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1.  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
2.  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
3.  Patent Foramen Ovale Closure and Medical Treatments for Secondary Stroke Prevention A Systematic Review of Observational and Randomized Evidence 
Background and Purpose
Patients discovered to have a patent foramen ovale in the setting of a cryptogenic stroke may be treated with percutaneous closure, antiplatelet therapy, or anticoagulants. A recent randomized trial (CLOSURE I) did not detect any benefit of closure over medical treatment alone; the optimal medical therapy is also unknown. We synthesized the available evidence on secondary stroke prevention in patients with patent foramen ovale and cryptogenic stroke.
Methods
A MEDLINE search was performed for finding longitudinal studies investigating medical treatment or closure, meta-analysis of incidence rates (IR), and IR ratios of recurrent cerebrovascular events.
Results
Fifty-two single-arm studies and 7 comparative nonrandomized studies and the CLOSURE I trial were reviewed. The summary IR of recurrent stroke was 0.36 events (95% CI, 0.24–0.56) per 100 person-years with closure versus 2.53 events (95% CI, 1.91–3.35) per 100 person-years with medical therapy. In comparative observational studies, closure was superior to medical therapy (IR ratio=0.19; 95% CI, 0.07–0.54). The IR for the closure arm of the CLOSURE I trial was higher than the summary estimate from observational studies; there was no significant benefit of closure over medical treatment (P=0.002 comparing efficacy estimates between observational studies and the trial). Observational and randomized data (9 studies) comparing medical therapies were consistent and suggested that anticoagulants are superior to antiplatelets for preventing stroke recurrence (IR ratio=0.42; 95% CI, 0.18–0.98).
Conclusions
Although further randomized trial data are needed to precisely determine the effects of closure on stroke recurrence, the results of CLOSURE I challenge the credibility of a substantial body of observational evidence strongly favoring mechanical closure over medical therapy.
doi:10.1161/STROKEAHA.111.631648
PMCID: PMC3342835  PMID: 22180252
meta-analysis; observational; studies; patent; foramen; ovale; stroke
4.  An empirical assessment of validation practices for molecular classifiers 
Briefings in Bioinformatics  2011;12(3):189-202.
Proposed molecular classifiers may be overfit to idiosyncrasies of noisy genomic and proteomic data. Cross-validation methods are often used to obtain estimates of classification accuracy, but both simulations and case studies suggest that, when inappropriate methods are used, bias may ensue. Bias can be bypassed and generalizability can be tested by external (independent) validation. We evaluated 35 studies that have reported on external validation of a molecular classifier. We extracted information on study design and methodological features, and compared the performance of molecular classifiers in internal cross-validation versus external validation for 28 studies where both had been performed. We demonstrate that the majority of studies pursued cross-validation practices that are likely to overestimate classifier performance. Most studies were markedly underpowered to detect a 20% decrease in sensitivity or specificity between internal cross-validation and external validation [median power was 36% (IQR, 21–61%) and 29% (IQR, 15–65%), respectively]. The median reported classification performance for sensitivity and specificity was 94% and 98%, respectively, in cross-validation and 88% and 81% for independent validation. The relative diagnostic odds ratio was 3.26 (95% CI 2.04–5.21) for cross-validation versus independent validation. Finally, we reviewed all studies (n = 758) which cited those in our study sample, and identified only one instance of additional subsequent independent validation of these classifiers. In conclusion, these results document that many cross-validation practices employed in the literature are potentially biased and genuine progress in this field will require adoption of routine external validation of molecular classifiers, preferably in much larger studies than in current practice.
doi:10.1093/bib/bbq073
PMCID: PMC3088312  PMID: 21300697
predictive medicine; genes; gene expression; proteomics
5.  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
6.  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
7.  Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography in Response Assessment Before High-Dose Chemotherapy for Lymphoma: A Systematic Review and Meta-Analysis 
The Oncologist  2010;15(7):750-759.
A systematic review and meta-analysis were conducted to better define the prognostic ability of fluorine-18-fluorodeoxyglucose positron emission tomography following salvage chemotherapy before high-dose therapy with autologous stem cell transplantation for relapsed or refractory Hodgkin's lymphoma and aggressive non-Hodgkin's lymphoma. This appears to be an appropriate test to predict treatment failure.
Background.
We conducted a systematic review and meta-analysis to better define the prognostic ability of fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) following salvage chemotherapy for relapsed or refractory Hodgkin's lymphoma (HL) and aggressive non-Hodgkin's lymphoma.
Methods.
We searched PubMed (from inception to January 31, 2010), bibliographies, and review articles without language restriction. Two assessors independently assessed study characteristics, quality, and results. We performed a meta-analysis to determine prognostic accuracy.
Results.
Twelve studies including 630 patients were eligible. The most commonly evaluated histologies were diffuse large B-cell lymphoma (n = 313) and HL (n = 187), which were typically treated with various salvage and high-dose chemotherapy regimens. Studies typically employed nonstandardized protocols and diagnostic criteria. The prognostic accuracy was heterogeneous across the included studies. 18F-FDG PET had a summary sensitivity of 0.69 (95% confidence interval [CI], 0.56–0.81) and specificity of 0.81 (95% CI, 0.73–0.87). The summary estimates were stable in sensitivity analyses. In four studies that performed direct comparisons between PET and conventional restaging modalities, PET had a superior accuracy for predicting treatment outcomes. Subgroup and metaregression analyses did not identify any particular factor to explain the observed heterogeneity.
Conclusion.
18F-FDG PET performed after salvage therapy appears to be an appropriate test to predict treatment failure in patients with refractory or relapsed lymphoma who receive high-dose chemotherapy. Some evidence suggests PET is superior to conventional restaging for this purpose. Given the methodological limitations in the primary studies, prospective studies with standardized methodologies are needed to confirm and refine these promising results.
doi:10.1634/theoncologist.2010-0054
PMCID: PMC2992843  PMID: 20587551
Lymphoma; Positron emission tomography; Fluorodeoxyglucose F18;  Hematopoietic stem cell transplantation; Prognosis; Meta-analysis
8.  Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography in Response Assessment before High-Dose Chemotherapy for Lymphoma: A Systematic Review and Meta-Analysis 
The oncologist  2010;15(7):750-759.
Background
We conducted a systematic review and meta-analysis to better define the prognostic ability of fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) following salvage chemotherapy for relapsed or refractory Hodgkin’s lymphoma (HL) and aggressive Non-Hodgkin’s lymphoma,
Methods
We searched PubMed (from inception to January 31st, 2010), bibliographies, and review articles without language restriction. Two assessors independently assessed study characteristics, quality, and results. We performed a meta-analysis to determine prognostic accuracy.
Results
Twelve studies including 630 patients were eligible. The most commonly evaluated histologies were diffuse large B-cell lymphoma (n=313) and HL (n=187), which were typically treated with various salvage and high-dose chemotherapy regimens. Studies typically employed non-standardized protocols and diagnostic criteria. Prognostic accuracy was heterogeneous across the included studies. 18F-FDG PET had a summary sensitivity of 0.69 (95% CI, 0.56–0.81) and specificity of 0.81 (95% CI, 0.73–0.87). The summary estimates were stable in sensitivity analyses. In 4 studies that performed direct comparisons between PET and conventional restaging modalities, PET had a superior accuracy for predicting treatment outcomes. Subgroup and meta-regression analyses did not identify any particular factor to explain the observed heterogeneity.
Conclusion
18F-FDG PET performed after salvage therapy appears to be an appropriate test to predict treatment failures in patients with refractory or relapsed lymphoma who receive high-dose chemotherapy. Some evidence suggests PET is superior to conventional re-staging for this purpose. Given the methodological limitations in the primary studies, prospective studies with standardized methodologies are needed to confirm and refine these promising results.
doi:10.1634/theoncologist.2010-0054
PMCID: PMC2992843  PMID: 20587551
Lymphoma; Positron-Emission Tomography; Fluorodeoxyglucose F18; Hematopoietic Stem Cell Transplantation; Prognosis; Meta-Analysis

Results 1-8 (8)