheap lasix view that, with respect to polygenic models, progress has been made with respect to assay development, but PGS-based tests are yet to be developed and evaluated. This can enable a clearer understanding of their potential clinical utility and issues that may arise for clinical implementation.11 18 55 It is clear that this is still an evolving field, and going forward different models may be required for different traits due to their underlying genetic architecture,26 different clinical contexts and needs.Clinical contexts where risk stratification is already established practice are most likely where implementation of PGS will occur first. Risk prediction models where to buy cheap lasix based on non-genetic factors have been developed for many conditions and are used in clinical care, for example, in cardiovascular disease over 100 such models exist.56 In such contexts, how a PGS and its ability to predict risk compared with, or improves on, these existing models is being investigated.3 44 57–61 The extent to which PGS improves prediction, as well as the cost implications of including this, is likely to impact on implementation.Integration of PGS into clinical practice, for any application, requires robust and validated mechanisms to generate these scores.

    Therefore, given the numerous models available, an assessment of their suitability as part of a test is required. Parameters or guidelines with respect to aspects of model where to buy cheap lasix performance and metrics that could assist in selecting the model to take forward as a PGS-based test are limited and need to be addressed. Currently, there are different mechanisms to generate PGS and have arisen in response to the challenges in aggregating large-scale genomic data for prediction. For example, a review reported 29 PGS models for breast cancer from 22 publications.62 Due to there being a number of different methodologies to generate a score, numerous models may exist for the same where to buy cheap lasix condition and each of the resulting models could perform differently.

    Models may perform differently because the population, measured outcome or context of the development data sets used to generate the models is diverse, for example, a score for risk of breast cancer versus where to buy cheap lasix a breast cancer subtype.44 63 This diversity, alongside the lack of established best practice and standardised reporting in publications, makes comparison and evaluation of polygenic models for use in clinical settings challenging. It is clear that moving the field forward is reliant on transparent reporting and evaluation. Recommendations for best practices on the reporting of polygenic models in literature have been proposed14 64 as well as a database,65 where to buy cheap lasix 66 which could allow for such comparisons. Statements and guidelines for risk prediction model development, such as the Genetic Risk Prediction Studies and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD), already exist, but are not consistently used.

    TRIPOD explicitly covers the development and validation of prediction models for both diagnosis and prognosis, for all medical domains.One clear issue is generalisability and drop in performance of polygenic models once they are applied in a population group different from the one in which they were developed.22 46 67–70 This is an ongoing challenge in genomics as most GWAS, from which most PGS are being developed, have been conducted in European-Caucasian populations.71 Efforts to improve representation are underway72 and there are attempts to reweight/adjust scores when applied to different population groups which are showing some potential but need further research.47 Others have demonstrated that models developed in more diverse population groups have improved performance when applied to external data where to buy cheap lasix sets in different populations.24 73 It is important to consider this issue when moving towards clinical applications as it may pose an ethical challenge if the PGS is not generalisable.A greater understanding of different complex traits and the impact of pleiotropy is only beginning to be investigated.74 There is growing appreciation of the role of pleiotropy as multiple variants have been identified to be associated with multiple traits and exert diverse effects, providing insight into overlapping mechanisms.75 76 This, together with the impact of population stratification, genetic relatedness, ascertainment and other sources of heterogeneity leading to spurious signals and reduced power in genetic association studies, all impacting on the predictive ability of PGS in different populations and for different diseases.While many publications report on model development and evaluation, often there is a lack of clarity on intended purpose,50 77 leading to uncertainties as to the clinical pathways in which implementation is envisaged. A clear description of intended use within clinical pathways is a central component in evaluating the use of an application with any form of PGS and in considering practical implications, such as mechanisms of obtaining the score, incorporation into health records, interpretation of scores, relevant cut-offs for intervention initiation, mechanisms for feedback of results and costs, among other issues. These parameters will where to buy cheap lasix also be impacted by the polygenic model that is taken forward for implementation. Meaning that there are still some important questions that need to be addressed to determine how and where PGS could work within current healthcare systems, particularly at a population level.78It is widely accepted that genotyping using arrays is a lower cost endeavour in comparison to genome sequencing, making the incorporation of PGS into routine healthcare an attractive proposition.

    However, we were unable to find any studies reporting on where to buy cheap lasix the use or associated costs of such technology for population screening. Studies are beginning to examine use case scenarios and model cost-effectiveness, but this has only been in very few, specific investigations.79 80 Costs will also be influenced by the testing technology and by the downstream consequences of testing, which is likely to differ depending on specific applications that are developed and the pathways in which such tests are incorporated. This is particularly the case in screening or primary care settings, where such testing is currently not an established part of care pathways and may require additional resources, not least as a result of the volume of testing where to buy cheap lasix that could be expected. Moving forward, the clinical role of PGS needs to be developed further, including defining the clinical applications as well as supporting evidence, for example, on the effect of clinical outcomes, the feasibility for use in routine practice and cost-effectiveness.ConclusionThere is a large amount of diversity in the PGS field with respect to model development approaches, and this continues to evolve.

    There is rapid progress which is being driven by the availability of larger data sets, primarily from GWAS and concomitant developments in where to buy cheap lasix statistical methodologies. As understanding and knowledge develops, the usefulness and appropriateness of polygenic models for different diseases and contexts are being explored. Nevertheless, this is where to buy cheap lasix still an emerging field, with a variable evidence base demonstrating some potential. The validity of PGS needs to be clearly demonstrated, and their applications evaluated prior to clinical implementation..

    IntroductionThere has been considerable interest in elucidating the contribution of genetic factors to the get lasix prescription development of common diseases and using this information for adverse reaction of lasix better prediction of disease risk. The common get lasix prescription disease common variant hypothesis predicts that variants that are common in the population play a role in disease susceptibility.1 Genome-wide association studies (GWAS) using single nucleotide polymorphism (SNP) arrays were developed as a mechanism by which to investigate these genetic factors and it was hoped this would lead to identification of variants associated with disease risk and subsequent development of predictive tests. Variants identified as associated with particular traits by these studies, for the large part, are SNPs that individually have a minor effect on disease risk and hence, by themselves, cannot be reliably used in disease prediction. Looking at the aggregate impact of these SNPs in the form of a polygenic score (PGS) appeared to be one possible means of using this information to predict disease.2 It is thought this will be of benefit as our genetic make-up is largely stable from birth and dictates a ‘baseline risk’ on get lasix prescription which external influences act and modulate. Therefore, PGS are a potential mechanism to act as a risk predictor by capturing information on this genetic liability.The use of PGS as a predictive biomarker is being explored in a number of different disease areas, including cancer,3 4 psychiatric disorders,5–7 metabolic disorders (diabetes,8 obesity9) and coronary artery disease (CAD).10 The proposed applications range from aiding disease diagnosis, informing selection of therapeutic interventions, improvement of risk prediction, informing disease screening and, on a personal level, informing life planning.

    Therefore, genetic risk information in get lasix prescription the form of a PGS is considered to have potential in informing both clinical and individual-level decision-making.Recent advances in statistical techniques, improved computational power and the availability of large data sets have led to rapid developments in this area over the past few years. This has resulted in a variety of approaches to construction of models for score calculation and the investigation of these scores for prediction of common diseases.11 Several review articles aimed at researchers with a working knowledge of this field have been produced.6 11–17 In this article, we provide an overview of the key aspects of PGS construction to assist clinicians and researchers in other areas of academia to gain an understanding of the processes involved in score construction. We also consider the implications of evolving methodologies get lasix prescription for the development of applications of PGS in healthcare.Evolution in polygenic model construction methodologiesTerminology with respect to PGS has evolved over time, reflecting evolving approaches and methodology. Other terms include PGS, polygenic risk score, polygenic load, genotype score, genetic burden, polygenic hazard score, genetic risk score (GRS), metaGRS and allelic risk score. Throughout this article we use the terms get lasix prescription polygenic models to refer to the method used to calculate an output in the form of a PGS.

    Different polygenic models can be used to calculate a PGS and analysis of these scores can be used to examine associations with particular markers or to predict an individuals risk of diseases.12Usual practice in calculating PGS is as a weighted sum of a number of risk alleles carried by an individual, where the risk alleles and their weights are defined by SNPs and their measured effects (figure 1).11 Polygenic models have been constructed using a few, hundreds or thousands of SNPs, and more recently SNPs across the whole genome. Consequently, determining which SNPs to include and the disease-associated weighting to assign to SNPs are important aspects of model construction (figure 2).18 These aspects are influenced by available genotype data and effect size estimates as well as the methodology get lasix prescription employed in turning this information into model parameters (ie, weighted SNPs).Polygenic score calculation. This calculation aggregates the SNPs and their weights selected for a polygenic score. Common diseases are thought to be influenced get lasix prescription by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score." data-icon-position data-hide-link-title="0">Figure 1 Polygenic score calculation.

    This calculation aggregates the SNPs and their weights selected for get lasix prescription a polygenic score. Common diseases are thought to be get lasix prescription influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score.Construction of a polygenic score. In the process of developing a polygenic score, numerous models are tested and then compared get lasix prescription. The model that performs best (as determined by one or more measures) is then selected for validation in the external data set.

    GWAS, genome-wide association studies." data-icon-position data-hide-link-title="0">Figure 2 Construction of get lasix prescription a polygenic score. In the process of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by get lasix prescription one or more measures) is then selected for validation in the external data set. GWAS, genome-wide association studies.Changes in data availability over time have had an impact on the approach taken in SNP selection and weighting. Early studies to identify variants associated with common diseases took the form of candidate gene get lasix prescription studies.

    The small size of candidate gene studies, the limitation of technologies available for genotyping and stringent significance thresholds meant that these studies investigated fewer variants and those that were identified with disease associations had relatively large effect sizes.19 Taken together, this meant that a relatively small number of variants were available for consideration for inclusion in a polygenic model.20 21 Furthermore, weighting parameters for these few variants were often simplistic, such as counts of the number of risk alleles carried, ignoring their individual effect sizes.16The advent of GWAS enabled assessment of SNPs across the genome, leading to the identification of a larger number of disease-associated variants and therefore more variants suitable for inclusion in a polygenic model. In addition, the increasing number of individuals in the association studies meant that the power of these studies increased, allowing for more precise estimates of effect sizes.19 get lasix prescription Furthermore, some theorised that lowering stringent significance thresholds set for SNP–trait associations could also identify SNPs that might play a part in disease risk.11 16 This resulted in more options with respect to polygenic model parameters of SNPs to include and weights to assign to them. However, the inclusion of more SNPs and direct application of GWAS effect sizes as a weighting parameter does not always equate to better predictive performance.4 16 This is because GWAS do not provide perfect information with respect to the causal SNP, the effect sizes or the number of SNPs that contribute to the trait. Therefore, different get lasix prescription methods have been developed to address these issues and optimise predictive performance of the score. Current common practice is to construct models with different iterations of SNPs and weighting, with assessment of the performance of each to identify the optimum configuration of SNPs and their weights (figure 2).Methods used in SNP selection and weighting assignmentSome methods of model development will initially involve selection of SNPs followed by optimisation of weighting, whereas others may involve optimisation of weightings for all SNPs that have been genotyped using their overall GWAS effect sizes, the linkage disequilibrium (LD) and an estimate of the proportion of SNPs that are expected to contribute to the risk.22LD is the phenomenon where some SNPs are coinherited more frequently with other SNPs due to their close proximity on the genome.

    Segments with strong LD between SNPs are referred to as haplotype get lasix prescription blocks. This phenomenon means that GWAS often identify multiple SNPs in the same haplotype block associated with disease and the true causal SNP is not known. As models have started to assess more SNPs, careful consideration is required to take into get lasix prescription account possible correlation between SNPs as a result of this phenomenon. Correlation between SNPs get lasix prescription can lead to double counting of SNPs and association redundancy, where multiple SNPs in a region of LD are identified as being associated with the outcome. This can lead to reduction in the predictive performance of the model.

    Therefore, processes for filtering SNPs and using one SNP (tag SNP) to act as a marker in an area of high LD, through LD thinning, were developed get lasix prescription. Through these processes SNPs correlated with other SNPs in a block are removed, by either pruning or clumping. Pruning ignores p value thresholds and ‘eliminates’ SNPs by a process of iterative comparison between a pair of SNPs to assess if they are correlated, and subsequently could remove SNPs that are deemed to have evidence get lasix prescription of association. Clumping (also known as informed pruning) is guided by GWAS p values and chooses the most significant SNP, therefore keeping the most significant SNP within a block.23 This is all done with the aim of pinpointing relatively small areas of the genome that contribute to risk of the trait. Different significance thresholds may be used to select SNPs from this subgroup for inclusion in models.Poor performance of a model can result from imperfect tagging with the underlying causal SNP.16 This is because the causal SNP that is associated with disease might not be in LD with the tag SNP that is in the model but is in LD with another SNP which is not in the get lasix prescription model.

    This particularly occurs where the LD and variant frequency differs between population groups.24 An alternate approach to filter SNPs is stepwise regression where SNPs are selected based on how much the SNPs improve the model’s performance. This is a get lasix prescription statistical approach and does not consider the impact of LD or effect size.As described above, early studies used simple weighting approaches or directly applied effect sizes from GWAS as weighting parameters for SNPs. However, application of effect sizes as a weighting parameter directly from a GWAS may not be optimal, due to differences in the population that the GWAS was conducted in and the target population. Also as described above, LD get lasix prescription and the fact that not all SNPs may contribute to the trait mean that these effect sizes from GWAS are imperfect estimates. Therefore, methods have been developed that adjust effect size estimates from GWAS using statistical techniques which make assumptions about factors such as the number of causal SNPs, level of LD between SNPs or knowledge of their potential function to better reflect their impact on a trait.

    Numerous statistical methodologies have been developed to improve weighting with a view to enhancing the discriminative power of a PGS.25 26 Examples of some methodological approaches are LDpred,22 winner’s curse correction,23 empirical Bayes estimation,27 shrinkage regression (Lasso),28 linear get lasix prescription mixed models,29 with more being developed or tested. An additional improvement on the methods is to embed non-genetic information (eg, age-specific ORs).6 Determination of which methodology or hybrid of methodologies is most appropriate for various settings and conditions is continuously being explored and is evolving with new statistical approaches developing at a rapid pace.In summary, model development has evolved in an attempt to gain the most from available GWAS data and address some of the issues that arise due to working with data sets which cannot be directly translated into parameters for prediction models. The different approaches taken in SNP selection and get lasix prescription weighting, and the impact on the predictive performance of a model are important to consider when assessing different models. This is because different approaches to PGS modelling can achieve the same or a similar level of prediction. From a health system implementation perspective, particular approaches may be preferred following get lasix prescription practical considerations and trade-offs between obtaining genotype data, processes for score construction and model performance.

    In addition, the degree to which these parameters need to be optimised will also be impacted by the input data and validation data set, and the quality control procedures that need to be applied to these data sets.12Sources of input data for score constructionKey to the development of a polygenic model get lasix prescription is the availability of data sets that can provide input parameters for model construction. Genotype data used in model construction can either be available as raw GWAS data or provided as GWAS summary statistics. Data in the raw format are individual-level data from a SNP array and may not have undergone basic quality control such as assessment of missingness, sex discrepancy checks, deviation from Hardy-Weinberg equilibrium, heterozygosity rate, relatedness or assessment for outliers.30 31 Availability of raw GWAS data allows for different polygenic models to be developed because of the richness of the data, however computational issues arise because of the get lasix prescription size of the data sets. Data based on genome sequencing, as opposed to SNP arrays, could also be used in model construction. There have been limited studies of PGS developed from this form of data get lasix prescription due to limitations in data availability, which is mainly due to cost restraints.15 32 Individual-level genomic data are also often not available to researchers due to privacy concerns.Due to these issues, the focus of polygenic model development has therefore been on using well-powered GWAS summary statistics.33 These are available from open access repositories and contain summary information such as the allele positions, ORs, CIs and allele frequency, without containing confidential information on individuals.

    These data sets have usually been through the basic quality control measures mentioned above. There are, however, no standards for publicly get lasix prescription available files, meaning some further processing steps may be required, in particular when various data sets are combined for a meta-analysis. Quality control on summary statistics is only possible if information such as missing genotype rate, minor allele frequency, Hardy-Weinberg equilibrium failures and non-Mendelian transmission rates is provided.12Processing of GWAS data may include additional quality control steps, imputation and filtering of the SNP information, which can be done at the level of genotype or summary statistics data. SNP arrays used in GWAS only have common SNPs represented on them as they rely get lasix prescription on LD between SNPs to cover the entire genome. As described above, one tag SNP on the array can represent many other SNPs.

    Imputation of SNPs is common in GWAS and describes the process of predicting genotypes that get lasix prescription have not been directly genotyped but are statistically inferred (imputed) based on haplotype blocks from a reference sequence.33–35 Often association tests between the imputed SNPs and trait are repeated. As genotype imputation requires individual-level data, researchers have proposed summary statistics imputation as a mechanism to infer the association between untyped SNPs and a trait. The performance of imputation has been evaluated and shown that, with certain limitations, summary statistics imputation is an efficient and cost-effective methodology to identify loci associated with traits when compared with imputation done on genotypes.36An alternative source of input data for the selection of SNPs and their weightings is through literature or in existing databases, where already known trait-associated SNPs and their effect sizes are used as the input parameters in model development get lasix prescription. A number of studies have taken this approach37 38 and it is possible to use multiple sources when developing various polygenic models and establishing the preferred parameters to use.Currently, there does not appear to be one methodology that works across all contexts and traits, each trait will need to be assessed to determine which method is the most suitable for the trait being evaluated. For example, four different polygenic model construction strategies were explored for three skin cancer subtypes4 by using data on SNPs and their effect sizes from different sources, such as the latest GWAS meta-analysis results, the National Human Genome Research Institute (NHGRI) EBI GWAS catalogue, UK Biobank GWAS summary statistics with different thresholds and GWAS summary statistics with get lasix prescription LDpred.

    In this setting for basal cell carcinoma and melanoma, the meta-analysis and catalogue-derived models were found to perform similarly but that the latter was ultimately used as it included more SNPs. For squamous cell http://www.amisdepasteur.fr/where-to-get-lasix-pills/ carcinoma the meta-analysis-derived model performed better than get lasix prescription the catalogue-derived model. This demonstrates how each disease subtype, model get lasix prescription construction strategy and data set can have their own limitations and advantages.Knowledge of the sources of input data and its subsequent use in model development is important in understanding the limitations of available models. Models that are developed using data sets that reflect the population in which prediction is to be carried out will perform better. For example, data collected from a symptomatic or high-risk population may not be suitable as an input data set for the development of a polygenic model that will be used for disease prediction in the general get lasix prescription population.

    Large GWAS studies were previously focused on high-risk individuals, such as patients with breast cancer with a strong family history or known pathogenic variants in BRCA1 or BRCA2. These studies would not be suitable for the development of PGS for use in the general population but can inform risk assessment in high-risk individuals get lasix prescription. The source of the data for SNP selection and weighting also has implications for downstream uses and validation. For example, variant frequency and LD patterns can vary between populations and this can translate to poor performance of the polygenic model if the external validation population is different from that of the input data set.39–41 Furthermore, get lasix prescription the power and validity of polygenic analyses are influenced by the input data sources.12 42From a model to a scorePGS can be calculated using one of the methodologies discussed above. The resulting PGS units of measurement depend on which measurement is used for the weighting.12 For example, the weightings may have been calculated based on logOR for discrete traits or linear regression coefficient (β/beta) in continuous traits from univariate regression tests carried out in the GWAS.

    The resulting scores are then usually transformed to a standard normal distribution to give scores ranging from −1 get lasix prescription to 1, or 0 to 100 for ease of interpretation. This enables further examination of the association between the score and a trait and the predictive ability of different scores generated by different models. Similar to other biomarker analyses, this involves using the PGS as a get lasix prescription predictor of a trait with other covariates (eg, age, smoking, and so on) added, if appropriate, in a target sample. Examination of differences in the distribution of scores in cases and controls, or by examining differences in traits between different strata of PGS can enable assessment of predictive ability (figure 3). Common practice is for individual-level PGS values to be used to stratify populations into distinct groups of risk based on percentile cut-off or threshold get lasix prescription values (eg, the top 1%).Example distribution of polygenic scores across a population.

    Thresholds can be set to stratify risk as low (some), average (most) and high (some)." data-icon-position data-hide-link-title="0">Figure 3 Example distribution of polygenic scores across a population. Thresholds can be set to stratify risk as low (some), average (most) get lasix prescription and high (some).Model validationPolygenic model development is reliant on further data sets for model testing and validation and the composition of these data sets is important in ensuring that the models are appropriate for a particular purpose. The development of a model to calculate a get lasix prescription PGS involves refinement of the previously discussed input parameters, and selection of the ‘best’ of several models based on performance (figure 2). Therefore, a testing/training data set is often required to assess the model’s ability to accurately predict the trait of interest. This is get lasix prescription often a data set that is independent of the base/input/discovery data set.

    It may comprise a subset of the discovery data set that is only used for testing and was not included in the initial development of the model but should ideally be a separate independent data set.Genotype and phenotype data are needed in these data sets. Polygenic models are used to calculate PGS for individuals get lasix prescription in the training data set and regression analysis is performed with the PGS as a predictor of a trait. Other covariates may also be included, if appropriate. This testing phase get lasix prescription can be considered a process for identifying models with better overall performance and/or informing refinements needed. Hence, this phase often involves comparison of different models that are developed using the same input data set to identify those models that have optimal performance.The primary purpose is to determine which model best discriminates between cases and controls.

    The area under the curve (AUC) or the C-statistic is the get lasix prescription most commonly used measure in assessing discriminative ability. It has been criticised as being an insensitive measure that is not able to fully capture all aspects of predictive ability. For instance, in some instances, AUC can remain unchanged between models but the individuals within are categorised into a different risk group.43 Alternative metrics get lasix prescription that have been used to evaluate model performance include increase in risk difference, integrated discrimination improvement, R2 (estimate of variance explained by the PGS after covariate adjustment), net classification index and the relative risk (highest percentile vs lowest percentile). A clear understanding on how to interpret the performance within various settings is important in determining which model is most suitable.44As per normal practice when developing any prediction model, polygenic models with the optimal performance in a testing/training data set should be further validated in external data sets. External data sets get lasix prescription are critical in validation of models and assessment of generalisability, hence must also conform to the desired situations in which a model is to be used.

    The goal is to find a model with suitable parameters of predictive performance in data sets outside of those in which it was developed. Ideally, external validation requires replication get lasix prescription in independent data sets. Few existing polygenic models have been validated to this extent, the focus being rather on the development of new models rather than evaluation of existing ones. One example where replication has been carried out is in the field of CAD, where the GPSCAD45 get lasix prescription and metaGRSCAD10 polygenic models (both developed using UK Biobank data) were evaluated in a Finnish population cohort.46 Predictive ability was found to be lower in the Finnish population. This is likely to be get lasix prescription due to the differences in genetic structure of this population and the population of the data set used for polygenic model development.

    Research is ongoing to evaluate polygenic models in other populations and strategies are being developed to ensure the same performance when used more widely, possibly through reweighting and adjustment of the scores.47Moving towards clinical applicationsPGS are thought to be useful information that could improve risk estimation and provide an avenue for disease prevention and deciding treatment strategies. There are indications from a number of fields that genetic information in the form of PGS can act as independent biomarkers and aid stratification.11 16 48 However, the clinical benefits of stratification using get lasix prescription a PGS and the implications for clinical practice are only just beginning to be examined. The use of PGS as part of existing risk prediction tools or as a stand-alone predictor has been suggested. This latter option may be true for diseases where knowledge or predictive ability get lasix prescription with other risk factors is limited, such as in prostate cancer.49 In either case, polygenic models need to be individually examined to determine suitability and applicability for the specific clinical question.50 Despite some commercial companies developing PGS,51 52 currently PGS are not an established part of clinical practice.Integration into clinical practice requires evaluation of a PGS-based test. An important concept to consider in this regard is the distinction between an assay and a test.

    This has been previously discussed with respect to genetic test evaluation.53 54 It is worth examining get lasix prescription this concept as applied to PGS, as their evaluation is reliant on a clear understanding of the test to be offered. As outlined by Zimmern and Kroese,54 the method used to analyse a substance in a sample is considered the assay, whereas a test is the use of an assay within a specific context. With respect to get lasix prescription PGS, the process of developing a model to derive a score can be considered the assay, while the use of this model for a particular disease, population and purpose can be considered the test. This distinction is important when assessing if studies are reporting on assay performance as opposed to test performance. It is our view that, with respect to polygenic models, progress has been made with respect to assay development, but PGS-based tests are yet to be developed and get lasix prescription evaluated.

    This can enable a clearer understanding of their potential clinical utility and issues that may arise for clinical implementation.11 18 55 It is clear that this is still an evolving field, and going forward different models may be required for different traits due to their underlying genetic architecture,26 different clinical contexts and needs.Clinical contexts where risk stratification is already established practice are most likely where implementation of PGS will occur first. Risk prediction models based on non-genetic factors have been developed for many conditions and are used in clinical care, for example, in cardiovascular disease over 100 such models exist.56 In such contexts, how get lasix prescription a PGS and its ability to predict risk compared with, or improves on, these existing models is being investigated.3 44 57–61 The extent to which PGS improves prediction, as well as the cost implications of including this, is likely to impact on implementation.Integration of PGS into clinical practice, for any application, requires robust and validated mechanisms to generate these scores. Therefore, given the numerous models available, an assessment of their suitability as part of a test is required. Parameters or guidelines with respect to aspects of get lasix prescription model performance and metrics that could assist in selecting the model to take forward as a PGS-based test are limited and need to be addressed. Currently, there are different mechanisms to generate PGS and have arisen in response to the challenges in aggregating large-scale genomic data for prediction.

    For example, a review reported 29 PGS models for get lasix prescription breast cancer from 22 publications.62 Due to there being a number of different methodologies to generate a score, numerous models may exist for the same condition and each of the resulting models could perform differently. Models may perform differently because the population, measured outcome or context of the development data sets used to generate the models is diverse, for example, a score for risk of breast cancer versus a breast cancer subtype.44 63 This diversity, alongside the lack of established best practice and standardised reporting in publications, makes comparison and evaluation of polygenic models for use in get lasix prescription clinical settings challenging. It is clear that moving the field forward is reliant on transparent reporting and evaluation. Recommendations for best practices on the reporting of polygenic models in literature have been proposed14 64 get lasix prescription as well as a database,65 66 which could allow for such comparisons. Statements and guidelines for risk prediction model development, such as the Genetic Risk Prediction Studies and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD), already exist, but are not consistently used.

    TRIPOD explicitly covers the development and validation of prediction models for both diagnosis and prognosis, for all medical domains.One clear issue is generalisability and drop in performance of polygenic models once they are applied in a population group different from the one in which they were developed.22 46 67–70 This is get lasix prescription an ongoing challenge in genomics as most GWAS, from which most PGS are being developed, have been conducted in European-Caucasian populations.71 Efforts to improve representation are underway72 and there are attempts to reweight/adjust scores when applied to different population groups which are showing some potential but need further research.47 Others have demonstrated that models developed in more diverse population groups have improved performance when applied to external data sets in different populations.24 73 It is important to consider this issue when moving towards clinical applications as it may pose an ethical challenge if the PGS is not generalisable.A greater understanding of different complex traits and the impact of pleiotropy is only beginning to be investigated.74 There is growing appreciation of the role of pleiotropy as multiple variants have been identified to be associated with multiple traits and exert diverse effects, providing insight into overlapping mechanisms.75 76 This, together with the impact of population stratification, genetic relatedness, ascertainment and other sources of heterogeneity leading to spurious signals and reduced power in genetic association studies, all impacting on the predictive ability of PGS in different populations and for different diseases.While many publications report on model development and evaluation, often there is a lack of clarity on intended purpose,50 77 leading to uncertainties as to the clinical pathways in which implementation is envisaged. A clear description of intended use within clinical pathways is a central component in evaluating the use of an application with any form of PGS and in considering practical implications, such as mechanisms of obtaining the score, incorporation into health records, interpretation of scores, relevant cut-offs for intervention initiation, mechanisms for feedback of results and costs, among other issues. These parameters will also be impacted by the polygenic model that is taken forward for get lasix prescription implementation. Meaning that there are still some important questions that need to be addressed to determine how and where PGS could work within current healthcare systems, particularly at a population level.78It is widely accepted that genotyping using arrays is a lower cost endeavour in comparison to genome sequencing, making the incorporation of PGS into routine healthcare an attractive proposition. However, we were unable to find any get lasix prescription studies reporting on the use or associated costs of such technology for population screening.

    Studies are beginning to examine use case scenarios and model cost-effectiveness, but this has only been in very few, specific investigations.79 80 Costs will also be influenced by the testing technology and by the downstream consequences of testing, which is likely to differ depending on specific applications that are developed and the pathways in which such tests are incorporated. This is particularly the case in screening or primary care settings, where such testing is get lasix prescription currently not an established part of care pathways and may require additional resources, not least as a result of the volume of testing that could be expected. Moving forward, the clinical role of PGS needs to be developed further, including defining the clinical applications as well as supporting evidence, for example, on the effect of clinical outcomes, the feasibility for use in routine practice and cost-effectiveness.ConclusionThere is a large amount of diversity in the PGS field with respect to model development approaches, and this continues to evolve. There is rapid progress which is being driven by the availability of larger data sets, primarily from GWAS and concomitant developments in get lasix prescription statistical methodologies. As understanding and knowledge develops, the usefulness and appropriateness of polygenic models for different diseases and contexts are being explored.

    Nevertheless, this is still an get lasix prescription emerging field, with a variable evidence base demonstrating some potential. The validity of PGS needs to be clearly demonstrated, and their applications evaluated prior to clinical implementation..

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  • Is furosemide lasix

    Louis Pasteur et le ver à soie :


    Une exposition présentera à la Maison natale des aspects actuels de l'utilisation de la soie, dans les domaines industriels et techniques, dans la création artistique, avec un clin d'oeil aux travaux de Pasteur sur les maladies des vers à soie en...

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  • Is furosemide lasix

    Visite passion

    Pendant les vacances , venez faire la connaissance de Louis PASTEUR, visitez sa maison natale à Dole et la salle scientifique exposant les découvertes de notre grand savant Jurassien.
    Les bénévoles des Amis de PASTEUR vous proposent une "visite passion...

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