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1.  Empirical evaluation of meta-analytic approaches for nutrient and health outcome dose-response data 
Research synthesis methods  2013;4(3):256-268.
The objective of this study is to empirically compare alternative meta-analytic methods for combining dose-response data from epidemiological studies. We identified meta-analyses of epidemiological studies that analyzed the association between a single nutrient and a dichotomous outcome. For each topic, we performed meta-analyses of odds ratios with five approaches: using extreme exposure categories only, two-step approach (first calculated study-specific effects then combined across studies) using unadjusted data, two-step approach using adjusted data, one-step approach (analyzed all data in one regression model) using unadjusted data, and one-step approach using adjusted data. Meta-analyses including only extreme exposure categories gave consistently bigger effects and wider confidence intervals than meta-analyses using all data. Confidence intervals of effect sizes were generally wider in meta-analyses with the two-step approach, compared with the one-step approach. Meta-analyses using unadjusted data and adjusted data differed, with no consistent pattern of discordance in direction, statistical significance, or magnitude of effect. We discourage using meta-analysis approaches that only use data from extreme exposure categories. The one step approach generally has higher precision than the two-step approach. Sensitivity analysis comparing results between meta-analyses of adjusted and unadjusted data may be useful in indicating the presence of confounding.
doi:10.1002/jrsm.1084
PMCID: PMC4219760  PMID: 25379059
meta-analysis; dose-response data; evidence-based methodology; epidemiological data
2.  Seeing the forests and the trees—innovative approaches to exploring heterogeneity in systematic reviews of complex interventions to enhance health system decision-making: a protocol 
Systematic Reviews  2014;3:88.
Background
To improve quality of care and patient outcomes, health system decision-makers need to identify and implement effective interventions. An increasing number of systematic reviews document the effects of quality improvement programs to assist decision-makers in developing new initiatives. However, limitations in the reporting of primary studies and current meta-analysis methods (including approaches for exploring heterogeneity) reduce the utility of existing syntheses for health system decision-makers. This study will explore the role of innovative meta-analysis approaches and the added value of enriched and updated data for increasing the utility of systematic reviews of complex interventions.
Methods/Design
We will use the dataset from our recent systematic review of 142 randomized trials of diabetes quality improvement programs to evaluate novel approaches for exploring heterogeneity. These will include exploratory methods, such as multivariate meta-regression analyses and all-subsets combinatorial meta-analysis. We will then update our systematic review to include new trials and enrich the dataset by surveying authors of all included trials. In doing so, we will explore the impact of variables not, reported in previous publications, such as details of study context, on the effectiveness of the intervention. We will use innovative analytical methods on the enriched and updated dataset to identify key success factors in the implementation of quality improvement interventions for diabetes. Decision-makers will be involved throughout to help identify and prioritize variables to be explored and to aid in the interpretation and dissemination of results.
Discussion
This study will inform future systematic reviews of complex interventions and describe the value of enriching and updating data for exploring heterogeneity in meta-analysis. It will also result in an updated comprehensive systematic review of diabetes quality improvement interventions that will be useful to health system decision-makers in developing interventions to improve outcomes for people with diabetes.
Systematic review registration
PROSPERO registration no. CRD42013005165
doi:10.1186/2046-4053-3-88
PMCID: PMC4174390  PMID: 25115289
Diabetes care; Knowledge translation; Quality improvement interventions; Complex Interventions; Health system decision-makers; Systematic review; Meta-analysis; Implementation science; Heterogeneity; Hierarchical modeling
3.  Genotype Misclassification in Genetic Association Studies of the rs1042522 TP53 (Arg72Pro) Polymorphism: A Systematic Review of Studies of Breast, Lung, Colorectal, Ovarian, and Endometrial Cancer 
American Journal of Epidemiology  2013;177(12):1317-1325.
Preferential loss of heterozygosity at the rs1042522 locus of the tumor protein 53 gene (TP53) (Arg72Pro) is observed in several tumors. Genetic association studies in oncology often use tumor tissue rather than unaffected tissue for genotyping; in such cases, loss of heterozygosity at the TP53 locus could lead to differential misclassification and could bias estimates of association. We searched multiple databases (through March 8, 2011) for studies investigating the association of Arg72Pro with breast, lung, colorectal, ovarian, or endometrial cancer. Meta-analysis was performed with multilevel Bayesian models. Informative priors for the bias effect were derived from a meta-analysis of the same polymorphism in cervical cancer. Of 160 studies (68 breast, 42 lung, 26 colorectal, 16 ovarian, and 8 endometrial cancer), 22 used tumor tissue as the source of genotyping material for cases. Use of tumor tissue versus other sources of genotyping material was associated with an apparent protective effect of the proline allele (relative odds ratio = 0.78, 95% credible interval: 0.70, 0.88). The probability that use of tumor tissue induced bias was estimated to be higher than 99%. Use of tumor tissue as the source of genotyping material for cases is associated with significant bias in the estimate of the genetic effect in cancer genetic association studies.
doi:10.1093/aje/kws394
PMCID: PMC3676148  PMID: 23729685
Arg72Pro; cancer; meta-analysis; rs1042522; TP53
4.  Dose of Erythropoiesis-Stimulating Agents and Adverse Outcomes in CKD: A Metaregression Analysis 
Background
Targeting higher hemoglobin with erythropoiesis-stimulating agents (ESAs) to treat anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk.
Study Design
Meta-regression analysis examining the association of ESA dose with adverse outcomes, independent of target or achieved hemoglobin.
Setting and Population
Patients with anemia of CKD, irrespective of dialysis status.
Selection Criteria for Studies
We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for treatment of anemia in adults with CKD, with minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis.
Predictors
ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels.
Outcomes
All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression or transfusion requirement.
Results
31 trials (12,956 patients) met criteria. All-cause mortality was associated with higher (per epoetin-alfa–equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10–1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02–1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin (IRR, 1.48; 95% CI, 1.02- 2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin (IRR, 2 1.41; 95% CI, 1.08–1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction but not statistically significant. Higher total-study-period mean ESA dose was also associated with increased rate of hypertension, stroke, and thrombotic events including dialysis vascular access-related thrombotic events.
Limitations
use of study-level aggregated data; use of epoetin alfa–equivalent doses; lack of adjustment for confounders.
Conclusions
In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin.
doi:10.1053/j.ajkd.2012.07.014
PMCID: PMC3525813  PMID: 22921639
erythropoietin; ESA; epoetin; darbepoetin; anemia; CKD; dose; mortality; cardiovascular morbidity; meta-regression
5.  Data extraction from machine-translated versus original language randomized trial reports: a comparative study 
Systematic Reviews  2013;2:97.
Background
Google Translate offers free Web-based translation, but it is unknown whether its translation accuracy is sufficient to use in systematic reviews to mitigate concerns about language bias.
Methods
We compared data extraction from non-English language studies with extraction from translations by Google Translate of 10 studies in each of five languages (Chinese, French, German, Japanese and Spanish). Fluent speakers double-extracted original-language articles. Researchers who did not speak the given language double-extracted translated articles along with 10 additional English language trials. Using the original language extractions as a gold standard, we estimated the probability and odds ratio of correctly extracting items from translated articles compared with English, adjusting for reviewer and language.
Results
Translation required about 30 minutes per article and extraction of translated articles required additional extraction time. The likelihood of correct extractions was greater for study design and intervention domain items than for outcome descriptions and, particularly, study results. Translated Spanish articles yielded the highest percentage of items (93%) that were correctly extracted more than half the time (followed by German and Japanese 89%, French 85%, and Chinese 78%) but Chinese articles yielded the highest percentage of items (41%) that were correctly extracted >98% of the time (followed by Spanish 30%, French 26%, German 22%, and Japanese 19%). In general, extractors’ confidence in translations was not associated with their accuracy.
Conclusions
Translation by Google Translate generally required few resources. Based on our analysis of translations from five languages, using machine translation has the potential to reduce language bias in systematic reviews; however, pending additional empirical data, reviewers should be cautious about using translated data. There remains a trade-off between completeness of systematic reviews (including all available studies) and risk of error (due to poor translation).
doi:10.1186/2046-4053-2-97
PMCID: PMC4226266  PMID: 24199894
Data extraction; Machine translation; Randomized controlled trials; Systematic review
6.  Concordance of randomized and nonrandomized studies was unrelated to translational patterns of two nutrient-disease associations 
Journal of clinical epidemiology  2011;65(1):10.1016/j.jclinepi.2011.07.006.
Objective
There are several examples in nutrition of discordance between the results of observational studies and randomized controlled trials (RCTs). We hypothesized that this discordance is attributable to differences in the translational paths of nutrient–disease associations. Translational paths can be assessed using citation analysis.
Study Design and Setting
We compared the characteristics of citation networks using examples, where RCTs and observational studies agreed (long-chain n-3 polyunsaturated fatty acids [n-3 PUFA]) or disagreed (vitamin E). We performed systematic reviews in each example, constructed citation networks, and compared them with respect to the number of articles and citation relationships between them, as well as the distribution of articles’ hub and authority scores.
Results
For n-3 PUFA, meta-analyses of 14 RCTs and 10 observational studies both suggested that higher intake was associated with lower cardiovascular mortality. For vitamin E, the meta-analysis of 14 RCTs excluded a clinically significant effect, whereas 14 observational studies reported a significant inverse association. The respective citation networks consisted of 392 (n-3 PUFA) and 351 (vitamin E) articles. No differences between the characteristics of the two networks were identified. There was no evidence that the observational studies predated RCTs in the translational process in either example.
Conclusion
In the two examples, citation network characteristics do not predict concordance in the results of observational studies and RCTs.
doi:10.1016/j.jclinepi.2011.07.006
PMCID: PMC3809069  PMID: 22047889
Citation analysis; Network analysis; Translational research; Nutritional associations; Vitamin E; Omega-3 fatty acids
7.  Do observational studies using propensity score methods agree with randomized trials? A systematic comparison of studies on acute coronary syndromes 
European Heart Journal  2012;33(15):1893-1901.
Aims
Randomized controlled trials (RCTs) are the gold standard for assessing the efficacy of therapeutic interventions because randomization protects from biases inherent in observational studies. Propensity score (PS) methods, proposed as a potential solution to confounding of the treatment–outcome association, are widely used in observational studies of therapeutic interventions for acute coronary syndromes (ACS). We aimed to systematically assess agreement between observational studies using PS methods and RCTs on therapeutic interventions for ACS.
Methods and results
We searched for observational studies of interventions for ACS that used PS methods to estimate treatment effects on short- or long-term mortality. Using a standardized algorithm, we matched observational studies to RCTs based on patients’ characteristics, interventions, and outcomes (‘topics’), and we compared estimates of treatment effect between the two designs. When multiple observational studies or RCTs were identified for the same topic, we performed a meta-analysis and used the summary relative risk for comparisons. We matched 21 observational studies investigating 17 distinct clinical topics to 63 RCTs (median = 3 RCTs per observational study) for short-term (7 topics) and long-term (10 topics) mortality. Estimates from PS analyses differed statistically significantly from randomized evidence in two instances; however, observational studies reported more extreme beneficial treatment effects compared with RCTs in 13 of 17 instances (P = 0.049). Sensitivity analyses limited to large RCTs, and using alternative meta-analysis models yielded similar results.
Conclusion
For the treatment of ACS, observational studies using PS methods produce treatment effect estimates that are of more extreme magnitude compared with those from RCTs, although the differences are rarely statistically significant.
doi:10.1093/eurheartj/ehs114
PMCID: PMC3409422  PMID: 22711757
Observational studies; Randomized controlled trials; Acute coronary syndromes; Myocardial infarction; Unstable angina; Propensity score
8.  Electrocardiogram Screening for Disorders That Cause Sudden Cardiac Death in Asymptomatic Children: A Meta-analysis 
Pediatrics  2012;129(4):e999-e1010.
BACKGROUND AND OBJECTIVES:
Pediatric sudden cardiac death (SCD) occurs in an estimated 0.8 to 6.2 per 100 000 children annually. Screening for cardiac disorders causing SCD in asymptomatic children has public appeal because of its apparent potential to avert tragedy; however, performance of the electrocardiogram (ECG) as a screening tool is unknown. We estimated (1) phenotypic (ECG- or echocardiogram [ECHO]-based) prevalence of selected pediatric disorders associated with SCD, and (2) sensitivity, specificity, and predictive value of ECG, alone or with ECHO.
METHODS:
We systematically reviewed literature on hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), and Wolff-Parkinson-White syndrome, the 3 most common disorders associated with SCD and detectable by ECG.
RESULTS:
We identified and screened 6954 abstracts, yielding 396 articles, and extracted data from 30. Summary phenotypic prevalences per 100 000 asymptomatic children were 45 (95% confidence interval [CI]: 10–79) for HCM, 7 (95% CI: 0–14) for LQTS, and 136 (95% CI: 55–218) for Wolff-Parkinson-White. The areas under the receiver operating characteristic curves for ECG were 0.91 for detecting HCM and 0.92 for LQTS. The negative predictive value of detecting either HCM or LQTS by using ECG was high; however, the positive predictive value varied by different sensitivity and specificity cut-points and the true prevalence of the conditions.
CONCLUSIONS:
Results provide an evidence base for evaluating pediatric screening for these disorders. ECG, alone or with ECHO, was a sensitive test for mass screening and negative predictive value was high, but positive predictive value and false-positive rates varied.
doi:10.1542/peds.2011-0643
PMCID: PMC3313631  PMID: 22392183
sudden cardiac death; ECG screening; hypertrophic cardiomyopathy; long QT syndrome; Wolff-Parkinson-White syndrome
9.  Meta-analysis of genome-wide linkage scans for renal function traits 
Background.
Several genome scans have explored the linkage of chronic kidney disease phenotypes to chromosomic regions with disparate results. Genome scan meta-analysis (GSMA) is a quantitative method to synthesize linkage results from independent studies and assess their concordance.
Methods.
We searched PubMed to identify genome linkage analyses of renal function traits in humans, such as estimated glomerular filtration rate (GFR), albuminuria, serum creatinine concentration and creatinine clearance. We contacted authors for numerical data and extracted information from individual studies. We applied the GSMA nonparametric approach to combine results across 14 linkage studies for GFR, 11 linkage studies for albumin creatinine ratio, 11 linkage studies for serum creatinine and 4 linkage studies for creatinine clearance.
Results.
No chromosomal region reached genome-wide statistical significance in the main analysis which included all scans under each phenotype; however, regions on Chromosomes 7, 10 and 16 reached suggestive significance for linkage to two or more phenotypes. Subgroup analyses by disease status or ethnicity did not yield additional information.
Conclusions.
While heterogeneity across populations, methodologies and study designs likely explain this lack of agreement, it is possible that linkage scan methodologies lack the resolution for investigating complex traits. Combining family-based linkage studies with genome-wide association studies may be a powerful approach to detect private mutations contributing to complex renal phenotypes.
doi:10.1093/ndt/gfr255
PMCID: PMC3275782  PMID: 21622988
albuminuria; chronic kidney disease; glomerular filtration rate; linkage scans; meta-analysis
10.  Chapter 8: Meta-analysis of Test Performance When There is a “Gold Standard” 
Journal of General Internal Medicine  2012;27(Suppl 1):56-66.
Synthesizing information on test performance metrics such as sensitivity, specificity, predictive values and likelihood ratios is often an important part of a systematic review of a medical test. Because many metrics of test performance are of interest, the meta-analysis of medical tests is more complex than the meta-analysis of interventions or associations. Sometimes, a helpful way to summarize medical test studies is to provide a “summary point”, a summary sensitivity and a summary specificity. Other times, when the sensitivity or specificity estimates vary widely or when the test threshold varies, it is more helpful to synthesize data using a “summary line” that describes how the average sensitivity changes with the average specificity. Choosing the most helpful summary is subjective, and in some cases both summaries provide meaningful and complementary information. Because sensitivity and specificity are not independent across studies, the meta-analysis of medical tests is fundamentaly a multivariate problem, and should be addressed with multivariate methods. More complex analyses are needed if studies report results at multiple thresholds for positive tests. At the same time, quantitative analyses are used to explore and explain any observed dissimilarity (heterogeneity) in the results of the examined studies. This can be performed in the context of proper (multivariate) meta-regressions.
doi:10.1007/s11606-012-2029-1
PMCID: PMC3364353  PMID: 22648676
gold standard; test performance; meta-analysis
11.  Chapter 10: Deciding Whether to Complement a Systematic Review of Medical Tests with Decision Modeling 
Journal of General Internal Medicine  2012;27(Suppl 1):76-82.
Limited by what is reported in the literature, most systematic reviews of medical tests focus on “test accuracy” (or better, test performance), rather than on the impact of testing on patient outcomes. The link between testing, test results and patient outcomes is typically complex: even when testing has high accuracy, there is no guarantee that physicians will act according to test results, that patients will follow their orders, or that the intervention will yield a beneficial endpoint. Therefore, test performance is typically not sufficient for assessing the usefulness of medical tests. Modeling (in the form of decision or economic analysis) is a natural framework for linking test performance data to clinical outcomes. We propose that (some) modeling should be considered to facilitate the interpretation of summary test performance measures by connecting testing and patient outcomes. We discuss a simple algorithm for helping systematic reviewers think through this possibility, and illustrate it by means of an example.
doi:10.1007/s11606-012-2019-3
PMCID: PMC3364358  PMID: 22648678
decision modeling; test accuracy; test performance; systematic review; medical tests
12.  Chapter 9: Options for Summarizing Medical Test Performance in the Absence of a “Gold Standard” 
Journal of General Internal Medicine  2012;27(Suppl 1):67-75.
The classical paradigm for evaluating test performance compares the results of an index test with a reference test. When the reference test does not mirror the “truth” adequately well (e.g. is an “imperfect” reference standard), the typical (“naïve”) estimates of sensitivity and specificity are biased. One has at least four options when performing a systematic review of test performance when the reference standard is “imperfect”: (a) to forgo the classical paradigm and assess the index test’s ability to predict patient relevant outcomes instead of test accuracy (i.e., treat the index test as a predictive instrument); (b) to assess whether the results of the two tests (index and reference) agree or disagree (i.e., treat them as two alternative measurement methods); (c) to calculate “naïve” estimates of the index test’s sensitivity and specificity from each study included in the review and discuss in which direction they are biased; (d) mathematically adjust the “naïve” estimates of sensitivity and specificity of the index test to account for the imperfect reference standard. We discuss these options and illustrate some of them through examples.
doi:10.1007/s11606-012-2031-7
PMCID: PMC3364362  PMID: 22648677
medical test; diagnostic test; alloy standard
13.  Associations of APOE Gene Polymorphisms with Bone Mineral Density and Fracture Risk: A Meta-Analysis 
Purpose
Apolipoprotein E (APOE) has been studied for its potential role in osteoporosis risk. It is hypothesized that genetic variation at APOE locus, known as E2, E3, and E4, may modulate bone mineral density (BMD) through its effects on lipoproteins and vitamin K transport. The purpose of this study was to determine the association of the APOE-E4 gene polymorphism with bone-related phenotypes.
Methods
We conducted a meta-analysis that combined newly-analyzed individual data from two community-based cohorts, the Framingham Offspring Study (N=1,495) and the Vitamin K Clinical Trial (N=377), with fifteen other eligible published reports. Bone phenotypes included BMD measurements of the hip (total hip and trochanteric and femoral neck sites) and lumbar spine (from the L2 to L4 vertebrae) and prevalence or incidence of vertebral, hip and other fractures.
Results
In sex-pooled analyses, APOE4 carriers had a 0.018 g/cm2 lower weighted mean trochanteric BMD than non carriers (p=0.0002) with no evidence for between-study heterogeneity. A significant association was also detected with lumbar spine BMD (p=0.006); however, inter-study heterogeneity was observed. Associations with lumbar spine and trochanteric BMD were observed predominantly in women and became less significant in meta-regression (p=0.055 and 0.01, respectively). There were no consistent associations of APOE4 genotype with BMD at other skeletal sites or with fracture risk.
Conclusions
Based on these findings, there is insufficient evidence to support a strong and consistent association of the APOE genotype with BMD and fracture incidence.
doi:10.1007/s00198-010-1311-5
PMCID: PMC3144470  PMID: 20533025
Apolipoprotein E; BMD; Fracture; meta-analysis; polymorphism
14.  Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis 
Jama  2008;299(11):1277-1290.
Context
Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.
Objective
To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.
Design and Setting
Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.
Main Outcome Measures
Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.
Results
The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n =25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P=3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P=2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P =3.8 × 10−5) and 8 mg/cm2 (P=5.0×10−6) for the Met667 and Val1330 alleles, respectively (n=25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08–1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01–1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05–1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01–1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.
Conclusions
Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P<10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
doi:10.1001/jama.299.11.1277
PMCID: PMC3282142  PMID: 18349089
15.  Heterogeneity of the Phenotypic Definition of Coronary Artery Disease and Its Impact on Genetic Association Studies 
Background
Variability in phenotypic characterization of coronary artery disease (CAD) may contribute to the heterogeneity of genetic association studies, and more consistency in phenotype definitions might improve replication of genetic associations. We assessed the extent of phenotypic heterogeneity, and quantified its impact, in a large literature sample of association studies.
Methods and Results
We searched for large (≥15 studies) meta-analyses of genetic associations and reviewed all studies included therein. From each primary study, we extracted phenotypic definitions, demographics, study design characteristics and genotypic data. For each association, we assessed the magnitude and heterogeneity of genetic effects within and across CAD phenotypes using meta-analytic methodologies. 965 individual studies investigating 32 distinct variants in 22 genes were included, from which we grouped CAD phenotypes into 3 categories: acute coronary syndromes (ACS) (426 studies, 44%), angiographically-documented disease (323 studies, 34%) and “broad, not otherwise specified CAD” (216 studies, 22%). These clinical phenotypes were overlapping. Subgroup meta-analyses by phenotype showed discordant results but phenotypic classification generally explained small proportions of between-study heterogeneity. Differences between phenotypic groups were minimized for associations with robust statistical support. No CAD phenotype was consistently associated with larger or more homogeneous genetic effects in meta-analyses.
Conclusions
Substantial phenotypic heterogeneity exists in CAD genetic associations, but differences in phenotype definition have a small contribution to between-study heterogeneity. We did not find a consistent effect in terms of the magnitude or homogeneity of summary effects for a specific phenotype to support its preferential use in genetic studies or meta-analyses for CAD.
doi:10.1161/CIRCGENETICS.110.957738
PMCID: PMC3048058  PMID: 21149552
coronary artery disease; myocardial infarction; meta-analysis; genetic association study; phenotype; heterogeneity
16.  Vitamin D and Cardiometabolic Outcomes: A Systematic Review 
Annals of internal medicine  2010;152(5):307-314.
Background
Vitamin D may modify risk of cardiometabolic outcomes (type 2 diabetes, hypertension, or cardiovascular disease).
Purpose
Examine the association of vitamin D status and the effect of vitamin D supplementation on cardiometabolic outcomes in generally healthy adults.
Data Sources
English-language studies in MEDLINE (inception to 4 November 2009) and the Cochrane Clinical Trials Register (4th quarter of 2009).
Study Selection
Eleven reviewers screened citations to identify longitudinal cohort studies reporting associations of vitamin D status and randomized trials of vitamin D supplementation on cardiometabolic outcomes.
Data Extraction
Five independent reviewers extracted data about study conduct, participant characteristics, outcomes, and quality. Differences were resolved by consensus.
Data Synthesis
Thirteen observational studies (14 cohorts) and 18 trials were eligible. Three of 6 analyses (from 4 different cohorts) reported a lower incident diabetes risk in highest versus lowest vitamin D status groups. Seven trials found no effect of vitamin D supplementation on glycemia or incident diabetes. By meta-analysis of 3 cohorts, lower 25-hydroxyvitamin D concentration was associated with incident hypertension (relative risk 1.8; 95% confidence interval [CI] 1.3, 2.4). By meta-analyses of 10 trials, supplementation nonsignificantly reduced systolic blood pressure (weighted mean difference [WMD] −1.9; 95% CI −4.2, 0.4 mm Hg) and did not affect diastolic blood pressure (WMD −0.1; 95% CI −0.7, 0.5 mm Hg). Lower 25-hydroxyvitamin D concentration was associated with incident cardiovascular disease in 5 of 7 analyses (6 cohorts). Four trials found no effect of supplementation on cardiovascular outcomes.
Limitations
Studies included primarily whites. Observational studies were heterogeneous. Several trials reported post hoc analyses.
Conclusions
An association between vitamin D status and cardiometabolic outcomes is uncertain. Trials showed no clinically significant effect of vitamin D supplementation at doses given.
doi:10.1059/0003-4819-152-5-201003020-00009
PMCID: PMC3211092  PMID: 20194237
Vitamin D; diabetes mellitus; hypertension; cardiovascular disease; systematic review; meta-analysis
17.  The Empirical Basis for Determinations of Medical Futility 
Journal of General Internal Medicine  2010;25(10):1083-1089.
BACKGROUND
Decisions to limit treatment in critically ill patients often rely on publications that make claims of futility based on outcome data. Our objective was to systematically review the criteria for futility and the strength of empirical evidence across clinical studies that purport to support or refute claims of futility.
METHODS
The MEDLINE database was searched for relevant articles published between1980 and 2008. Selected studies reported original outcome data in critically ill or cardiac arrest patients and claimed that these data can support or refute decisions to limit treatment in comparable patients. Two authors independently abstracted data on patient characteristics, intervention, outcomes, cost, and design.
RESULTS
Forty seven studies supporting a claim of futility and 45 refuting it were reviewed. Median point estimate for adverse outcome in studies supporting claims of futility was 100% (range 75% to 100%); median lower 95% confidence limit was 91% (range 48% to 99%). Explicit thresholds for futility were missing in 88% of articles. The original criteria for quantitative futility were fulfilled by only 28% of data, and almost exclusively in studies of cardiopulmonary resuscitation (CPR) for cardiac arrest. Substantial statistical overlap was observed between data brought in support of futility claims and data brought to refute them.
CONCLUSIONS
Most studies that purport to guide determinations of futility are based on insufficient data to provide statistical confidence for clinical decision-making. They usually lack explicit a priori thresholds for determination of futility. Many studies draw disparate conclusions based on statistically similar data. In most circumstances these problems preclude confident determinations of futility.
doi:10.1007/s11606-010-1445-3
PMCID: PMC2955478  PMID: 20645019
critically ill; futility; empirical evidence; cardiac arrest
18.  Paraoxonase 1 polymorphisms and ischemic stroke risk: a systematic review and meta-analysis 
Purpose
Paraoxonase 1 (PON1) polymorphisms have been implicated as risk factors for coronary artery disease, but the results of genetic association studies on the related phenotype of ischemic stroke are inconclusive. We performed a meta-analysis of published studies investigating the association between ischemic stroke and two non-synonymous PON1 polymorphisms, rs662 (p.Q192R) and rs854560 (p.L55M) in humans.
Methods
We searched multiple electronic databases through 06/30/2009 for eligible studies. In main analyses we calculated allele-based odds ratios (OR) with random effects models. In secondary analyses we examined dominant and recessive genetic models as well, and performed subgroup and sensitivity analyses.
Results
Regarding rs662, we identified 22 eligible studies (total of 7384 cases/11,074 controls), yielding a summary OR of 1.10 per G allele (95% confidence interval, CI, 1.04–1.17) with no evidence of between-study heterogeneity. For rs854560, 16 eligible studies (total of 5518 cases/8951 controls) yielded a summary OR of 0.97 per T allele (95% CI, 0.90–1.04), again with no evidence of between-study heterogeneity. For both polymorphisms, analyses with dominant and recessive genetic models yielded the same inferences as allele-based comparisons. Subgroup and sensitivity analyses showed similar results.
Conclusion
In agreement with observations in coronary artery disease, PON1 rs662 appears to be associated with a small increase in the risk of ischemic stroke.
doi:10.1097/GIM.0b013e3181ee81c6
PMCID: PMC3081717  PMID: 20856122
paraoxonase 1; PON1; rs662; rs854560; stroke; meta-analysis
20.  Are “Treatment” Bare Metal Stents Superior to “Control” Bare Metal Stents? A meta-analytic approach 
American heart journal  2008;155(4):624-629.e2.
Background
It has been suggested that the benefits of drug-eluting stents compared to bare metal stents (BMS) have been over-estimated in part because target lesion/vessel revascularization (TLR/TVR) rates in the BMS control group of these trials were spuriously high.
Methods
We used meta-analytic techniques to systematically compare clinical event rates among patients treated with BMS in trials where BMS were the experimental (BMSexperimental) rather than the control (BMScontrol) intervention. MEDLINE searches were performed to identify eligible randomized trials comparing either drug-eluting stents with BMScontrol, or BMSexperimental with balloon angioplasty in patients with non-acute coronary artery disease. Trial characteristics and 6 to 12 month rates for death, myocardial infarction, TLR/TVR and major adverse cardiac events (MACE) were extracted and assessed.
Results
Eligible trials yielded 50 BMS cohorts: 19 in the BMScontrol group (4 046 patients) and 31 in the BMSexperimental group (5 068 patients). Summary death and infarction rates did not differ between groups. The summary TLR/TVR rates were 16.2% (95% confidence interval, CI: 13.5, 19.3) versus 13.8% (95% CI: 12.0, 15.7) in BMScontrol versus BMSexperimental groups, respectively (p=0.15). Among 39 BMS cohorts with ≤250 patients, TLR/TVR rates were significantly higher in BMScontrol versus BMSexperimental groups (18.9% [95% CI: 16.0, 22.2] versus 13.7% [95% CI: 11.5, 16.3], p=0.01). There were no between-group differences among larger BMS cohorts (p=0.98).
Conclusions
While overall clinical event rates did not differ in the BMScontrol and the BMSexperimental groups, a higher rate of TVR/TLR was seen in the BMScontrol group among smaller trials.
doi:10.1016/j.ahj.2007.11.005
PMCID: PMC3065934  PMID: 18371468
21.  Therapeutic Innovations and Diminishing Returns 
doi:10.1001/jama.2009.1679
PMCID: PMC3063072  PMID: 19934428
22.  CYP2D6 testing to predict response to tamoxifen in women with breast cancer 
PLoS Currents  2010;2:RRN1176.
Tamoxifen, a selective estrogen receptor modulator, is the standard of care for premenopausal women with estrogen or progesterone receptor-positive breast cancer and a valid option for treating post-menopausal women. However, a substantial number of tamoxifen-treated patients relapse following surgical resection, while others remain disease-free for many years. It appears that the primary effectors of tamoxifen activity are its active metabolites, rather than tamoxifen itself. Cytochrome P450 (CYP) enzymes, CYP2D6 in particular, play a major role in the metabolism of tamoxifen to active metabolites. More than 75 germline CYP2D6 variants have been identified.
A test predicting lack of response to tamoxifen could supplement information used by clinicians and patients in treatment decision-making. For example, physicians and patients may opt to switch to an alternative therapy upfront.
doi:10.1371/currents.RRN1176
PMCID: PMC2940141  PMID: 20877451
23.  The COPD genetic association compendium: a comprehensive online database of COPD genetic associations 
Human Molecular Genetics  2009;19(3):526-534.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. COPD is thought to arise from the interaction of environmental exposures and genetic susceptibility, and major research efforts are underway to identify genetic determinants of COPD susceptibility. With the exception of SERPINA1, genetic associations with COPD identified by candidate gene studies have been inconsistently replicated, and this literature is difficult to interpret. We conducted a systematic review and meta-analysis of all population-based, case–control candidate gene COPD studies indexed in PubMed before 16 July 2008. We stored our findings in an online database, which serves as an up-to-date compendium of COPD genetic associations and cumulative meta-analysis estimates. On the basis of our systematic review, the vast majority of COPD candidate gene era studies are underpowered to detect genetic effect odds ratios of 1.2–1.5. We identified 27 genetic variants with adequate data for quantitative meta-analysis. Of these variants, four were significantly associated with COPD susceptibility in random effects meta-analysis, the GSTM1 null variant (OR 1.45, CI 1.09–1.92), rs1800470 in TGFB1 (0.73, CI 0.64–0.83), rs1800629 in TNF (OR 1.19, CI 1.01–1.40) and rs1799896 in SOD3 (OR 1.97, CI 1.24–3.13). In summary, most COPD candidate gene era studies are underpowered to detect moderate-sized genetic effects. Quantitative meta-analysis identified four variants in GSTM1, TGFB1, TNF and SOD3 that show statistically significant evidence of association with COPD susceptibility.
doi:10.1093/hmg/ddp519
PMCID: PMC2798725  PMID: 19933216
24.  BCR-ABL mutation testing to predict response to tyrosine kinase inhibitors in patients with chronic myeloid leukemia 
PLoS Currents  2011;2:RRN1204.
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). Although randomized evidence demonstrates that imatinib (a commercially available TKI) prolongs event–free survival in patients with CML, some patients develop imatinib intolerance or resistance. In addition, imatinib is less effective in patients who have progressed to more advanced disease stages, such as accelerated phase and blastic phase CML. For these reasons, 2nd generation TKIs that can inhibit the BCR-ABL protein more effectively or target additional disease mechanisms have been developed. Two such drugs have also been approved for clinical use by the FDA, nilotinib and dasatinib. Resistance to TKI treatment is thought to be mediated through various mechanisms, the most common of which is BCR-ABL1 mutations. Testing for mutations in BCR-ABL1 may predict lack of response to imatinib or may inform the choice between alternative TKIs.
doi:10.1371/currents.RRN1204
PMCID: PMC3001986  PMID: 21188137
25.  BCR-ABL mutation testing to predict response to tyrosine kinase inhibitors in patients with chronic myeloid leukemia 
PLoS Currents  2010;2:RRN1204.
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). Although randomized evidence demonstrates that imatinib (a commercially available TKI) prolongs event–free survival in patients with CML, some patients develop imatinib intolerance or resistance. In addition, imatinib is less effective in patients who have progressed to more advanced disease stages, such as accelerated phase and blastic phase CML. For these reasons, 2nd generation TKIs that can inhibit the BCR-ABL protein more effectively or target additional disease mechanisms have been developed. Two such drugs have also been approved for clinical use by the FDA, nilotinib and dasatinib. Resistance to TKI treatment is thought to be mediated through various mechanisms, the most common of which is BCR-ABL1 mutations. Testing for mutations in BCR-ABL1 may predict lack of response to imatinib or may inform the choice between alternative TKIs.
doi:10.1371/currents.RRN1204
PMCID: PMC3001986  PMID: 21188137

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