Search

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

BackgroundIn the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.Methods and ResultsIn the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.ConclusionThe CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called “PRSsum”, forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%., The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Background While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. Results Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10− 7). Conclusions Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.

Background Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP). Methods We assayed immune cells from cryopreserved samples collected at the baseline examination (2000–2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10 years. The analysis provides estimates of the association with blood pressure level. Results The mean age of the MESA participants at baseline was 64 ± 10 years and 53% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40 mmHg [95% confidence interval (CI) 1.34–3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88 mmHg (95% CI 0.82–2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14++CD16−) was associated with 2.01 mmHG (95% CI 0.79–3.24) lower average systolic blood pressure. There were no associations of CD4+ T helper cell subsets with average systolic blood pressure. Conclusion These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells.

Background Cox proportional hazards regression models are used to evaluate associations between exposures of interest and time-to-event outcomes in observational data. When exposures are measured on only a sample of participants, as they are in a case-cohort design, the sampling weights must be incorporated into the regression model to obtain unbiased estimating equations. Methods Robust Cox methods have been developed to better estimate associations when there are influential outliers in the exposure of interest, but these robust methods do not incorporate sampling weights. In this paper, we extend these robust methods, which already incorporate influence weights, so that they also accommodate sampling weights. Results Simulations illustrate that in the presence of influential outliers, the association estimate from the weighted robust method is closer to the true value than the estimate from traditional weighted Cox regression. As expected, in the absence of outliers, the use of robust methods yields a small loss of efficiency. Using data from a case-cohort study that is nested within the Multi-Ethnic Study of Atherosclerosis (MESA) longitudinal cohort study, we illustrate differences between traditional and robust weighted Cox association estimates for the relationships between immune cell traits and risk of stroke. Conclusions Robust weighted Cox regression methods are a new tool to analyze time-to-event data with sampling, e.g. case-cohort data, when exposures of interest contain outliers.

International audience; Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.

National Institutes for Health Research (NIHR), portfolio of translational research of the NIHR Biomedical Research Centre at Barts. London School of Medicine and Dentistry, Queen Mary University of London .

Publisher's version (útgefin grein)., Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes., 23Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA. 24Research Unit-Genetic Epidemiology, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria. 25Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA. 26Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA. 27Department of Radiology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. 28Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto M4G 1R8, Canada. 29Departments of Psychology and Psychiatry, University of Toronto, Toronto M5S 1A1, Canada.

Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.

Publisher's version (útgefin grein) Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = −0.59, p-value = 3.14 × 10−6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology., See Supplementary Note 2 for information on funding sources.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerstrom Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

After an initial episode of atrial fibrillation (AF), AF may recur and become permanent. AF progression is associated with higher morbidity and mortality. Understanding the risk factors for permanent AF could help identify people who would benefit most from interventions.To determine whether body mass index (BMI), diabetes, hypertension, and blood pressure levels are associated with permanent AF among people whose initial AF episode terminated.Population-based inception cohort study.Enrollees in Group Health, an integrated health care system, aged 30-84 with newly diagnosed AF in 2001-2004, whose initial AF terminated within 6 months and who had at least 6 months of subsequent follow-up (N = 1,385).Clinical characteristics were determined from medical records. Permanent AF was determined from medical records and ECG and administrative databases. Permanent AF was defined as AF present on two separate occasions 6-36 months apart, without any documented sinus rhythm between the two occasions. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs).Five-year cumulative incidence of permanent AF was 24 %. Compared with normal BMI (18.5-24.9 kg/m(2)), BMI levels of 25.0-29.9 (overweight), 30.0-34.9 (obese 1), 35.0-39.9 (obese 2), and ≥ 40.0 kg/m(2) (obese 3) were associated with HRs of permanent AF of 1.26 (95 % CI: 0.92, 1.72); 1.35 (0.96, 1.91); 1.50 (0.97, 2.33); and 1.79 (1.13, 2.84), adjusted for age, sex, diabetes, hypertension, blood pressure, coronary heart disease, valvular heart disease, heart failure, and prior stroke. Diabetes, hypertension, and blood pressure were not associated with permanent AF.For people whose initial AF episode terminates, benefits of having lower BMI may include a lower risk of permanent AF. Risk of permanent AF was similar for people with and without diabetes or hypertension and across blood pressure levels.

Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA(2) levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study.We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses.At baseline, Lp-PLA(2) mass did not differ significantly by type 2 diabetes status; however, Lp-PLA(2) activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA(2) (OR 1.68 [95% CI 1.31-2.15] vs OR 1.67 [95% CI 1.30-2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA(2) activity.In this older cohort, differences in Lp-PLA(2) activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.

1992-1993 and annual clinic visits through 1999, CHS was adequately powered to address the study's primary aims. In the US, the Atherosclerosis Risk in Communities (ARIC) Study had a similar design and recruited about 16,000 middle-aged adults from four US sites [2], and the Coronary Artery Risk Development in Young Adults (CARDIA) study included 5,116 subjects aged 18-30 years [3]. Historically, collaboration with the older Framingham Heart Study (FHS) [4], the European Rotterdam Study (RS) [5] or even among the three major US cohorts launched in the 1980s occurred only rarely [6, 7]. The technological innovations that made genome-wide association studies (GWAS) possible have changed the epidemiological landscape. In a review of the first 151 published GWAS papers that evaluated the main effects of genetic variants [8], the median odds ratio was 1.33 (interquartile range, 1.21-1.61). For detecting these smallto-modest effect sizes, few studies have enough participants to provide adequate statistical power, particularly in view of the multiple-testing inherent in GWAS analyses.

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.

Rapid evaluation of phenotypes, SNPs and results through the dbGaP CHARGE Summary Results site

To describe the prevalence of benzodiazepine use, sociodemographic and physical health factors associated with use, dosages taken, and directions for use among individuals aged 65 years and older.Cross-sectional analysis of baseline data from the community-based, prospective observational Cardiovascular Health Study.Medicare eligibility lists from four U.S. communities were used to recruit a representative sample of 5,201 community-dwelling elderly, of which 5,181 participants met all study criteria.Among participants, 511 (9.9%) were taking at least one benzodiazepine, primarily anxiolytics (73%). Benzodiazepines were often prescribed to be taken pro re nata (PRN "as needed"), and 36.5% of prescriptions with instructions to be taken regularly were taken at a dose lower than prescribed. Reported over-the-counter (OTC) sleep aid medication use was 39.2% in benzodiazepine users and 3.3% in nonusers. In a multivariate logistic model, the significant independent correlates of benzodiazepine use were being white (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.0, 3.4), female (OR 1.7; CI 1.4, 2.2), and living in Forsyth County, North Carolina, or Washington County, Maryland, compared with living in Sacramento County, California, or Allegheny County, Pennsylvania (OR 2.3; CI 1.4, 2.2); having coronary heart disease (OR 1.6; CI 1.2, 2.1), health status reported as poor or fair (OR 1.8; CI 1.4, 2.3), self-reported diagnosis of nervous or emotional disorder (OR 6.7; CI 5.1, 8.7), and reporting use of an OTC sleep aid medication (OR 18.7; CI 14.1, 24.7).One in 10 participants reported taking a benzodiazepine, most frequently an anxiolytic, often at a lower dose than prescribed and usually PRN. The high prevalence of OTC sleep aid medication and benzodiazepine use may place the patient at increased risk of psychomotor impairment. Physicians should assess OTC sleep aid medication use when prescribing benzodiazepines.

The calcium antagonist (CA) controversy has been fueled in part by disagreements among scientists and clinicians over the scientific documentation required for drugs used to treat lifelong conditions. From a public health perspective, there are three unanswered questions: (1) Does long-term use of CAs convey health benefits to patients with cardiovascular disease (CVD)? (2) Is the long-term use of CAs safe? (3) Is the use of CAs cost effective? The answers to these questions determine the pertinence of three secondary questions: (4) Do the effects of CAs reflect a class action or are there important differences in health outcomes among subclasses of CAs? (5) Are the short-acting, immediate-release (IR) formulations different from the long-acting or the slow-release (SR) formulations? (6) What is prudent use of CAs? The purpose of this report is to summarize the answers to these questions from a public health perspective. (1) To date, use of CAs has not been documented to reduce the risks of cardiovascular complications of hypertension-stroke, myocardial infarction, congestive heart failure, or renal dysfunction. (2) The clinical trial database is inadequate to determine the long-term safety of CAs. The available data suggest that some formulations of CAs may be associated with an increased risk of cardiovascular and noncardiovascular events. (3) Even if slow-release CAs conveyed a benefit, their cost-effectiveness ratios are unlikely to be acceptable. (4) The non-dihydropyridines may offer an advantage over the dihydropyridines. (5) Whether the slow-release formulations differ from the immediate-release formulations in terms of their health effects remains to be seen. (6) It may be prudent clinically to restrict the use of CAs until proper documentation of long-term safety and efficacy and cost effectiveness is available.

The current paradigm in medicine generally distinguishes between genetic and environmental causes of disease. Although the word "paradigm" has become a commonplace, the theories of Thomas Kuhn have not received much attention in the journals of medicine. Kuhn's structuralist method differs radically from the daily activities of the scientific method itself. Using linguistic theory, this essay offers a structuralist reading of Thomas Kuhn's The Structure of Scientific Revolutions. Our purpose is to highlight the similarities between these structuralist models of science and language. In part, we focus on the logic that enables Kuhn to assert the priority of perception over interpretation in the history of science. To illustrate some of these issues, we refer to the distinction between environmental and genetic causes of disease. While the activity of scientific research results in the revision of concepts in science, the production of significant differences that shape our knowledge is in part a social and linguistic process.

You, or at least many of your colleagues, have failed to provide optimal care to your patients with high blood pressure. The U.S. national recommendations to use low-dose diuretics or beta-blockers as first-line antihypertensive therapy are based on strong evidence from large long-term randomized controlled clinical trials.1 Yet clinical practice seems to be disconnected from the evidence and from these recommendations. In a paper by Knight and colleagues,2 calcium-channel blockers, not low-dose thiazide diuretics, were the most frequently prescribed antihypertensive medication for older adults in the early 1990s. At the same time that new evidence about the effectiveness of low-dose diuretic therapy was published in 1991–1992,3,4 the use of thiazide diuretics declined from 22% in 1991 to 10% in 1995.2 Other authors have described similar trends for the use of anti-hypertensive agents in the 1990s.5,6 Although it may be astonishing that a safe, effective and inexpensive therapy such as low-dose diuretic therapy is used so infrequently, there are a number of potential explanations. An accompanying paper by Smith and colleagues in this issue suggests that teaching evidence-based medicine skills, especially critical appraisal skills, is difficult.7 In this editorial, we would like to focus on two other explanations. Both hypotheses represent an excessive dependence on form rather than content, and we would like to insist on the importance of the content of the outcome and the content of the intervention. In the hierarchy of evidence, the randomized controlled trial reigns as queen. One extreme version of evidence-based medicine suggests that in making clinical decisions, we should only read or rely on information from articles that describe randomized controlled trials, preferably ones that are doubled blinded. The defining feature of a high-quality study is thus its form, the study design as randomized trial. This emphasis on form makes it all too easy to ignore or gloss over the content. What question is the trial posing? For hypertension, which is rarely symptomatic, the critical outcomes and thus the critical questions are the effects of specific drugs in preventing the devastating complications of untreated high blood pressure—stroke, myocardial infarction, heart failure and renal failure. We treat high blood pressure not simply to lower blood pressure, nor to have beneficial effects on cholesterol, nor to have a low incidence of side effects, but mainly to prevent cardiovascular complications of untreated hypertension. Between 1990 and 1995, 14,525 articles were published and indexed as referring to calcium-channel blockers; 8,759 articles had calcium-channel blockers as their main focus; and indeed, 1,430 were randomized controlled trials, almost all short-term studies focusing on outcomes such as blood pressure, side effects, or metabolic factors.8 If practitioners were to over-value treatments or therapies simply because they have been used frequently in randomized trials, they might well have felt confident about prescribing calcium-channel blockers in the early 1990s. Here, the form of the small randomized clinical trial may serve as a marketing tool among practitioners and scientists alike. In this new age of a superabundance of small randomized clinical trials, it is important to remember that if a clinical trial does not provide new information about a clinically important end point, that study, despite the perfection of its form, is not an ethical study.9,10 Even placebo-controlled trials of the effect of anti-hypertensive agents on major disease end points, which answer the question whether hypertension should be treated, are no longer interesting or ethical since the answer is already known.8 An appreciation for the importance of the end point has been late in coming to discussions of evidence-based medicine, especially for the treatment of risk factors such as high blood pressure.11 McAlister and colleagues drew attention to the issue in 1998,12 and the first evidence-based users' guide on surrogate end points did not appear until 1999.13 The recent publication of the ALLHAT trial is a stunning reminder about the importance of staying focused on the critical end points. While alpha blockers are associated with an improved lipid profile—one that should theoretically reduce the risk of cardiovascular events, doxazosin, compared with low-dose diuretic therapy, increased the risk of stroke by 19% and the risk of heart failure by 100%.14 If the content of the outcome is important, so is the content of the intervention. For risk factors such as high blood pressure, early epidemiologic studies suggested that hypertension was associated with cardiovascular complications. Subsequently, intervention studies suggested that blood-pressure-lowering medications reduced the risk of selected outcomes. As physicians, we regularly monitor blood pressure levels during therapy. Trained in physiology, we find it easy or natural to think of our intervention as “blood-pressure lowering.” This inclination is reinforced by the studies that use blood pressure as an end point. The clinical trials that supported the use of anti-hypertensive treatment are not tests of blood-pressure lowering per se; they are trials of specific medications or strategies of treatment. For example, the SHEP trial, which used low-dose diuretics as first-line drug therapy, suggested that this particular treatment strategy reduced the risk of cardiovascular complications in older adults with isolated systolic hypertension.3 If other drugs such as calcium-channel blockers or alpha blockers also lower blood pressure, should we therefore conclude that they also prevent cardiovascular complications? To do so is to generalize the findings from one class of drugs to another class of drug on the basis of the effect on the surrogate end point, blood pressure. This line of reasoning is an argument for doing a clinical trial with another class of drugs rather than using another class of drugs in clinical practice.11 Indeed, the mechanisms of action of anti-hypertensive drugs—diuretics, beta-blockers, alpha-blockers, calcium-channel blockers, and angiotensin-converting enzyme inhibitors—are all so different that it would be astonishing if all classes of antihypertensive drugs had the same effects on all major disease end points. Randomized clinical trials test specific interventions. Insofar as physicians use the same intervention and the same drug and dose in clinical practice as was used in the clinical trial, the findings are directly generalizable to study-eligible patients who would, if asked, have enrolled in the trial. While it is often reasonable to generalize findings for a drug to other populations with the same condition, we prefer to use the specific agent that was evaluated in large long-term trials. Generalization from one proven member of a class of drugs to another unproven member of the same class may be problematic.15 From the point of view of public health, it is prudent to use the proven agents rather than those that are theoretically similar or theoretically superior on the basis of some ancillary drug effect. Moreover, each prescription written for a drug proven to be safe and effective in large long-term trials may function as a vote on behalf of the conduct of trials of sufficient scope and duration to answer key public health questions. One approach to sort through the plethora of randomized clinical trials that are published nowadays is to focus on the study content by asking whether the trial is posing a serious and important scientific question. For the treatments of cardiovascular risk factors such as blood pressure, lipids, and glucose, we need large long-term trials that directly compare therapies or strategies of treatment. ALLHAT is an excellent example of the kind of trial that will help answer the critical questions about antihypertensive treatments. Based on the evidence available to date, if your drug-treated hypertensive patient is not on a low-dose diuretic, why not?

Background Environments conducive to walking may help people avoid sedentary lifestyles and associated diseases. Recent studies developed walkability models combining several built environment characteristics to optimally predict walking. Developing and testing such models with the same data could lead to overestimating one's ability to predict walking in an independent sample of the population. More accurate estimates of model fit can be obtained by splitting a single study population into training and validation sets (holdout approach) or through developing and evaluating models in different populations. We used these two approaches to test whether built environment characteristics near the home predict walking for exercise. Study participants lived in western Washington State and were adult members of a health maintenance organization. The physical activity data used in this study were collected by telephone interview and were selected for their relevance to cardiovascular disease. In order to limit confounding by prior health conditions, the sample was restricted to participants in good self-reported health and without a documented history of cardiovascular disease. Results For 1,608 participants meeting the inclusion criteria, the mean age was 64 years, 90 percent were white, 37 percent had a college degree, and 62 percent of participants reported that they walked for exercise. Single built environment characteristics, such as residential density or connectivity, did not significantly predict walking for exercise. Regression models using multiple built environment characteristics to predict walking were not successful at predicting walking for exercise in an independent population sample. In the validation set, none of the logistic models had a C-statistic confidence interval excluding the null value of 0.5, and none of the linear models explained more than one percent of the variance in time spent walking for exercise. We did not detect significant differences in walking for exercise among census areas or postal codes, which were used as proxies for neighborhoods. Conclusion None of the built environment characteristics significantly predicted walking for exercise, nor did combinations of these characteristics predict walking for exercise when tested using a holdout approach. These results reflect a lack of neighborhood-level variation in walking for exercise for the population studied.