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Many TB programs need clinical advice as they seek to roll how to order renova online out such regimens in their specific setting. In this Perspective, we highlightour early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.No Reference information available - sign in for access. No Supplementary Data.No Article MediaNo MetricsKeywords:MDR-TB;TB;drug-resistant;human rights;oral regimenDocument Type.

Research ArticleAffiliations:1 how to order renova online. Center for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, Soauth Africa 2. Treatment Action Group, New York, NY, USA 3.

Médecins Sans Frontières (MSF), Khayelitsha, South Africa how to order renova online 4. Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, and Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University ofCape Town, Cape Town, South Africa 5. Eswatini National TB Control Programme, Manzini, Eswatini 6.

Global TB Program, Baylor College of Medicine, how to order renova online Houston, TX, USA 7. Hinduja Hospital &. Research Centre, Mumbai, India 8.

MSF, Cape how to order renova online Town, South Africa 9. Independent Consultant, Maputo, Mozambique 10. Republican Scientific and Practical Centre for Pulmonology and TB, Minsk, Belarus 11.

Department of Infectious Diseases, Imperial College London, UK, and Desmond Tutu TB Centre, Department how to order renova online of Paediatrics and Child Health, University of Stellenbosch, Tygerberg, South Africa 12. National Department of Health, Mahikeng, North West Province, South Africa 13. Partners In Health (PIH), Boston, MA, USA 14.

National Department of Health, Johannesburg, Gauteng Province, South Africa 15. PIH, Maseru, Lesotho 16. MSF, Eshowe, South Africa 17.

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NEED TO KNOW PAST MEDICAID INCOME AND RESOURCE LEVELS?. Which household size applies?. The rules renova ireland are complicated. See rules here. On the HRA Medicaid Levels chart - Boxes 1 and 2 are NON-MAGI Income and Resource levels -- Age 65+, Blind or Disabled and other adults who need to use "spend-down" because they are over the MAGI income levels.

Box 10 on page 3 are the MAGI income levels -- The Affordable Care Act changed the renova ireland rules for Medicaid income eligibility for many BUT NOT ALL New Yorkers. People in the "MAGI" category - those NOT on Medicare -- have expanded eligibility up to 138% of the Federal Poverty Line, so may now qualify for Medicaid even if they were not eligible before, or may now be eligible for Medicaid without a "spend-down." They have NO resource limit. Box 3 on page 1 is Spousal Impoverishment levels for Managed Long Term Care &. Nursing Homes and Box 8 has the Transfer Penalty rates for nursing home eligibility Box 4 has Medicaid Buy-In for Working People with Disabilities Under Age 65 (still 2017 levels til April 2018) Box 6 are Medicare Savings Program levels (will be updated in April 2018) MAGI INCOME LEVEL of 138% FPL applies to most adults who are renova ireland not disabled and who do not have Medicare, AND can also apply to adults with Medicare if they have a dependent child/relative under age 18 or under 19 if in school. 42 C.F.R.

§ 435.4. Certain populations have an even higher income limit - 224% FPL for pregnant women and renova ireland babies <. Age 1, 154% FPL for children age 1 - 19. CAUTION. What is counted as income may not renova ireland be what you think.

For the NON-MAGI Disabled/Aged 65+/Blind, income will still be determined by the same rules as before, explained in this outline and these charts on income disregards. However, for the MAGI population - which is virtually everyone under age 65 who is not on Medicare - their income will now be determined under new rules, based on federal income tax concepts - called "Modifed Adjusted Gross Income" (MAGI). There are good renova ireland changes and bad changes. GOOD. Veteran's benefits, Workers compensation, and gifts from family or others no longer count as income.

BAD. There is no more "spousal" or parental renova ireland refusal for this population (but there still is for the Disabled/Aged/Blind.) and some other rules. For all of the rules see. ALSO SEE 2018 Manual on Lump Sums and Impact on Public Benefits - with resource rules The income limits increase with the "household size." In other words, the income limit for a family of 5 may be higher than the income limit for a single person. HOWEVER, Medicaid rules about how to calculate the household size renova ireland are not intuitive or even logical.

There are different rules depending on the "category" of the person seeking Medicaid. Here are the 2 basic categories and the rules for calculating their household size. People who are Disabled, Aged 65+ or Blind - renova ireland "DAB" or "SSI-Related" Category -- NON-MAGI - See this chart for their household size. These same rules apply to the Medicare Savings Program, with some exceptions explained in this article. Everyone else -- MAGI - All children and adults under age 65, including people with disabilities who are not yet on Medicare -- this is the new "MAGI" population.

Their household size will be determined using renova ireland federal income tax rules, which are very complicated. New rule is explained in State's directive 13 ADM-03 - Medicaid Eligibility Changes under the Affordable Care Act (ACA) of 2010 (PDF) pp. 8-10 of the PDF, This PowerPoint by NYLAG on MAGI Budgeting attempts to explain the new MAGI budgeting, including how to determine the Household Size. See renova ireland slides 28-49. Also seeLegal Aid Society and Empire Justice Center materials OLD RULE used until end of 2013 -- Count the person(s) applying for Medicaid who live together, plus any of their legally responsible relatives who do not receive SNA, ADC, or SSI and reside with an applicant/recipient.

Spouses or legally responsible for one another, and parents are legally responsible for their children under age 21 (though if the child is disabled, use the rule in the 1st "DAB" category. Under this rule, a child may be excluded from the household if that child's income causes other family members to lose Medicaid eligibility renova ireland. See 18 NYCRR 360-4.2, MRG p. 573, NYS GIS 2000 MA-007 CAUTION. Different people in the same household may be in different "categories" and hence have different household sizes AND Medicaid income and resource limits.

If a man is age 67 and has Medicare and his wife is age 62 and not disabled or blind, the husband's household size for Medicaid is determined under Category 1/ Non-MAGI above and his wife's is under Category 2/MAGI. The following programs were available prior to 2014, but are now discontinued because they are folded into MAGI Medicaid. Prenatal Care Assistance Program (PCAP) was Medicaid for pregnant women and children under age 19, with higher income limits for pregnant woman and infants under one year (200% FPL for pregnant women receiving perinatal coverage only not full Medicaid) than for children ages 1-18 (133% FPL). Medicaid for adults between ages 21-65 who are not disabled and without children under 21 in the household. It was sometimes known as "S/CC" category for Singles and Childless Couples.

This category had lower income limits than DAB/ADC-related, but had no asset limits. It did not allow "spend down" of excess income. This category has now been subsumed under the new MAGI adult group whose limit is now raised to 138% FPL. Family Health Plus - this was an expansion of Medicaid to families with income up to 150% FPL and for childless adults up to 100% FPL.

65, Does Extra resources not have Medicare)(OR has Medicare how to order renova online and has dependent child <. 18 or <. 19 in school) 138% FPL*** Children <.

5 and pregnant women have HIGHER LIMITS than shown ESSENTIAL PLAN For MAGI-eligible people over MAGI income limit how to order renova online up to 200% FPL No long term care. See info here 1 2 1 2 3 1 2 Income $875 (up from $859 in 201) $1284 (up from $1,267 in 2019) $1,468 $1,983 $2,498 $2,127 $2,873 Resources $15,750 (up from $15,450 in 2019) $23,100 (up from $22,800 in 2019) NO LIMIT** NO LIMIT SOURCE for 2019 figures is GIS 18 MA/015 - 2019 Medicaid Levels and Other Updates (PDF). All of the attachments with the various levels are posted here.

NEED how to order renova online TO KNOW PAST MEDICAID INCOME AND RESOURCE LEVELS?. Which household size applies?. The rules are complicated.

See how to order renova online rules here. On the HRA Medicaid Levels chart - Boxes 1 and 2 are NON-MAGI Income and Resource levels -- Age 65+, Blind or Disabled and other adults who need to use "spend-down" because they are over the MAGI income levels. Box 10 on page 3 are the MAGI income levels -- The Affordable Care Act changed the rules for Medicaid income eligibility for many BUT NOT ALL New Yorkers.

People in the "MAGI" category - those NOT on Medicare -- have expanded eligibility up to 138% of the Federal Poverty Line, so may now qualify for how to order renova online Medicaid even if they were not eligible before, or may now be eligible for Medicaid without a "spend-down." They have NO resource limit. Box 3 on page 1 is Spousal Impoverishment levels for Managed Long Term Care &. Nursing Homes and Box 8 has the Transfer Penalty rates for nursing home eligibility Box 4 has Medicaid Buy-In for Working People with Disabilities Under Age 65 (still 2017 levels til April 2018) Box 6 are Medicare Savings Program levels (will be updated in April 2018) MAGI INCOME LEVEL of 138% FPL applies to most adults who are not disabled and who do not have Medicare, AND can also apply to adults with Medicare if they have a dependent child/relative under age 18 or under 19 if in school.

42 C.F.R how to order renova online. § 435.4. Certain populations have an even higher income limit - 224% FPL for pregnant women and babies <.

Age 1, 154% FPL for children age 1 how to order renova online - 19. CAUTION. What is counted as income may not be what you think.

For the NON-MAGI Disabled/Aged 65+/Blind, income will still be determined by how to order renova online the same rules as before, explained in this outline and these charts on income disregards. However, for the MAGI population - which is virtually everyone under age 65 who is not on Medicare - their income will now be determined under new rules, based on federal income tax concepts - called "Modifed Adjusted Gross Income" (MAGI). There are good changes and bad changes.

GOOD how to order renova online. Veteran's benefits, Workers compensation, and gifts from family or others no longer count as income. BAD.

There is how to order renova online no more "spousal" or parental refusal for this population (but there still is for the Disabled/Aged/Blind.) and some other rules. For all of the rules see. ALSO SEE 2018 Manual on Lump Sums and Impact on Public Benefits - with resource rules The income limits increase with the "household size." http://bookcollaborative.com/artists/pam-utton/ In other words, the income limit for a family of 5 may be higher than the income limit for a single person.

HOWEVER, Medicaid rules about how to calculate the household size are not intuitive or even logical. There are different rules depending on the "category" of the how to order renova online person seeking Medicaid. Here are the 2 basic categories and the rules for calculating their household size.

People who are Disabled, Aged 65+ or Blind - "DAB" or "SSI-Related" Category -- NON-MAGI - See this chart for their household size. These same rules apply to the Medicare Savings how to order renova online Program, with some exceptions explained in this article. Everyone else -- MAGI - All children and adults under age 65, including people with disabilities who are not yet on Medicare -- this is the new "MAGI" population.

Their household size will be determined using federal income tax rules, which are very complicated. New rule is explained in State's directive 13 ADM-03 - Medicaid Eligibility Changes under the Affordable Care Act (ACA) of 2010 (PDF) pp. 8-10 of the PDF, This PowerPoint by NYLAG on MAGI Budgeting attempts to explain the new MAGI budgeting, including how to determine the Household Size.

See slides 28-49. Also seeLegal Aid Society and Empire Justice Center materials OLD RULE used until end of 2013 -- Count the person(s) applying for Medicaid who live together, plus any of their legally responsible relatives who do not receive SNA, ADC, or SSI and reside with an applicant/recipient. Spouses or legally responsible for one another, and parents are legally responsible for their children under age 21 (though if the child is disabled, use the rule in the 1st "DAB" category.

Under this rule, a child may be excluded from the household if that child's income causes other family members to lose Medicaid eligibility. See 18 NYCRR 360-4.2, MRG p. 573, NYS GIS 2000 MA-007 CAUTION.

Different people in the same household may be in different "categories" and hence have different household sizes AND Medicaid income and resource limits. If a man is age 67 and has Medicare and his wife is age 62 and not disabled or blind, the husband's household size for Medicaid is determined under Category 1/ Non-MAGI above and his wife's is under Category 2/MAGI. The following programs were available prior to 2014, but are now discontinued because they are folded into MAGI Medicaid.

Prenatal Care Assistance Program (PCAP) was Medicaid for pregnant women and children under age 19, with higher income limits for pregnant woman and infants under one year (200% FPL for pregnant women receiving perinatal coverage only not full Medicaid) than for children ages 1-18 (133% FPL). Medicaid for adults between ages 21-65 who are not disabled and without children under 21 in the household. It was sometimes known as "S/CC" category for Singles and Childless Couples.

This category had lower income limits than DAB/ADC-related, but had no asset limits. It did not allow "spend down" of excess income. This category has now been subsumed under the new MAGI adult group whose limit is now raised to 138% FPL.

Family Health Plus - this was an expansion of Medicaid to families with income up to 150% FPL and for childless adults up to 100% FPL. This has now been folded into the new MAGI adult group whose limit is 138% FPL. For applicants between 138%-150% FPL, they will be eligible for a new program where Medicaid will subsidize their purchase of Qualified Health Plans on the Exchange.

PAST INCOME &. RESOURCE LEVELS -- Past Medicaid income and resource levels in NYS are shown on these oldNYC HRA charts for 2001 through 2019, in chronological order.

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There are many overlapping reasons for this, says Brinkerhoff renova tablet online. Awareness has gone up since the 1970s, when Lyme was first described in the U.S. Landscape changes like cutting forests and building suburbs near wooded areas has put humans in closer contact with ticks and tick-carrying animals.

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It’s possible that more people trying to get outside could mean more people exposed to ticks and, therefore, Lyme disease, says Brinkerhoff, who wrote an article in The Conversation on the issue earlier this year. Animals have been behaving differently during the renova as well, especially during the early days of lockdown, and it’s unclear if that could also have an effect on Lyme disease rates, he says.In some parts of the country, however, Lyme may be less of a concern this summer than it normally is. Maine is usually a Lyme hotspot in renova tablet online early summer, but unusually hot and dry weather this year may be keeping ticks close to the ground and away from human contact, says Robert P.

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Many who develop Lyme disease are bitten by poppy seed-sized immature ticks that can stay on the body unnoticed for two or three days before dropping off, he says.There is some overlap between skin care products and Lyme disease symptoms that could cause confusion. In both cases, people usually develop renova tablet online a fever and muscle aches, says Smith. He has heard secondhand about a few cases in Maine in which patients with these symptoms were first tested for skin care products and were later found to have Lyme disease.However, there are some crucial differences between the two illnesses, Smith says.

The majority of people with symptomatic skin care products will have a cough or shortness of breath, whereas Lyme disease generally renova tablet online has no respiratory component, says Smith. skin care products patients also have a higher risk for gastrointestinal issues, and Lyme patients do not. While not all people with Lyme disease develop a rash, 70 to 80 percent do, Smith notes.

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At the start of http://bendwild.com/deschutes-brewerys-red-chair-northwest-pale-ale/ field work season, ecologist Jory Brinkerhoff how to order renova online usually advises his crew to watch out for summertime fevers. If you develop a fever at that time of year, he tells them, it’s probably not the flu, but a tick-borne illness.But this year, Brinkerhoff, who studies human risk for flea- and tick-transmitted diseases at the University of Richmond, didn’t know exactly what to tell his field crew. A fever in the middle how to order renova online of summer 2020 could mean a tick-borne illness.

Or, it could mean skin care products.With the novel skin care renova still spreading across the country, some experts worry about the overlap between skin care products and Lyme disease, which is caused by a bacterium carried by black-legged ticks. While it’s too soon to know exactly how the renova how to order renova online will affect Lyme disease rates this year, experts like Brinkerhoff wonder if more people spending time outside beating the quarantine blues could lead to more people being exposed to disease-carrying ticks. Some overlapping symptoms might also lead to delayed diagnosis and treatment of Lyme, he notes.

At the same time, weather patterns in some parts of the country may actually lead to fewer Lyme disease cases this year. No matter how to order renova online the broader trends, there are things anyone getting outside can do to protect themselves from ticks. Lyme Disease on the MoveOver the last few decades, Lyme disease has been on the rise in the United States.

There are many how to order renova online overlapping reasons for this, says Brinkerhoff. Awareness has gone up since the 1970s, when Lyme was first described in the U.S. Landscape changes like cutting forests and building suburbs near wooded areas has put humans in closer contact with ticks and tick-carrying animals.

Deer populations how to order renova online have exploded in the last 100 years, he notes. And climate change is likely allowing ticks to spread to and thrive in new parts of the continent. This year, people have flocked how to order renova online to the great outdoors to escape their home quarantines and engage in socially-distant fun.

It’s possible that more people trying to get outside could mean more people exposed to ticks and, therefore, Lyme disease, says Brinkerhoff, who wrote an article in The Conversation on the issue earlier this year. Animals have been behaving differently during the renova as well, especially during the early days of lockdown, and it’s unclear if that could also have an effect on Lyme disease rates, he says.In some parts of the country, however, Lyme may be less of a concern this summer than it normally is. Maine is usually a Lyme hotspot in early summer, but unusually hot and dry weather this year may be keeping ticks close to the ground how to order renova online and away from human contact, says Robert P.

Smith Jr., an infectious disease physician http://maxatp.com/uncategorized/hello-world/ and director of the division of infectious diseases at Maine Medical Center. While it’s too early to tell, Lyme how to order renova online disease rates in Maine could actually go down this summer as a result, he says.Overlapping SymptomsWith everyone rightfully concerned about skin care products, Lyme disease likely isn’t at the forefront of someone’s mind if they develop a fever. Plus, about two-thirds of people with Lyme disease don’t remember being bitten by a tick, says Smith.

Many who develop Lyme disease are bitten by poppy seed-sized immature ticks that can stay on the body unnoticed for two or three days before dropping off, he says.There is some overlap between skin care products and Lyme disease symptoms that could cause confusion. In both cases, people usually develop a fever and muscle aches, how to order renova online says Smith. He has heard secondhand about a few cases in Maine in which patients with these symptoms were first tested for skin care products and were later found to have Lyme disease.However, there are some crucial differences between the two illnesses, Smith says.

The majority of people with symptomatic skin care products will have a cough or shortness of breath, whereas Lyme disease how to order renova online generally has no respiratory component, says Smith. skin care products patients also have a higher risk for gastrointestinal issues, and Lyme patients do not. While not all people with Lyme disease develop a rash, 70 to 80 percent do, Smith notes.

Rashes are not common symptoms for skin care products s how to order renova online. Receiving an accurate diagnosis and relatively quick treatment can greatly reduce the severity of a Lyme disease . €œIt doesn’t how to order renova online have to be immediate.

If you think you might have Lyme disease, you need to get diagnosed with a week or so,” says Smith. €œThat’s usually very early in the disease and you can expect an excellent response to antibiotic treatment.” Delaying treatment by a couple of weeks can lead to more serious complications, including nerve-related symptoms, Lyme meningitis, facial muscle weakness (Bell’s palsy), Lyme arthritis and other conditions, he says. While antibiotics are still effective at this stage, it tends to take longer to fully recover.Fortunately, for anyone concerned about safe outdoor excursions here and now, there are several practical steps you can how to order renova online take to avoid ticks.

Use insect repellant and wear protective layers. Stick to how to order renova online the path instead of straying into dense underbrush, says Smith. When you return from an adventure, put your clothes in the washer and check yourself for ticks.

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IntroductionThere has been considerable interest in elucidating the contribution renova vs retin a micro of genetic factors http://www.ec-dossenheim-zinsel.ac-strasbourg.fr/archives/11986 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 (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 renova vs retin a micro 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 renova vs retin a micro 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 renova vs retin a micro in 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 for the development of applications of PGS in healthcare.Evolution in polygenic model construction methodologiesTerminology with respect renova vs retin a micro 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 calculate an output in the renova vs retin a micro 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 renova vs retin a micro available genotype data and effect size estimates 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 are thought to be influenced renova vs retin a micro 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 a polygenic renova vs retin a micro score. Common diseases are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction renova vs retin a micro 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 renova vs retin a micro 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 2 renova vs retin a micro 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 renova vs retin a micro 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 renova vs retin a micro of candidate gene 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 renova vs retin a micro 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 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 renova vs retin a micro 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 renova vs retin a micro 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 started to assess more renova vs retin a micro 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 renova vs retin a micro 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 renova vs retin a micro in an area of high LD, through LD thinning, were developed.

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 renova vs retin a micro 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 that is in the model but is in LD with another SNP which is not in renova vs retin a micro 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 not consider the impact of LD or effect size.As described above, early studies used simple weighting approaches renova vs retin a micro 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 renova vs retin a micro 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 mixed models,29 renova vs retin a micro 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 renova vs retin a micro 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 practical considerations and trade-offs between obtaining genotype data, processes for score construction and model performance renova vs retin a micro. In addition, the degree to which these parameters need to be optimised will also be impacted by the input data renova vs retin a micro 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 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 renova vs retin a micro 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 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 renova vs retin a micro 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 available files, meaning some further processing steps renova vs retin a micro 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 renova vs retin a micro on them 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 renova vs retin a micro genotypes that 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 renova vs retin a micro 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.

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 LDpred renova vs retin a micro. 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 renova vs retin a micro where to buy renova cell carcinoma the meta-analysis-derived model performed better than the catalogue-derived model. This demonstrates how each disease subtype, model 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 renova vs retin a micro 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 renova vs retin a micro 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 renova vs retin a micro for use in the general population but can 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 renova vs retin a micro 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 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 renova vs retin a micro to give scores ranging from −1 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 predictor of a trait with other covariates (eg, age, smoking, and so on) added, renova vs retin a micro 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 renova vs retin a micro individual-level PGS values to be 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 data sets is important in ensuring that the models are appropriate renova vs retin a micro for a particular purpose. The development of a model to calculate a PGS involves refinement of the previously discussed input renova vs retin a micro 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 renova vs retin a micro 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 in the training data set and regression analysis is performed with renova vs retin a micro the PGS as a predictor of a trait.

Other covariates may also be included, if appropriate. This testing phase can be considered a renova vs retin a micro 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 renova vs retin a micro 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 renova vs retin a micro 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 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 validation of models and assessment of generalisability, hence must also conform to the desired situations in which a model is to renova vs retin a micro 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 in independent data renova vs retin a micro 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 renova vs retin a micro 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 renova vs retin a micro 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 renova vs retin a micro 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 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 renova vs retin a micro 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 this concept as applied to PGS, as their evaluation is reliant on a clear understanding renova vs retin a micro 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 renova vs retin a micro 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 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 renova vs retin a micro 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 based on non-genetic factors have been developed for many conditions and are used in clinical care, renova vs retin a micro 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 performance and metrics that could assist in selecting renova vs retin a micro 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 condition and each of the resulting models could perform renova vs retin a micro 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 renova vs retin a micro 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 66 which renova vs retin a micro 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 renova vs retin a micro 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 renova vs retin a micro 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 the use or associated costs of such technology for population renova vs retin a micro 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 renova vs retin a micro 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 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 renova vs retin a micro of larger data sets, primarily from GWAS and concomitant developments in 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 renova vs retin a micro 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 how to order renova online contribution directory of genetic factors to the development of common diseases and using this information for better prediction of disease risk. The common disease how to order renova online 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 how to order renova online 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 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 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 how to order renova online 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 respect to PGS has evolved over time, how to order renova online 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 how to order renova online terms 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 employed in turning this information into model parameters how to order renova online (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 by many genetic variants with small individual how to order renova online 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 how to order renova online their weights selected for a polygenic score. Common diseases are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction necessitates how to order renova online 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 how to order renova online. 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 how to order renova online data-hide-link-title="0">Figure 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) is then how to order renova online 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 how to order renova online form of candidate gene 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 how to order renova online 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 how to order renova online 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 blocks how to order renova online. 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 account possible correlation between SNPs how to order renova online 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 how to order renova online 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 how to order renova online thinning, were developed. 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 how to order renova online 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 that is in the model but is in LD with another SNP which is not in the how to order renova online 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 not consider the how to order renova online 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 not all SNPs may contribute to the trait mean that these effect sizes from how to order renova online 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 mixed models,29 with more being developed or how to order renova online 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 how to order renova online approaches taken in SNP selection and 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 practical how to order renova online considerations and trade-offs between obtaining genotype data, processes for score construction and model performance.

In addition, how to order renova online 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 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 how to order renova online 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 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 how to order renova online 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 available files, meaning some how to order renova online 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 how to order renova online 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 how to order renova online SNPs is common in GWAS and describes the process of predicting genotypes that 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 how to order renova online. 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 how to order renova online 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 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 cheap renova online canada meta-analysis-derived model performed better than the how to order renova online catalogue-derived model. This demonstrates how each disease subtype, model 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 how to order renova online 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 how to order renova online 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 how to order renova online PGS for use in the general population but can 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 how to order renova online 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 how to order renova online scores are then usually transformed to a standard normal distribution to give scores ranging from −1 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 predictor of a trait with other covariates (eg, age, smoking, and so on) added, if appropriate, in a target sample how to order renova online. 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 how to order renova online 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 data sets is important in ensuring that the models are appropriate for a particular purpose how to order renova online. The development of a model to calculate a PGS involves refinement of the previously how to order renova online 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 set that is independent how to order renova online 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 how to order renova online PGS as a predictor of a trait. Other covariates may also be included, if appropriate. This testing phase can how to order renova online 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 most how to order renova online 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 index and the relative risk (highest percentile vs lowest how to order renova online 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 how to order renova online sets 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 how to order renova online validation 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 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 how to order renova online Finnish population. This is likely to be due to the how to order renova online 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 a PGS and the implications for clinical practice how to order renova online 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 currently PGS are not an established part of clinical practice.Integration into clinical practice requires evaluation how to order renova online 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 how to order renova online is worth examining 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 PGS, the process of developing a model to derive how to order renova online 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 how to order renova online 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 a PGS and its ability to predict risk compared how to order renova online 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 performance and metrics that could assist in selecting the model to take forward as a PGS-based test how to order renova online 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 how to order renova online 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 how to order renova online 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 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 66 which how to order renova online 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 how to order renova online 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 how to order renova online 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 the use or associated how to order renova online 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 how to order renova online 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 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 how to order renova online by the availability of larger data sets, primarily from GWAS and concomitant developments in 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 emerging field, with a variable evidence base demonstrating some potential how to order renova online. The validity of PGS needs to be clearly demonstrated, and their applications evaluated prior to clinical implementation..

Renova0.02

Add public transit to the list of things Americans renova0.02 took for my review here granted before skin care products. In the months since congregating indoors renova0.02 became a public health threat, many who built their daily routines around this affordable, climate-friendly public service have felt compelled to stay away from it.Essential workers from the health-care, food and other industries don’t all have the ability to opt out, nor do citizens with no other way to get to the groceries or medicine they need. Keeping passengers safe is just one strand in the unprecedented web of challenges now facing transportation directors, and the problems that lie ahead may well be the most daunting of all.Carl Sedoryk, CEO of the Monterey-Salinas Transit District, leads a system that serves a fifth of the California coast, from Paso Robles to San Jose.

MST’s service area renova0.02 is almost 300 square miles. In the past, it has carried over 4 million passengers a year. In order to keep on top of service needs during the renova0.02 renova, Sedoryk says that he and his staff have found it necessary to monitor and adjust day by day, hour by hour, “almost trip by trip.”“It’s a huge amount of work and we’re exhausted, but no one’s complaining,” he says.

€œOthers in our community don’t have jobs and there’s satisfaction in knowing we’re here to serve them.”Prepared, But Not for ThisWildfires, earthquakes and floods are all potential risks for Sedoryk’s region and because of this, MST developed a business continuity plan five years ago. MST also is part of the county’s emergency services team and may be called on to transport citizens out of a danger zone or take first responders into it.Over the years, Sedoryk and his team met regularly and ran tabletop exercises to consider the best responses to natural disasters, renova0.02 civil disturbances or mass casualty events. €œIn many ways, we were remarkably prepared but in some areas, we were less prepared,” he says.The continuity plan even included a section on renova response, but it did not anticipate an extended public health emergency.

€œA disaster like a fire has a definable beginning, middle renova0.02 and end — it starts, it rages, it gets put out and then you start recovering,” says Sedoryk. €œThis thing is just never ending.”When the first skin care products fatality was recorded in San Jose, a city to which MST travels, Sedoryk gathered his executive team and implemented the first step of the emergency plan, creating an emergency operations center and shifting responsibilities among managers to improve resilience. MST also acquired a stock of personal protective renova0.02 equipment.

Ever since a hepatitis outbreak in the region four years ago, the agency had been disinfecting buses and had the supplies and expertise to continue this practice.“We were less prepared for the run on the market for cleaners, masks and supplies,” says Sedoryk. €œWe had to scramble for a couple of months, like everyone else, renova0.02 to get our supply chain back in order.”A sanitizer dispenser on a bus. (Photo.

MST)Empty Buses and FareboxesThrough the month of April, ridership plummeted as much as 80 percent renova0.02. Service was cut from 1,100 trips per day to 500. Bus occupancy was restricted to ensure physical distancing could be maintained and passengers were required to wear masks.“We didn’t renova0.02 put a hard stop on boarding,” Sedoryk says.

€œEspecially in Monterey, people travel in family units and we didn’t want to separate a mother from a child or force members of the same household to sit six feet apart.”So far, California weather has allowed drivers to keep bus windows open. The manufacturers of MST’s buses claim this results in complete air exchange renova0.02 every two minutes.The agency provided its drivers with masks, goggles and face shields. €œWe stopped collecting fares and instituted rear door boarding, to keep passengers from congregating at the front of the bus and potentially exposing the driver,” says Sedoryk.Over time, passengers began to return.

Sedoryk estimates that about 60 percent are back, and he has restored service to 70 percent of what renova0.02 it was before the renova, about 740 buses. Demand is monitored constantly, and new vehicles are added if drivers report that buses are getting crowded.Video cameras on buses allow managers to pay attention to whether drivers are using their PPE properly and ensure that passengers follow public health renova0.02 guidelines. €œOver time, fatigue sets in and some stop paying attention,” says Sedoryk.

€œWe continue to encourage renova0.02 them to stay up to speed, but this isn’t the time to be punitive.”MST invested half a million dollars in plastic shields at the front of buses to further protect drivers, and has applied to be reimbursed by FEMA. At the beginning of August, it began to collect fares again, for the first time since March 18.Farms in MST's service area are critical to the nation's food supply. The district donated renova0.02 buses to be converted to mobile skin care products testing labs that could be brought to work sites.

(Photo. Grower-Shipper Association of Central California)Finding New Ways to renova0.02 Serve the CommunityWhile public demand for transportation services waned, Sedoryk and his team began to look for other ways to use their resources to support the community. €œAs a public service provider, you don’t restore your service just to restore your service, you try to identify where you can accomplish the most good,” he says.MST reached out to stakeholders in its service zone — the agriculture and hospitality industries, military bases, community colleges, school districts and health-care providers and the groups that represent them to find out what they needed.

€œBased on what we were renova0.02 hearing, we started doing a number of things,” says Sedoryk.Unemployment in the county had gone from 3.5 percent to 20 percent, causing a tenfold increase in persons with food insecurity. Over the summer, MST's drivers and vehicles that would have otherwise been idle helped Meals on Wheels in Salinas Valley to deliver 8,000 meals to seniors and persons with disabilities.Students living in agricultural communities were having difficulty keeping up with remote learning mandates. Many had been provided Chromebooks by the state, renova0.02 but they didn’t have Internet access.

In response, MST parked its Wi-Fi-enabled commuter buses in rural areas to provide hot spots for them.“We’d set them up in parking lots, and people could come in their cars and piggyback on our signal,” says Sedoryk. €œWe were out there every day during the end of the school year, and we’re ramping it up again as the new school year is starting.”MST donated a vehicle it no longer needed to a veterans group who used it to take homeless veterans renova0.02 to food, medical services and shelter. The transit agency gave another vehicle to a nonprofit that trains at-risk youth to work in the hospitality industry.

Upon discovering that drivers who take disabled veterans to medical appointments had stopped volunteering because they were old, disabled and at high risk of illness, MST found CARES Act funds to take over this service.To support the local agriculture renova0.02 industry, which is critical to the national food supply, MST provided two buses to be converted into mobile skin care products testing facilities, to get testing capability out to the workers in the fields. It offered additional support by arranging for 7,500 masks received from the federal government to be distributed to families by organizations serving farmworker communities.Safety messaging and distanced passengers. (Photo.

MST)Constant RecalibrationMST also looked at data to understand how transportation needs had changed. €œWe used the Slido app (an online survey tool) that you see at conferences to survey our passengers and employees and to resurvey community stakeholders,” says Sedoryk.Community colleges have not yet resumed in-person classes. The people going back to work are in tourist-serving industries such as restaurants and hotels, and the shipping and packing facilities of the Salinas Valley.

€œWe’re focusing our services there for now,” says Sedoryk.Service to Santa Clara is currently discontinued due to lack of demand. An additional factor at play my latest blog post is the complications from inconsistent health guidelines. The Santa Clara health officer does not want riders to touch the tape on the bus wall to request a stop, but to call out “next stop.”“I’d rather have people press the button and use the hand sanitizer we have on the bus,” says Sedoryk.

€œIn places like Japan and Korea, they discourage talking at all because it spreads aerosol whether you’re wearing a mask or not.”Sedoryk recognizes that this is a “granular” problem, but it only adds to the difficulty of doing his job when there is not a coordinated national response to the renova. €œWHO information contradicts CDC information, which contradicts state health officer information, which contradicts county health officer operation,” he says.While a typical government agency operates in one location, public transit operations move through multiple locations, across different jurisdictions. MST serves Santa Clara, Monterey, Santa Cruz and San Luis Obispo counties, all of which have different rules.

€œAll you can do is the best you can do, right?. € says Sedoryk.Breaking ground for a new operations and maintenance facility. (Photo.

MST)Window Opens for Capital ProjectsDespite challenges, MST is making progress. Sedoryk says that if it weren’t for the renova and the loss of ridership, it would be having a banner year.The agency has broken ground on a new bus operations and maintenance facility, financed through a credit program created under the Transportation Infrastructure Finance and Innovation Act (TIFIA). The district’s 35-year loan could be at a rate as low as 0.75 percent, with no payments for the first five years.In this case, the renova made Sedoryk’s life easier.

€œNormally, it would require several trips to Washington to get this financing, but we were able to do this via virtual conferencing and have people from all over the country involved," he says.MST also has been selected as the first transportation district in the state to implement a new program from CalTrans, called the California Integrated Travel Project (Cal-ITP). Sedoryk describes this as “an open loop contactless credit card payment system.” The goal is to to have a fee-less VISA card that could be used to pay fares on any transit system in the state. Because of the renova, the state has decided to accelerate development and deployment.As with the TIFIA loan, Sedoryk has been able to collaborate on this work with partners in far-flung locations thanks to Web conferencing.

€œWe have people from Sacramento, Toronto, Melbourne and New York on these calls,” he says.There’s a long-range social equity aspect to all this, according to Sedoryk. Many low-income residents don’t have bank accounts, which complicates the process of accessing benefits such as food assistance and creates a paperwork burden on both sides. Eventually, such funds could be sent to the card account and the card could be used for purposes such as purchasing groceries.Wi-Fi-enabled commuter buses were parked in communities where students did not have Internet access, to help them manage remote learning assignments.

(Photo. MST)Cash Flow Is a ProblemAs the renova crisis heads into the fall, transit systems are in financial freefall around the country. Big city systems, such as New York City and San Francisco, have seen ridership plummet 90 percent.

That has cut into revenue just as states have reduced subsidies in an effort to trim budgets. The result. Transit agencies across the country are projected to rack up close to $40 billion in budget shortfalls, dwarfing the $2 billion loss inflicted by the 2008 financial crisis, according to The New York Times.MST does not have financial support from local sales taxes, and depends on state sales taxes along with state and federal fuel taxes and farebox revenues to pay for its operations.

Partnerships with community colleges, universities, the Monterey Bay Aquarium and military bases also help.But like so many other sources of revenue during the renova, partnership funding has disappeared. €œThe aquarium and the universities and the community colleges and the bases are all closed,” he says. €œWe’re not getting any money from there.”Thanks to CARES Act funding, Sedoryk is confident he can “sail” through the end of this fiscal year.

But depending on the situation at the end of the calendar year, he may be forced to look at reductions in force and restructuring of services.So far, he’s been able to avoid layoffs and has been particularly attentive to keeping his drivers on the payroll — he doesn’t want them taking jobs elsewhere, leaving him short-handed if the recovery gains steam. The California transit association has said that CARES Act funding is $3.1 billion short of what the state needs, with major urban areas like Los Angeles and San Francisco most at risk. At this point, it’s uncertain what another federal stimulus package might bring.“If nothing happens there, and nothing happens in Sacramento, there will be a $3.1 billion contraction in our industry and it will affect different localities differently,” he says.

€œIt really depends on their local economies and local funding streams.”For now, he’s watching state sales tax revenue, and there aren’t enough data points yet for him to see a trend. He’ll know more by the end of the year, and if relief from Congress or the state could be in sight.“The fares that passengers pay cover about 20 percent of our costs, and the rest is picked up by a variety of state and federal funding sources,” says Sedoryk. €œBut there’s only so much a person is going to be able to pay.”It’s too early to know what the numbers will be, but at some point, MST, like other transit providers around the country, may have to reconsider the level of service that it is able to provide with the cash flow available to it.The average taxpayer may not think much about the large section of the population that can’t afford a car, or who are too old or disabled to drive, Sedoryk says.

€œThere’s a lot of noise to filter through to get that message out, especially these days.”Strength, Stamina and FlexibilityFor now, MST’s attention is on service and safety. The agency has 250 workers. There was no confirmed skin care products case among them until recently and the employee in question had not had contact with passengers or the general public.

The county health officer has not identified any instances where a member of the public contracted skin care products while an MST passenger.Sedoryk had six district employees go through the contact tracing training developed by Johns Hopkins University. €œOur county is overwhelmed — it’s a small rural county and they weren’t set up to handle this type of emergency,” he says. €œWe decided to offer our employees help to get them a head start on some of these issues.”The renova has led to greatly improved relationships with the local union, in contrast to the complaints and lawsuits brought against leaders of transit districts in other parts of the country by union members who feel they have been put in danger.

Sedoryk and the local union president have been meeting daily. €œThis has forced us to not just talk about problems, but to get to know each other as people and develop a relationship — that’s helped out a lot.”MST’s response to the renova has changed how the community perceives it, particularly those who work in agriculture. €œThey see us providing buses to turn into mobile skin care products labs — not as a stodgy, bureaucratic entitlement program but as a solution that they need.”Better relationships within and without the organization and an enhanced reputation for service help offset the stress caused by conditions and risks that shift day to day, hour by hour.

Sedoryk’s volunteer work as a martial arts instructor, on hold for the time being, has also served him well, he believes.“We focus on strength, stamina and flexibility,” he says. €œThose are good attributes for a martial artist, and they are excellent attributes for an organization — you’ve got to be financially strong, flexible, and you’ve got to be in it for the long haul.” Carl Smith Senior Staff Writercarl.smith@governing.com.

Add public transit check my site to the list of things Americans how to order renova online took for granted before skin care products. In the months since congregating indoors became a public health threat, many how to order renova online who built their daily routines around this affordable, climate-friendly public service have felt compelled to stay away from it.Essential workers from the health-care, food and other industries don’t all have the ability to opt out, nor do citizens with no other way to get to the groceries or medicine they need. Keeping passengers safe is just one strand in the unprecedented web of challenges now facing transportation directors, and the problems that lie ahead may well be the most daunting of all.Carl Sedoryk, CEO of the Monterey-Salinas Transit District, leads a system that serves a fifth of the California coast, from Paso Robles to San Jose. MST’s service how to order renova online area is almost 300 square miles.

In the past, it has carried over 4 million passengers a year. In order to keep on top of service needs during the renova, Sedoryk says that he and his staff have found it necessary to monitor and adjust day by day, hour by hour, “almost trip by trip.”“It’s a huge amount of work and we’re exhausted, but no one’s complaining,” he says how to order renova online. €œOthers in our community don’t have jobs and there’s satisfaction in knowing we’re here to serve them.”Prepared, But Not for ThisWildfires, earthquakes and floods are all potential risks for Sedoryk’s region and because of this, MST developed a business continuity plan five years ago. MST also how to order renova online is part of the county’s emergency services team and may be called on to transport citizens out of a danger zone or take first responders into it.Over the years, Sedoryk and his team met regularly and ran tabletop exercises to consider the best responses to natural disasters, civil disturbances or mass casualty events.

€œIn many ways, we were remarkably prepared but in some areas, we were less prepared,” he says.The continuity plan even included a section on renova response, but it did not anticipate an extended public health emergency. €œA disaster like a fire has a definable beginning, middle how to order renova online and end — it starts, it rages, it gets put out and then you start recovering,” says Sedoryk. €œThis thing is just never ending.”When the first skin care products fatality was recorded in San Jose, a city to which MST travels, Sedoryk gathered his executive team and implemented the first step of the emergency plan, creating an emergency operations center and shifting responsibilities among managers to improve resilience. MST also acquired a stock of personal protective how to order renova online equipment.

Ever since a hepatitis outbreak in the region four years ago, the agency had been disinfecting buses and had the supplies and expertise to continue this practice.“We were less prepared for the run on the market for cleaners, masks and supplies,” says Sedoryk. €œWe had to scramble for a couple of months, like everyone else, to get our supply how to order renova online chain back in order.”A sanitizer dispenser on a bus. (Photo. MST)Empty Buses and FareboxesThrough the month of April, ridership how to order renova online plummeted as much as 80 percent.

Service was cut from 1,100 trips per day to 500. Bus occupancy was restricted to ensure physical distancing could be maintained and passengers were required to wear masks.“We didn’t put a hard stop on boarding,” how to order renova online Sedoryk says. €œEspecially in Monterey, people travel in family units and we didn’t want to separate a mother from a child or force members of the same household to sit six feet apart.”So far, California weather has allowed drivers to keep bus windows open. The manufacturers of MST’s buses claim this results in complete air exchange every two minutes.The agency provided its drivers with masks, goggles how to order renova online and face shields.

€œWe stopped collecting fares and instituted rear door boarding, to keep passengers from congregating at the front of the bus and potentially exposing the driver,” says Sedoryk.Over time, passengers began to return. Sedoryk estimates that about 60 percent are back, and he has restored service to 70 percent of what it how to order renova online was before the renova, about 740 buses. Demand is monitored how to order renova online constantly, and new vehicles are added if drivers report that buses are getting crowded.Video cameras on buses allow managers to pay attention to whether drivers are using their PPE properly and ensure that passengers follow public health guidelines. €œOver time, fatigue sets in and some stop paying attention,” says Sedoryk.

€œWe continue to encourage them to stay up to speed, but this isn’t the time to be punitive.”MST invested half a million dollars in plastic shields at the front of buses to further protect drivers, and has applied to be how to order renova online reimbursed by FEMA. At the beginning of August, it began to collect fares again, for the first time since March 18.Farms in MST's service area are critical to the nation's food supply. The district how to order renova online donated buses to be converted to mobile skin care products testing labs that could be brought to work sites. (Photo.

Grower-Shipper Association of Central California)Finding New Ways how to order renova online to Serve the CommunityWhile public demand for transportation services waned, Sedoryk and his team began to look for other ways to use their resources to support the community. €œAs a public service provider, you don’t restore your service just to restore your service, you try to identify where you can accomplish the most good,” he says.MST reached out to stakeholders in its service zone — the agriculture and hospitality industries, military bases, community colleges, school districts and health-care providers and the groups that represent them to find out what they needed. €œBased on how to order renova online what we were hearing, we started doing a number of things,” says Sedoryk.Unemployment in the county had gone from 3.5 percent to 20 percent, causing a tenfold increase in persons with food insecurity. Over the summer, MST's drivers and vehicles that would have otherwise been idle helped Meals on Wheels in Salinas Valley to deliver 8,000 meals to seniors and persons with disabilities.Students living in agricultural communities were having difficulty keeping up with remote learning mandates.

Many had been provided Chromebooks by the state, but they how to order renova online didn’t have Internet access. In response, MST parked its Wi-Fi-enabled commuter buses in rural areas to provide hot spots for them.“We’d set them up in parking lots, and people could come in their cars and piggyback on our signal,” says Sedoryk. €œWe were out there every day during the end of the school year, and we’re ramping it up again as the new school year is starting.”MST donated a vehicle it no longer needed to a veterans group who used it to take homeless veterans to food, medical services and how to order renova online shelter. The transit agency gave another vehicle to a nonprofit that trains at-risk youth to work in the hospitality industry.

Upon discovering that drivers who take disabled veterans to medical appointments had stopped volunteering because they were old, disabled and at high risk of illness, MST found CARES Act funds to take over this service.To support the local agriculture industry, which is critical to the how to order renova online national food supply, MST provided two buses to be converted into mobile skin care products testing facilities, to get testing capability out to the workers in the fields. It offered additional support by arranging for 7,500 masks received from the federal government to be distributed to families by organizations serving farmworker communities.Safety messaging and distanced passengers. (Photo. MST)Constant RecalibrationMST also looked at data to understand how transportation needs had changed.

€œWe used the Slido app (an online survey tool) that you see at conferences to survey our passengers and employees and to resurvey community stakeholders,” says Sedoryk.Community colleges have not yet resumed in-person classes. The people going back to work are in tourist-serving industries such as restaurants and hotels, and the shipping and packing facilities of the Salinas Valley. €œWe’re focusing our services there for now,” says Sedoryk.Service to Santa Clara is currently discontinued due to lack of demand. An additional factor at play is the complications from inconsistent health guidelines what i should buy with renova.

The Santa Clara health officer does not want riders to touch the tape on the bus wall to request a stop, but to call out “next stop.”“I’d rather have people press the button and use the hand sanitizer we have on the bus,” says Sedoryk. €œIn places like Japan and Korea, they discourage talking at all because it spreads aerosol whether you’re wearing a mask or not.”Sedoryk recognizes that this is a “granular” problem, but it only adds to the difficulty of doing his job when there is not a coordinated national response to the renova. €œWHO information contradicts CDC information, which contradicts state health officer information, which contradicts county health officer operation,” he says.While a typical government agency operates in one location, public transit operations move through multiple locations, across different jurisdictions. MST serves Santa Clara, Monterey, Santa Cruz and San Luis Obispo counties, all of which have different rules.

€œAll you can do is the best you can do, right?. € says Sedoryk.Breaking ground for a new operations and maintenance facility. (Photo. MST)Window Opens for Capital ProjectsDespite challenges, MST is making progress.

Sedoryk says that if it weren’t for the renova and the loss of ridership, it would be having a banner year.The agency has broken ground on a new bus operations and maintenance facility, financed through a credit program created under the Transportation Infrastructure Finance and Innovation Act (TIFIA). The district’s 35-year loan could be at a rate as low as 0.75 percent, with no payments for the first five years.In this case, the renova made Sedoryk’s life easier. €œNormally, it would require several trips to Washington to get this financing, but we were able to do this via virtual conferencing and have people from all over the country involved," he says.MST also has been selected as the first transportation district in the state to implement a new program from CalTrans, called the California Integrated Travel Project (Cal-ITP). Sedoryk describes this as “an open loop contactless credit card payment system.” The goal is to to have a fee-less VISA card that could be used to pay fares on any transit system in the state.

Because of the renova, the state has decided to accelerate development and deployment.As with the TIFIA loan, Sedoryk has been able to collaborate on this work with partners in far-flung locations thanks to Web conferencing. €œWe have people from Sacramento, Toronto, Melbourne and New York on these calls,” he says.There’s a long-range social equity aspect to all this, according to Sedoryk. Many low-income residents don’t have bank accounts, which complicates the process of accessing benefits such as food assistance and creates a paperwork burden on both sides. Eventually, such funds could be sent to the card account and the card could be used for purposes such as purchasing groceries.Wi-Fi-enabled commuter buses were parked in communities where students did not have Internet access, to help them manage remote learning assignments.

(Photo. MST)Cash Flow Is a ProblemAs the renova crisis heads into the fall, transit systems are in financial freefall around the country. Big city systems, such as New York City and San Francisco, have seen ridership plummet 90 percent. That has cut into revenue just as states have reduced subsidies in an effort to trim budgets.

The result. Transit agencies across the country are projected to rack up close to $40 billion in budget shortfalls, dwarfing the $2 billion loss inflicted by the 2008 financial crisis, according to The New York Times.MST does not have financial support from local sales taxes, and depends on state sales taxes along with state and federal fuel taxes and farebox revenues to pay for its operations. Partnerships with community colleges, universities, the Monterey Bay Aquarium and military bases also help.But like so many other sources of revenue during the renova, partnership funding has disappeared. €œThe aquarium and the universities and the community colleges and the bases are all closed,” he says.

€œWe’re not getting any money from there.”Thanks to CARES Act funding, Sedoryk is confident he can “sail” through the end of this fiscal year. But depending on the situation at the end of the calendar year, he may be forced to look at reductions in force and restructuring of services.So far, he’s been able to avoid layoffs and has been particularly attentive to keeping his drivers on the payroll — he doesn’t want them taking jobs elsewhere, leaving him short-handed if the recovery gains steam. The California transit association has said that CARES Act funding is $3.1 billion short of what the state needs, with major urban areas like Los Angeles and San Francisco most at risk. At this point, it’s uncertain what another federal stimulus package might bring.“If nothing happens there, and nothing happens in Sacramento, there will be a $3.1 billion contraction in our industry and it will affect different localities differently,” he says.

€œIt really depends on their local economies and local funding streams.”For now, he’s watching state sales tax revenue, and there aren’t enough data points yet for him to see a trend. He’ll know more by the end of the year, and if relief from Congress or the state could be in sight.“The fares that passengers pay cover about 20 percent of our costs, and the rest is picked up by a variety of state and federal funding sources,” says Sedoryk. €œBut there’s only so much a person is going to be able to pay.”It’s too early to know what the numbers will be, but at some point, MST, like other transit providers around the country, may have to reconsider the level of service that it is able to provide with the cash flow available to it.The average taxpayer may not think much about the large section of the population that can’t afford a car, or who are too old or disabled to drive, Sedoryk says. €œThere’s a lot of noise to filter through to get that message out, especially these days.”Strength, Stamina and FlexibilityFor now, MST’s attention is on service and safety.

The agency has 250 workers. There was no confirmed skin care products case among them until recently and the employee in question had not had contact with passengers or the general public. The county health officer has not identified any instances where a member of the public contracted skin care products while an MST passenger.Sedoryk had six district employees go through the contact tracing training developed by Johns Hopkins University. €œOur county is overwhelmed — it’s a small rural county and they weren’t set up to handle this type of emergency,” he says.

€œWe decided to offer our employees help to get them a head start on some of these issues.”The renova has led to greatly improved relationships with the local union, in contrast to the complaints and lawsuits brought against leaders of transit districts in other parts of the country by union members who feel they have been put in danger. Sedoryk and the local union president have been meeting daily. €œThis has forced us to not just talk about problems, but to get to know each other as people and develop a relationship — that’s helped out a lot.”MST’s response to the renova has changed how the community perceives it, particularly those who work in agriculture. €œThey see us providing buses to turn into mobile skin care products labs — not as a stodgy, bureaucratic entitlement program but as a solution that they need.”Better relationships within and without the organization and an enhanced reputation for service help offset the stress caused by conditions and risks that shift day to day, hour by hour.

Sedoryk’s volunteer work as a martial arts instructor, on hold for the time being, has also served him well, he believes.“We focus on strength, stamina and flexibility,” he says. €œThose are good attributes for a martial artist, and they are excellent attributes for an organization — you’ve got to be financially strong, flexible, and you’ve got to be in it for the long haul.” Carl Smith Senior Staff Writercarl.smith@governing.com.