Observational studies of the effectiveness of vaccines to prevent COVID-19 are needed to inform real-world use. These are now in planning amid the ongoing rollout of SARS-CoV-2 vaccines globally. While traditional case-control (TCC) and test-negative design (TND) studies feature prominently among strategies used to assess vaccine effectiveness, such studies may encounter important threats to validity. Here we review the theoretical basis for estimation of vaccine direct effects under TCC and TND frameworks, addressing specific natural history parameters of SARS-CoV-2 infection and COVID-19 relevant to these designs. Bias may be introduced by misclassification of cases and controls, particularly when clinical case criteria include common, non-specific indicators of COVID-19. When using diagnostic assays with high analytical sensitivity for SARS-CoV-2 detection, individuals testing positive may be counted as cases even if their symptoms are due to other causes. The TCC may be particularly prone to confounding due to associations of vaccination with healthcare-seeking behavior or risk of infection. The TND reduces but may not eliminate this confounding, for instance if individuals who receive vaccination seek care or testing for less-severe infection. These circumstances indicate the two study designs cannot be applied naively to datasets gathered through public health surveillance or administrative sources. We suggest practical strategies to reduce bias in vaccine effectiveness estimates at the study design and analysis stages.Competing Interest StatementJAL has received grants and consulting fees from Pfizer, Inc. unrelated to this research.Funding StatementThis work was supported by grants R01-AI14812701 from the National Institute for Allergy and Infectious Diseases to NPJ and JAL, and R01-AI139761 from the National Institute for Allergy and Infectious Diseases to NED.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:N/AAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThis is a theoretical study without patient data; equations used to generate the figures appear in the manuscript.

Public health laboratories (PHLs) provide specialized testing services for programs focused on the prevention and control of communicable diseases, early detection of congenital disorders, testing for antimicrobial resistance, and identification of environmental contaminants, among other responsibilities. Although national public health programs and partners provide some funding support, training, and technical resources to PHLs, no dedicated funding is provided from federal programs to fully support comprehensive PHL services across the United States or the underlying infrastructure needed for PHLs to provide and ensure their core functions and capabilities. Public health laboratories have begun to rely on a "community of practice" approach to addressing various service needs by creating and formalizing regional consortia, which are organized groups of geographically clustered PHLs that share expertise, capacities, and capabilities to enhance PHL services. The number of states participating in these networks increased from 13 to 48 from 2015 to 2020, including participation by multiple local PHLs and a territorial PHL. These consortia have enabled strengthening of partnerships and collaboration among PHLs to address regional priorities and challenges. We explore the background and evolution of regional consortia, outline some of their practices and activities, review lessons learned from these successful collaborations, and discuss the positive effect they have on the national public health system.

Laboratory scientists of the US Centers for Disease Control and Prevention (CDC) and other public health laboratories play a fundamental and increasingly complex role in implementing public health programs while ensuring laboratory safety and quality. In 2014, a series of laboratory safety incidents highlighted the need for improvement in federal and other government laboratories. One component of the CDC's response to these incidents was a new career-entry fellowship program, the Laboratory Leadership Service (LLS). Offering laboratory safety and quality training and leadership development for laboratory scientists, LLS is intended to create a pipeline of future laboratory leaders who prioritize quality and safety as a core part of their laboratory science and practice throughout their careers. LLS incorporates evidence-based practices such as the service-learning model, a competency-based curriculum, ongoing stakeholder engagement, and program evaluation to maximize the program's success. This article describes how the CDC created LLS as a workforce development measure to respond to an urgent public health need-to improve laboratory safety and quality-and presents key factors for success in quickly establishing the program.

BACKGROUND: Although uniform colonoscopy screening reduces colorectal cancer (CRC) mortality, risk-based screening may be more efficient. We investigated whether CRC screening based on polygenic risk is a cost-effective alternative to current uniform screening, and if not, under what conditions it would be. METHODS: The MISCAN-Colon model was used to simulate a hypothetical cohort of US 40-year-olds. Uniform screening was modeled as colonoscopy screening at ages 50, 60, and 70 years. For risk-stratified screening, individuals underwent polygenic testing with current and potential future discriminatory performance (area under the receiver-operating curve [AUC] of 0.60 and 0.65-0.80, respectively). Polygenic testing results were used to create risk groups, for which colonoscopy screening was optimized by varying the start age (40-60 years), end age (70-85 years), and interval (1-20 years). RESULTS: With current discriminatory performance, optimal screening ranged from once-only colonoscopy at age 60 years for the lowest-risk group to six colonoscopies at ages 40-80 years for the highest-risk group. While maintaining the same health benefits, risk-stratified screening increased costs by $59 per person. Risk-stratified screening could become cost-effective if the AUC value would increase beyond 0.65, the price per polygenic test would drop to less than $141, or risk-stratified screening would lead to a 5% increase in screening participation. CONCLUSIONS: Currently, CRC screening based on polygenic risk is unlikely to be cost-effective compared with uniform screening. This is expected to change with a greater than 0.05 increase in AUC value, a greater than 30% reduction in polygenic testing costs, or a greater than 5% increase in adherence with screening.

In many areas of health care, we have witnessed a trend toward increased collaborations and partnerships between investigators, teams, programs, institutions, and agencies. As challenges in health care are frequently complex, multifaceted approaches may result in more effective problem-solving than those undertaken by individual groups or facilities. We have seen these approaches in diverse areas, from cross-functional clinical care teams, to large research initiatives that harness the expertise of multiple investigators, to joint ventures and other collaborations among health care organizations. In public health, partnerships are essential for solving the increasingly complex, multifaceted challenges that are encountered. For public health laboratories (PHLs) in particular, collaborations may include a variety of alliances, including PHL networks; partnerships between PHLs and other laboratories (eg, clinical, commercial, environmental, agricultural, veterinary); and partnerships between PHLs and industry, academia, and other public agencies. The numerous benefits of these collaborations include improved service capabilities and efficiencies, as well as enhanced emergency response and disease prevention strategies.

Public health laboratories play a critical role in the detection, prevention and control of diseases. However, reliable laboratory testing continues to be limited in many low- and middle-income countries.1 The 2013–2016 Ebola virus disease outbreak in West Africa provided many examples of how functioning laboratories were needed for disease control and prevention efforts.2 This outbreak highlighted the need for laboratory directors to be able to influence national laboratory policy and to implement national laboratory strategic plans.3,4 Global health initiatives such as The United States President’s Emergency Plan for AIDS Relief (2003),5 the International Health Regulations (IHR; 2005),6 the Global Health Security Agenda (GHSA; 2014)5 and the health-related United Nations sustainable development goal (SDG 3) of the 2030 Agenda for sustainable development (2015),7 all emphasize the need for laboratory systems capable of providing affordable, sustainable and quality laboratory testing. However, despite progress made, only 22% (42/193) of countries reported meeting the IHR core capacities’ requirements for surveillance and response by the June 2012 target date and 34% (65/193) by the November 2015 target date.5,6 The GHSA was launched in 2014 to accelerate progress towards global health preparedness and to support capacity-building efforts. The GHSA objectives and IHR’s core capacities overlap in several areas, including laboratory systems and workforce development.5 | The GHSA Workforce Development Action Package8 outlines the need for rigorous and sustainable training programmes for public health professionals and emphasizes the need for practical, hands-on experience to support public health systems. Ideally, such programmes would help the public health laboratory workforce in gaining the skills and expertise to navigate an often-chaotic environment.9

Transferrin receptor 1 (Tfr1) facilitates cellular iron uptake through receptor-mediated endocytosis of iron-loaded transferrin. It is expressed in the intestinal epithelium but not involved in dietary iron absorption. To investigate its role, we inactivated the Tfr1 gene selectively in murine intestinal epithelial cells. The mutant mice had severe disruption of the epithelial barrier and early death. There was impaired proliferation of intestinal epithelial cell progenitors, aberrant lipid handling, increased mRNA expression of stem cell markers, and striking induction of many genes associated with epithelial-to-mesenchymal transition. Administration of parenteral iron did not improve the phenotype. Surprisingly, however, enforced expression of a mutant allele of Tfr1 that is unable to serve as a receptor for iron-loaded transferrin appeared to fully rescue most animals. Our results implicate Tfr1 in homeostatic maintenance of the intestinal epithelium, acting through a role that is independent of its iron-uptake function.

These competency guidelines outline the knowledge, skills, and abilities necessary for public health laboratory (PHL) professionals to deliver the core services of PHLs efficiently and effectively. As part of a 2-year workforce project sponsored in 2012 by CDC and the Association of Public Health Laboratories (APHL), competencies for 15 domain areas were developed by experts representing state and local PHLs, clinical laboratories, academic institutions, laboratory professional organizations, CDC, and APHL. The competencies were developed and reviewed by approximately 170 subject matter experts with diverse backgrounds and experiences in laboratory science and public health. The guidelines comprise general, cross-cutting, and specialized domain areas and are divided into four levels of proficiency: beginner, competent, proficient, and expert. The 15 domain areas are 1) Quality Management System, 2) Ethics, 3) Management and Leadership, 4) Communication, 5) Security, 6) Emergency Management and Response, 7) Workforce Training, 8) General Laboratory Practice, 9) Safety, 10) Surveillance, 11) Informatics, 12) Microbiology, 13) Chemistry, 14) Bioinformatics, and 15) Research. These competency guidelines are targeted to scientists working in PHLs, defined as governmental public health, environmental, and agricultural laboratories that provide analytic biological and/or chemical testing and testing-related services that protect human populations against infectious diseases, foodborne and waterborne diseases, environmental hazards, treatable hereditary disorders, and natural and human-made public health emergencies. The competencies support certain PHL workforce needs such as identifying job responsibilities, assessing individual performance, and providing a guiding framework for producing education and training programs. Although these competencies were developed specifically for the PHL community, this does not preclude their broader application to other professionals in a variety of different work settings.

PURPOSE: With the accelerated implementation of genomic medicine, health-care providers will depend heavily on professional guidelines and recommendations. Because genomics affects many diseases across the life span, no single professional group covers the entirety of this rapidly developing field. METHODS: To pursue a discussion of the minimal elements needed to develop evidence-based guidelines in genomics, the Centers for Disease Control and Prevention and the National Cancer Institute jointly held a workshop to engage representatives from 35 organizations with interest in genomics (13 of which make recommendations). The workshop explored methods used in evidence synthesis and guideline development and initiated a dialogue to compare these methods and to assess whether they are consistent with the Institute of Medicine report "Clinical Practice Guidelines We Can Trust." RESULTS: The participating organizations that develop guidelines or recommendations all had policies to manage guideline development and group membership, and processes to address conflicts of interests. However, there was wide variation in the reliance on external reviews, regular updating of recommendations, and use of systematic reviews to assess the strength of scientific evidence. CONCLUSION: Ongoing efforts are required to establish criteria for guideline development in genomic medicine as proposed by the Institute of Medicine.

The Global Burden of Disease (GBD) | 2010 team (Dec 15, p 2224)1 | estimate | that 3·2 million deaths per year | are attributable to inactivity. Yet in | The Lancet’s Physical Activity Series | (LPAS), we estimated 5·3 million such | deaths.2 | Why the substantial diff erence? | There are two key methodological | diff erences between the studies. First, | LPAS used data from standardised | surveys to estimate the level of | inactivity in adults in 122 countries, | defi ning inactive people as those not | meeting current guidelines—ie, 150 min | of moderate-intensity physical activity | (about 600 metabolic equivalent [MET] | min) per week. All others were regarded | as active. GBD did not give details | on countries that provided inactivity | data, but defi ned four categories: 0, | 600–3999, 4000–7999, and ≥8000 | MET min per week. It is unclear how | these levels were constructed, since | ≥8000 MET min per week is equivalent | to about 38 h per week of brisk walking

To provide an update on recent revisions to Evaluation of Genomic Applications in Practice and Prevention (EGAPP) methods designed to improve efficiency, and an assessment of the implications of whole genome sequencing for evidence-based recommendation development. Improvements to the EGAPP approach include automated searches for horizon scanning, a quantitative ranking process for topic prioritization, and the development of a staged evidence review and evaluation process. The staged process entails (i) triaging tests with minimal evidence of clinical validity, (ii) using and updating existing reviews, (iii) evaluating clinical validity prior to analytic validity or clinical utility, (iv) using decision modeling to assess potential clinical utility when direct evidence is not available. EGAPP experience to date suggests the following approaches will be critical for the development of evidence based recommendations in the whole genome sequencing era: (i) use of triage approaches and frameworks to improve efficiency, (ii) development of evidence thresholds that consider the value of further research, (iii) incorporation of patient preferences, and (iv) engagement of diverse stakeholders. The rapid advances in genomics present a significant challenge to traditional evidence based medicine, but also an opportunity for innovative approaches to recommendation development. (Genet Med 2013:15(1):14-24.)

BACKGROUND: Hemoglobin A1c (HbA1c) levels diagnose diabetes, predict mortality and are associated with ten single nucleotide polymorphisms (SNPs) in white individuals. Genetic associations in other race groups are not known. We tested the hypotheses that there is race-ethnic variation in 1) HbA1c-associated risk allele frequencies (RAFs) for SNPs near SPTA1, HFE, ANK1, HK1, ATP11A, FN3K, TMPRSS6, G6PC2, GCK, MTNR1B; 2) association of SNPs with HbA1c and 3) association of SNPs with mortality. METHODS: We studied 3,041 non-diabetic individuals in the NHANES (National Health and Nutrition Examination Survey) III. We stratified the analysis by race/ethnicity (NHW: non-Hispanic white; NHB: non-Hispanic black; MA: Mexican American) to calculate RAF, calculated a genotype score by adding risk SNPs, and tested associations with SNPs and the genotype score using an additive genetic model, with type 1 error = 0.05. RESULTS: RAFs varied widely and at six loci race-ethnic differences in RAF were significant (p < 0.0002), with NHB usually the most divergent. For instance, at ATP11A, the SNP RAF was 54% in NHB, 18% in MA and 14% in NHW (p < .0001). The mean genotype score differed by race-ethnicity (NHW: 10.4, NHB: 11.0, MA: 10.7, p < .0001), and was associated with increase in HbA1c in NHW (β = 0.012 HbA1c increase per risk allele, p = 0.04) and MA (β = 0.021, p = 0.005) but not NHB (β = 0.007, p = 0.39). The genotype score was not associated with mortality in any group (NHW: OR (per risk allele increase in mortality) = 1.07, p = 0.09; NHB: OR = 1.04, p = 0.39; MA: OR = 1.03, p = 0.71). CONCLUSION: At many HbA1c loci in NHANES III there is substantial RAF race-ethnic heterogeneity. The combined impact of common HbA1c-associated variants on HbA1c levels varied by race-ethnicity, but did not influence mortality.

TO SOME, the title may seem overstated and to others perhaps ironic, from a total lung health perspective. In 1974, following similar policy changes in many | countries, the World Health Organization (WHO) | Committee on Tuberculosis concluded that case fi nding by mass screening using chest radiography should | be abandoned.1 The WHO Committee placed a strong | emphasis on pursuing a diagnosis among symptomatic patients by sputum smear microscopy because | chest radiography could not be used independently | for diagnosis and was too expensive. Even after such | recommendations, and although it was often criticized | over the decades for its insuffi cient specifi city and sensitivity, the use of chest radiography was maintained | in clinical practice, including in many low-resource | country settings, as part of the diagnostic algorithm. | Chest radiography screening has been used for | prevalence surveys, and more recently it has been revived using targeted approaches among high-risk | populations. Its importance is being recognized again, | including in persons infected with the human immunodefi ciency virus and in children with tuberculosis. | As early as 1992, the WHO’s Essential Technologies | group made recommendations that stressed the role | of and access to chest radiographs (and ultrasound) | at the primary referral level.2 With the advent of digital technology, the operational and expense barriers | are declining for radiography as they are with mycobacterial culture, including in low-resource countries. | In 2006, the International Standards for Tuberculosis | Care carefully defi ned the role of chest radiography | in a clinical context,3 and the International Union | Against Tuberculosis and Lung Disease has also been | active in this area.* The use of mobile digital technology, dedicated expertise, and emerging techniques for | computer-aided reading may help address the challenges with observer error and experience

For decades, newborn screening was the only public health program in the US focused on reducing morbidity, mortality and disability in people affected by genetic conditions. The landscape has changed, however, as evidence-based recommendations are now available for several other genomic applications that can save lives now in the US. Many more such applications are expected to emerge in the next decade. An action plan, based on evidence, provides the impetus for a new paradigm for public health practice in genomics across the lifespan using established multilevel processes as a guide. These include policy interventions, education, clinical interventions, and surveillance. Applying what we know today in hereditary breast/ovarian cancer, Lynch syndrome and familial hypercholesterolemia has the potential to affect thousands of people in the US population every year. Enhanced partnerships between genetic and nongenetic providers of clinical medicine and public health are needed to overcome the challenges for implementing genomic medicine applications both now and in the future.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by abnormally high concentrations of low-density lipoprotein (LDL) cholesterol in the blood, which predisposes affected persons to premature coronary heart disease (CHD) and death. FH is one of the most common inherited disorders and the most common one known to cause premature CHD in people of European descent. The vast majority of people with FH have inherited a single mutation from one parent in either the LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Despite their greatly elevated risk of coronary heart disease, most individuals with FH remain undiagnosed, untreated, or inadequately treated. Cascade screening is a mechanism for identifying people at risk for a genetic condition by a process of systematic family tracing. The National Institute for Health and Clinical Excellence in the United Kingdom recommends cascade screening of close biological relatives of people with a clinical diagnosis of FH in order to effectively identify additional FH patients. The ultimate goal of this testing is to reduce morbidity and mortality from heart disease in persons with FH through early diagnosis and effective disease management. The goal of this article is to outline the available evidence on the clinical validity and utility of cascade screening for FH, while emphasizing the availability, usefulness, and recommendation for including DNA testing (if the disease-causing mutation has been identified).

BACKGROUND: Elevated insulin resistance (IR), triglycerides (TG), body mass index (BMI), and waist circumference (WC) are features of the metabolic syndrome. Although several single-nucleotide polymorphisms (SNPs) associated with these traits have been reported, no study has reported their risk allele frequencies and effect sizes among the major U.S. race/ethnic groups in a nationally representative sample. METHODS: We compared the risk allele frequencies of eight SNPs previously associated with IR, TG, BMI, or WC by race/ethnicity (non-Hispanic white, non-Hispanic black, Mexican American) in 3,030 participants of the National Health and Nutrition Examination Study III (NHANES III). In regression models predicting IR, TG, BMI, WC, and metabolic syndrome, we tested whether the SNP effect sizes on these traits varied by race/ethnicity. RESULTS: Risk allele frequencies varied by race/ethnicity for all eight loci (P<0.0001). The directionality of effects of the variants on IR, TG, WC, and BMI was generally consistent with previous observations and did not differ by race/ethnicity (P>0.001), although our study had low power for this test. No SNP predicted metabolic syndrome in any of the three groups (P>0.05). CONCLUSIONS: The significance of racial/ethnic differences in risk allele frequencies merits consideration if genetic discoveries are to have clinical and public health applicability.

Hepatitis A vaccination has dramatically reduced the incidence of hepatitis A virus (HAV) infection, but new infections continue to occur. To identify human genetic variants conferring a risk for HAV infection among the three major racial/ethnic populations in the United States, we assess associations between 67 genetic variants (single nucleotide polymorphisms, 'SNPs') among 31 candidate genes and serologic evidence of prior HAV infection using a population-based, cross-sectional study of 6779 participants, including 2619 non-Hispanic whites, 2095 non-Hispanic blacks, and 2065 Mexican Americans, enrolled in phase 2 (1991-1994) of the Third National Health and Nutrition Examination Survey. Among the three racial/ethnic groups, the number (weighted frequency) of seropositivity for antibody to HAV (anti-HAV) was 958 (24.9%), 802 (39.2%), and 1540 (71.5%), respectively. No significant associations with any of the 67 SNPs were observed among non-Hispanic whites or non-Hispanic blacks. In contrast, among Mexican Americans, variants in two genes were found to be associated with an increased risk of HAV infection: TGFB1 rs1800469 (adjusted odds ratio [OR] = 1.38; 95% confidence interval [CI], 1.14-1.68; p-value adjusted for false discovery rate [FDR-P] = 0.017) and XRCC1 rs1799782 (OR = 1.57; 95% CI, 1.27-1.94; FDR-P = 0.0007). A decreased risk was found with ABCB1 rs1045642 (OR = 0.79; 95% CI, 0.71-0.89; FDR-P = 0.0007). CONCLUSIONS: Genetic variants in ABCB1, TGFB1, and XRCC1 appear to be associated with susceptibility to HAV infection among Mexican Americans. Replication studies involving larger population samples are warranted. (HEPATOLOGY 2011).

BACKGROUND: The insertion/deletion (I/D) variant (rs4646994) of the angiotensin I-converting enzyme (ACE) gene is one of the most studied polymorphisms in relation to blood pressure and essential hypertension in humans. The evidence to date, however, on an association of this variant with blood pressure-related outcomes has been inconclusive. METHODS: We examined 5,561 participants of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States, who were ≥20 years of age and who self-identified as non-Hispanic white, non-Hispanic black, or Mexican American. Within each race/ethnicity, we assessed genetic associations of the I/D variant with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension, as well as genotype-sex interactions, in four genetic models (additive, dominant, recessive, and codominant). RESULTS: The frequency of the I/D variant differed significantly by race/ethnicity (P = 0.001). Among non-Hispanic blacks, the D allele was significantly associated (P < 0.05) with increased SBP in additive and dominant covariate-adjusted models and was also associated with increased DBP in dominant models when participants taking ACE inhibitors were excluded from the analyses. No other significant associations were observed in any race/ethnic group. Significant genotype-sex interactions were detected among Mexican Americans, for whom positive associations with SBP and hypertension were seen among females, but not males. CONCLUSIONS: This study gives limited support for association of the ACE I/D variant with blood pressure and for sex-specific effects among particular race/ethnic groups, though we cannot rule out the role of genetic or environmental interactions.

OBJECTIVE: To test the association of family history of diabetes with the adoption of diabetes risk-reducing behaviors and whether this association is strengthened by physician advice or commonly known factors associated with diabetes risk. RESEARCH DESIGN AND METHODS: We used cross-sectional data from the 2005-2008 National Health and Nutrition Examination Survey (NHANES) to examine the effects of family history of diabetes on the adoption of selected risk-reducing behaviors in 8,598 adults (aged ≥20 years) without diabetes. We used multiple logistic regression to model three risk reduction behaviors (controlling or losing weight, increasing physical activity, and reducing the amount of dietary fat or calories) with family history of diabetes. RESULTS: Overall, 36.2% of U.S. adults without diabetes had a family history of diabetes. Among them, ~39.8% reported receiving advice from a physician during the past year regarding any of the three selected behaviors compared with 29.2% of participants with no family history (P < 0.01). In univariate analysis, adults with a family history of diabetes were more likely to perform these risk-reducing behaviors compared with adults without a family history. Physician advice was strongly associated with each of the behavioral changes (P < 0.01), and this did not differ by family history of diabetes. CONCLUSIONS: Familial risk for diabetes and physician advice both independently influence the adoption of diabetes risk-reducing behaviors. However, fewer than half of participants with familial risk reported receiving physician advice for adopting these behaviors.

BACKGROUND: Genome-wide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) associated with serum lipid level in populations of European descent. The individual and the cumulative effect of these SNPs on blood lipids are largely unclear for the U.S. population. METHODS AND RESULTS: Using data from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a nationally-representative survey of the U.S. population, we examined associations of 57 GWAS-identified or well-established lipid-related genetic loci with plasma concentrations of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), TC/HDL-C ratio, and non-HDL-C. We used multivariable linear regression to examine single SNP associations and the cumulative effect of multiple SNPs (using a genetic risk score, GRS) on blood lipid levels. Analyses were conducted in adults for each of the three major racial/ethnic groups in the U.S.: non-Hispanic whites (n = 2,296), non-Hispanic blacks (n = 1,699), and Mexican Americans (n = 1,713). Allele frequencies for all SNPs varied significantly by race/ethnicity, except rs3764261 in CETP. Individual SNPs had very small effects on lipid levels, effects that were generally consistent in direction across racial/ethnic groups. More GWAS-validated SNPs were replicated in non-Hispanic whites (< 67%) than in non-Hispanic blacks (< 44%) or Mexican Americans (< 44%). Genetic risk scores were strongly associated with increased lipid levels in each race/ethnic group. The combination of all SNPs into a weighted GRS explained no more than 11% of the total variance in blood lipid levels. CONCLUSIONS: Our findings show that the combined association of SNPs, based on a genetic risk score, was strongly associated with increased blood lipid measures in all major race/ethnic groups in the U.S., which may help in identifying subgroups with a high risk for an unfavorable lipid profile.

IN 2011, tuberculosis (TB) will continue to kill nearly | 2 million people and will cause at least 25% of all | deaths in people living with HIV (PLHIV).1 Some | patients die from TB before they ever present to the | health care system; many more will die because a clinician did not suspect TB, tests failed to diagnose TB | or the patient did not receive correct treatment. | In 2007, the World Health Organization (WHO) | released new guidelines to improve the diagnosis of | smear-negative and extra-pulmonary TB in high HIV | prevalence settings.2 In this month’s issue of the Journal, Wilson et al. report an evaluation of these guidelines in South Africa.3 The likelihood ratios from | their analysis indicate that the WHO guidelines perform only moderately well at ruling out TB and not | so well at ruling in TB. The study’s use of highly sensitive diagnostic tests on multiple specimens strengthens its validity. In accordance with the 2007 WHO | guidelines, the study defi ned a TB suspect as a person with chronic cough. This defi nition has now been | shown to have low sensitivity for TB in PLHIV, leading the WHO to revise its guidelines.4,5 The overall | sensitivity of the 2007 algorithm, therefore, is likely | even lower than the 80% reported in this study.

Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths in the United States. Screening has been shown to be effective in reducing colorectal cancer incidence and mortality. Colonoscopy, sigmoidoscopy, and fecal occult blood tests are all recommended screening tests that have widespread availability. Nevertheless, many people do not receive the evidence-based recommended screening for colorectal cancer. Additional stool-based methods have been developed that offer more options for colorectal cancer screening, including a variety of fecal DNA tests. The only fecal DNA test that is currently available commercially in the United States is ColoSure(TM), which is marketed as a non-invasive test that detects an epigenetic marker (methylated vimentin) associated with colorectal cancer and pre-cancerous adenomas. We examined the published literature on the analytic validity, clinical validity, and clinical utility of ColoSure and we briefly summarized the current colorectal cancer screening guidelines regarding fecal DNA testing. We also addressed the public health implications of the test and contextual issues surrounding the integration of fecal DNA testing into current colorectal cancer screening strategies. The primary goal was to provide a basic overview of ColoSure and identify gaps in knowledge and evidence that affect the recommendation and adoption of the test in colorectal cancer screening strategies.

BACKGROUND: The identification of genetic variants related to blood lipid levels within a large, population-based and nationally representative study might lead to a better understanding of the genetic contribution to serum lipid levels in the major race/ethnic groups in the U.S. population. METHODS: Using data from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), we examined associations between 22 polymorphisms in 13 candidate genes and four serum lipids: high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG). Univariate and multivariable linear regression and within-gene haplotype trend regression were used to test for genetic associations assuming an additive mode of inheritance for each of the three major race/ethnic groups in the United States (non-Hispanic white, non-Hispanic black, and Mexican American). RESULTS: Variants within APOE (rs7412, rs429358), PON1 (rs854560), ITGB3 (rs5918), and NOS3 (rs2070744) were found to be associated with one or more blood lipids in at least one race/ethnic group in crude and adjusted analyses. In non-Hispanic whites, no individual polymorphisms were associated with any lipid trait. However, the PON1 A-G haplotype was significantly associated with LDL-C and TC. In non-Hispanic blacks, APOE variant rs7412 and haplotype T-T were strongly associated with LDL-C and TC; whereas, rs5918 of ITGB3 was significantly associated with TG. Several variants and haplotypes of three genes were significantly related to lipids in Mexican Americans: PON1 in relation to HDL-C; APOE and NOS3 in relation to LDL-C; and APOE in relation to TC. CONCLUSIONS: We report the significant associations of blood lipids with variants and haplotypes in APOE, ITGB3, NOS3, and PON1 in the three main race/ethnic groups in the U.S. population using a large, nationally representative and population-based sample survey. Results from our study contribute to a growing body of literature identifying key determinants of plasma lipoprotein concentrations and could provide insight into the biological mechanisms underlying serum lipid and cholesterol concentrations.

PURPOSE: Epidemiologic studies suggest that several gene variants increase the risk of stroke, and population-based studies help provide further evidence. We identified polymorphisms associated with the prevalence of self-reported stroke in US populations using a representative sample. METHODS: Our sample comprised US adults in the Third National Health and Nutrition Examination (NHANES III) DNA bank. We examined nine candidate gene variants within ACE, F2, F5, ITGA2, MTHFR, and NOS3 for associations with self-reported stroke. We used multivariate regression and Cox proportional hazards models to test the association between these variants and history of stroke. RESULTS: In regression models, the rs4646994 variant of ACE (I/I and I/D genotypes) was associated with higher prevalence adjusted prevalence odds ratio [APOR] = 2.66 [1.28, 5.55] and 2.23 [1.30, 3.85], respectively) compared with the D/D genotype. The heterozygous genotype of MTHFR rs1801131 (A/C) was associated with lower prevalence of stroke (APOR = 0.48 [0.25, 0.92]) compared with A/A and C/C genotypes. For rs2070744 of NOS3, both the C/T genotype (APOR = 1.91 [1.12, 3.27]) and C/C genotype (APOR = 3.31 [1.66, 6.60]) were associated with higher prevalence of stroke compared with the T/T genotype. CONCLUSION: Our findings suggest an association between the prevalence of self-reported stroke and polymorphisms in ACE, MTHFR, and NOS3 in a population-based sample.

BACKGROUND: Albuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease. While the underlying etiology is unclear, chronic, low-grade inflammation is a suspected key factor. Genetic variants within genes involved in inflammatory processes may, therefore, contribute to the development of albuminuria. METHODS: We evaluated 60 polymorphisms within 27 inflammatory response genes in participants from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States. Albuminuria was evaluated as logarithm-transformed albumin-to-creatinine ratio (ACR), as ACR ≥ 30 mg/g, and as ACR above sex-specific thresholds. Multivariable linear regression and haplotype trend analyses were conducted to test for genetic associations in 5321 participants aged 20 years or older. Differences in allele and genotype distributions among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans were tested in additive and codominant genetic models. RESULTS: Variants in several genes were found to be marginally associated (uncorrected P value < 0.05) with log(ACR) in at least one race/ethnic group, but none remained significant in crude or fully-adjusted models when correcting for the false-discovery rate (FDR). In analyses of sex-specific albuminuria, IL1B (rs1143623) among Mexican Americans remained significantly associated with increased odds, while IL1B (rs1143623), CRP (rs1800947) and NOS3 (rs2070744) were significantly associated with ACR ≥ 30 mg/g in this population (additive models, FDR-P < 0.05). In contrast, no variants were found to be associated with albuminuria among non-Hispanic blacks after adjustment for multiple testing. The only variant among non-Hispanic whites significantly associated with any outcome was TNF rs1800750, which failed the test for Hardy-Weinberg proportions in this population. Haplotypes within MBL2, CRP, ADRB2, IL4R, NOS3, and VDR were significantly associated (FDR-P < 0.05) with log(ACR) or albuminuria in at least one race/ethnic group. CONCLUSIONS: Our findings suggest a small role for genetic variation within inflammation-related genes to the susceptibility to albuminuria. Additional studies are needed to further assess whether genetic variation in these, and untested, inflammation genes alter the susceptibility to kidney damage.

The 1999 emergence of West Nile virus | (WNV) in the United States was a vector wake-up call for public health in | this country. By the end of 1999, WNV—an | illness previously confi ned primarily to Africa, the Middle East, and parts of Europe and | Asia—had sickened 62 persons in New York, | seven of whom died. WNV is now endemic | throughout the continental United States. | Although most infections are asymptomatic, | approximately 341,000 cases of West Nile fever (WNF) have occurred, 12,188 infections | have resulted in West Nile neuroinvasive | disease, and 1,164 infections have resulted | in death. Based on a ratio of 140 infections | for every case of West Nile neuroinvasive | disease, CDC projects that 1.7 million WNV | infections have occurred in the United States | since 1999.

The anti-platelet agent clopidogrel bisulfate (sold under the trade name Plavix in the United States) is a widely prescribed medication for the prevention of blood clots in patients with acute coronary syndrome, in those who have suffered other cardiovascular disease-related events such as ischemic stroke, and in patients who are undergoing percutaneous coronary intervention. Response to clopidogrel varies substantially due to genetic and acquired factors. Patients who experience recurrent cardiovascular ischemic or thrombotic events while taking clopidogrel are typically described as non-responsive or resistant. The drug's oxidation is mainly dependent on the cytochrome P450 enzyme 2C19 (CYP2C19). Patients with certain genetic variants in CYP2C19 have been found to have lower levels of the active metabolite, less platelet inhibition, and greater risk of major adverse cardiovascular events such as heart attack, stroke, and death. Testing for CYP2C19 polymorphisms may identify patients who will not respond adequately to the standard clopidogrel regimen and who should, consequently, be given an alternate treatment strategy. This article outlines the evidence concerning pharmacogenetic testing for clopidogrel response, including data on clinical validity and clinical utility, and summarizes the currently available tests marketed for this purpose.

OBJECTIVE: To estimate allele frequencies, marginal and combined effects of novel fasting glucose (FG)-associated SNPs on FG levels and on risk of impaired fasting glucose (IFG) among non-Hispanic white, non-Hispanic black and Mexican American. RESEARCH DESIGN AND METHODS: DNA samples from 3024 adult fasting participants in NHANES III (1991-1994) were genotyped for 16 novel FG-associated SNPs in multiple genes. We determined the allele frequencies and influence of these SNPs alone and in a weighted genetic risk score on FG, homeostasis model-assessed beta-cell function (HOMA-B), and IFG by race/ethnicity while adjusting for age and sex. RESULTS: All allele frequencies varied significantly by race/ethnicity. A weighted genetic risk score, based on the 16 SNPs, was associated with a 0.022 mmol/L (95% confidence interval [CI] 0.009, 0.035), 0.036 mmol/L (95% CI 0.019, 0.052), and 0.033 mmol/L (95% CI 0.020, 0.046) increase in FG levels per risk allele among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively. Adjusted odds ratios for IFG were 1.78 for non-Hispanic whites (95% CI 1.00, 3.17), 2.40 for non-Hispanic blacks (CI 1.07, 5.37), and 2.39 for Mexican American (95% CI 1.37, 4.14) when we compared the highest to lowest quintiles of genetic risk score (p = 0.365 for testing heterogeneity of effect across race/ethnicity). CONCLUSIONS: We conclude that allele frequencies of 16 novel FG-associated SNPs vary significantly by race/ethnicity, but the influence of these SNPs on FG levels, HOMA-B, and IFG were generally consistent across all racial/ethnic groups.

BACKGROUND: Evidence on the associations of emerging cardiovascular disease risk factors/markers with genes may help identify intermediate pathways of disease susceptibility in the general population. This population-based study is aimed to determine the presence of associations between a wide array of genetic variants and emerging cardiovascular risk markers among adult US women. METHODS: The current analysis was performed among the National Health and Nutrition Examination Survey (NHANES) III phase 2 samples of adult women aged 17 years and older (sample size n = 3409). Fourteen candidate genes within ADRB2, ADRB3, CAT, CRP, F2, F5, FGB, ITGB3, MTHFR, NOS3, PON1, PPARG, TLR4, and TNF were examined for associations with emerging cardiovascular risk markers such as serum C-reactive protein, homocysteine, uric acid, and plasma fibrinogen. Linear regression models were performed using SAS-callable SUDAAN 9.0. The covariates included age, race/ethnicity, education, menopausal status, female hormone use, aspirin use, and lifestyle factors. RESULTS: In covariate-adjusted models, serum C-reactive protein concentrations were significantly (P value controlling for false-discovery rate < or = 0.05) associated with polymorphisms in CRP (rs3093058, rs1205), MTHFR (rs1801131), and ADRB3 (rs4994). Serum homocysteine levels were significantly associated with MTHFR (rs1801133). CONCLUSION: The significant associations between certain gene variants with concentration variations in serum C-reactive protein and homocysteine among adult women need to be confirmed in further genetic association studies.

We analyzed the use of RefSNP (rs) numbers to identify genetic variants in abstracts of human genetic association studies published from 2001 through 2007. The proportion of abstracts reporting rs numbers increased rapidly but was still only 15% in 2007. We developed a web-based tool called Variant Name Mapper to assist in mapping historical genetic variant names to rs numbers. The consistent use of rs numbers in abstracts that report genetic associations would enhance knowledge synthesis and translation in this field.