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Thomas A Trikalinos

Publications and source records attributed to Thomas A Trikalinos.

At least 19 recordsLinked to original sources
PubMed2007

Bayesian meta-analysis and meta-regression for gene-disease associations and deviations from Hardy-Weinberg equilibrium.

Violation of Hardy-Weinberg equilibrium (HWE) can raise doubts about the validity of the conclusions from genetic association studies. However, for most currently performed gene-disease association studies, the available tests have low power to detect deviations from HWE. We consider this issue from a meta-analysis perspective, and suggest an approach to estimate the deviation and investigate its relationship with the observed genetic effects. Different degrees of deviation from HWE have previously been proposed as a potential source of heterogeneity across studies. We present a hierarchical meta-regression model that can be applied to test this assumption, using the concept of the fixation coefficient. We re-analyse seven meta-analyses to illustrate these methods. The uncertainty in the genetic effect estimate tended to increase once the fixation coefficient was taken into account. Dependence of the genetic effect size on the deviation from HWE was found in one meta-analysis, while in the other six examples, deviations from HWE did not clearly explain between-study heterogeneity in the genetic effects. The proposed hierarchical models allow the synthesis of data across gene-disease association studies with appropriate consideration of HWE issues.

Alleles↗
PubMed2006

Prosthesis infection: diagnosis after total joint arthroplasty with antigranulocyte scintigraphy with 99mTc-labeled monoclonal antibodies--a meta-analysis.

PURPOSE: To perform a meta-analysis of diagnostic studies regarding the accuracy of antigranulocyte scintigraphy (AGS) with monoclonal antibodies in the identification of prosthesis infection after total hip or knee arthroplasty. MATERIALS AND METHODS: PubMed and EMBASE searches were conducted for the identification of relevant studies. Data on the diagnostic performance of AGS with monoclonal antibodies were combined quantitatively across eligible studies, and the overall sensitivity and specificity, along with summary receiver operating characteristic (ROC) curves and likelihood ratios (LRs), were estimated. The above parameters were evaluated for all patients and for various subgroups among the eligible studies. The reference standard used in the individual studies was accepted. RESULTS: Thirteen eligible studies on nonoverlapping patient groups were included in the meta-analysis; there was a total sample size of 522 implants. The independent random effects summary estimates of sensitivity and specificity were 83% and 80%, respectively. The summary ROC curve estimate for weighted analysis was a sensitivity of 90% for a specificity of 80%. LR syntheses gave a weighted positive LR of 3.99 (95% confidence interval [CI]: 3.13, 5.09) and a weighted negative LR of 0.22 (95% CI: 0.15, 0.34); there was no statistically significant between-study heterogeneity for either metric. Various subgroup analyses did not reveal any statistically significant differences. CONCLUSION: AGS with monoclonal antibodies had a reasonably high discriminating ability to identify prosthesis infection in patients who underwent total joint arthroplasty.

Antibodies, Monoclonal↗
PubMed2006

Extreme between-study homogeneity in meta-analyses could offer useful insights.

OBJECTIVES: Meta-analyses are routinely evaluated for the presence of large between-study heterogeneity. We examined whether it is also important to probe whether there is extreme between-study homogeneity. STUDY DESIGN: We used heterogeneity tests with left-sided statistical significance for inference and developed a Monte Carlo simulation test for testing extreme homogeneity in risk ratios across studies, using the empiric distribution of the summary risk ratio and heterogeneity statistic. A left-sided P=0.01 threshold was set for claiming extreme homogeneity to minimize type I error. RESULTS: Among 11,803 meta-analyses with binary contrasts from the Cochrane Library, 143 (1.21%) had left-sided P-value <0.01 for the asymptotic Q statistic and 1,004 (8.50%) had left-sided P-value <0.10. The frequency of extreme between-study homogeneity did not depend on the number of studies in the meta-analyses. We identified examples where extreme between-study homogeneity (left-sided P-value <0.01) could result from various possibilities beyond chance. These included inappropriate statistical inference (asymptotic vs. Monte Carlo), use of a specific effect metric, correlated data or stratification using strong predictors of outcome, and biases and potential fraud. CONCLUSION: Extreme between-study homogeneity may provide useful insights about a meta-analysis and its constituent studies.

Databases, Bibliographic↗
PubMed2006

Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases.

Accumulated evidence from searching for candidate gene-disease associations of complex diseases can offer some insights as the field moves toward discovery-oriented approaches with massive genome-wide testing. Meta-analyses of 50 non-human lymphocyte antigen gene-disease associations with documented overall statistical significance (752 studies) show summary odds ratios with a median of 1.43 (interquartile range, 1.28-1.65). Many different biases may operate in this field, for both single studies and meta-analyses, and these biases could invalidate some of these seemingly "validated" associations. Studies with a sample size of >500 show a median odds ratio of only 1.15. The median sample size required to detect the observed summary effects in each population addressed in the 752 studies is estimated to be 3,535 (interquartile range, 1,936-9,119 for cases and controls combined). These estimates are steeply inflated in the presence of modest bias. Population heterogeneity, as well as gene-gene and gene-environment interactions, could steeply increase these estimates and may be difficult to address even by very large biobanks and observational cohorts. The one visible solution is for a large number of teams to join forces on the same research platforms. These collaborative studies ideally should be designed up front to also assess more complex gene-gene and gene-environment interactions.

Alleles↗
PubMed2006

Family-based versus unrelated case-control designs for genetic associations.

The most simple and commonly used approach for genetic associations is the case-control study design of unrelated people. This design is susceptible to population stratification. This problem is obviated in family-based studies, but it is usually difficult to accumulate large enough samples of well-characterized families. We addressed empirically whether the two designs give similar estimates of association in 93 investigations where both unrelated case-control and family-based designs had been employed. Estimated odds ratios differed beyond chance between the two designs in only four instances (4%). The summary relative odds ratio (ROR) (the ratio of odds ratios obtained from unrelated case-control and family-based studies) was close to unity (0.96 [95% confidence interval, 0.91-1.01]). There was no heterogeneity in the ROR across studies (amount of heterogeneity beyond chance I(2) = 0%). Differences on whether results were nominally statistically significant (p < 0.05) or not with the two designs were common (opposite classification rates 14% and 17%); this reflected largely differences in power. Conclusions were largely similar in diverse subgroup analyses. Unrelated case-control and family-based designs give overall similar estimates of association. We cannot rule out rare large biases or common small biases.

Case-Control Studies↗
PubMed2006

Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations.

The authors evaluated whether statistically significant violations of Hardy-Weinberg equilibrium (HWE) or the magnitude of deviations from HWE may contribute to the problem of replicating postulated gene-disease associations across different studies. Forty-two gene-disease associations assessed in meta-analyses of 591 studies were examined. Studies with disease-free controls in which HWE was violated gave significantly different results from HWE-conforming studies in five instances. Exclusion of the former studies resulted in loss of statistical significance of the overall meta-analysis in three instances and more than a 10% change in the summary odds ratio in six. Exclusion of HWE-violating studies changed the formal significance of the estimated between-study heterogeneity in three instances. After adjustment for the magnitude of the deviation from HWE for the controls, formal significance was lost in another three instances. Studies adjusted for the magnitude of deviation from HWE tended to become more heterogeneous among themselves, and, for seven gene-disease associations, between-study heterogeneity became significant, while it was not so in the unadjusted analyses. Gene-disease association studies and meta-analyses thereof should routinely scrutinize the potential impact of HWE violations as well as nonsignificant deviations from the exact frequencies expected under HWE. Postulated genetic associations with modest-sized odds ratios and borderline statistical significance may not be robust in such sensitivity analyses.

Bias↗
PubMed2006

Self-reported health in high and very high incomes.

The objective of the present study was to investigate whether self-reported health (SRH), an overall health indicator, continues to improve as individual income increases to very high levels or whether there is a threshold above which this relationship changes direction. We used data from the 2003 US Current Population Survey, focusing on the upper income decile. We modelled the relationship between income and SRH before and after adjustment for other socio-demographic parameters that are known to influence SRH. In the unadjusted model, SRH increased with increasing income up to the threshold of $326,000, above which SRH declined. After adjustment for all major socio-demographic parameters (age, gender, race, education, and marital status), the adjusted curve showed monotonically increasing SRH with increasing income. Adjustment for each of these parameters separately revealed that the threshold effect was lost only after adjusting for education. There were more people with low levels of educational attainment among those receiving more than $500,000 per year, compared to other people in the upper income decile. Increasing income does not always improve SRH. People in the very high income bracket tend to report slightly worse health, which may be explained by their lower education.

Adult↗
PubMed2006

Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study.

BACKGROUND: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. METHODS: Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. FINDINGS: In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. INTERPRETATION: Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.

Aged↗
PubMed2005

Local literature bias in genetic epidemiology: an empirical evaluation of the Chinese literature.

BACKGROUND: Postulated epidemiological associations are subject to several biases. We evaluated whether the Chinese literature on human genome epidemiology may offer insights on the operation of selective reporting and language biases. METHODS AND FINDINGS: We targeted 13 gene-disease associations, each already assessed by meta-analyses, including at least 15 non-Chinese studies. We searched the Chinese Journal Full-Text Database for additional Chinese studies on the same topics. We identified 161 Chinese studies on 12 of these gene-disease associations; only 20 were PubMed-indexed (seven English full-text). Many studies (14-35 per topic) were available for six topics, covering diseases common in China. With one exception, the first Chinese study appeared with a time lag (2-21 y) after the first non-Chinese study on the topic. Chinese studies showed significantly more prominent genetic effects than non-Chinese studies, and 48% were statistically significant per se, despite their smaller sample size (median sample size 146 versus 268, p < 0.001). The largest genetic effects were often seen in PubMed-indexed Chinese studies (65% statistically significant per se). Non-Chinese studies of Asian-descent populations (27% significant per se) also tended to show somewhat more prominent genetic effects than studies of non-Asian descent (17% significant per se). CONCLUSION: Our data provide evidence for the interplay of selective reporting and language biases in human genome epidemiology. These biases may not be limited to the Chinese literature and point to the need for a global, transparent, comprehensive outlook in molecular population genetics and epidemiologic studies in general.

Asian People↗
PubMed2005

Early extreme contradictory estimates may appear in published research: the Proteus phenomenon in molecular genetics research and randomized trials.

BACKGROUND AND OBJECTIVE: Divergent results on the same scientific question generate controversy. We hypothesized that controversial data are attractive to investigators and editors, and thus the most extreme, opposite results would appear very early rather than late, as data accumulate, provided data can be generated rapidly. METHODS: We used data from MEDLINE-indexed meta-analyses of case-control studies on genetic associations (retrospective, hypothesis-generating research with usually rapid turnaround) and meta-analyses of randomized trials of health care interventions (prospective, targeted research that usually takes longer) sampled from the Cochrane Library. Using cumulative meta-analysis, we evaluated how the between-study variance for studies on the same question changed over time and at what point the studies with the most extreme results ever observed had been published. RESULTS: The maximal between-study variance was more likely to be recorded early in the 44 eligible meta-analyses of genetic associations than in the 37 meta-analyses of health care interventions (P = .013). At the time of the first heterogeneity assessment, the most favorable-ever result in support of a specific association was more likely to appear than the least favorable-ever result (22 vs. 10, P = .017); the opposite was seen at the second heterogeneity assessment (15 vs. 5, P = .031). Such a sequence of extreme opposite results was not seen in the clinical trials meta-analyses. The estimated between-study variance decreased over time in genetic association studies (P = .010), but not in clinical trials (P = .30). CONCLUSION: In contrast to prospective trials, a rapid early sequence of extreme, opposite results is frequent in retrospective hypothesis-generating molecular research.

Case-Control Studies↗
PubMed2005

Decision analysis with Markov processes supports early surgery for large-angle infantile esotropia.

PURPOSE: To assess tradeoffs in time spent with aligned visual axes or stereopsis and risked reoperations between three strategies for the treatment of large-angle infantile esotropia: first surgery at 6, 24, or 48 months of age. DESIGN: Decision analysis. METHODS: We simulated three hypothetic cohorts of children with this condition until their eighth year. Potential achievement of stereopsis, the diagnosis of dissociated vertical divergence or inferior oblique overaction, and various complications were modeled. Probability estimates were obtained from a comprehensive literature review. Analyses aimed to determine the strategy that was associated with longer time spent with aligned eyes and/or stereopsis and fewer reoperations. RESULTS: Eight-year-old children are expected to spend 72.6 vs 58.0 vs 37.8 months with aligned eyes and 26.8 vs 9.0 vs 1.5 months with stereopsis and to receive on average 1.76 vs 1.67 vs 1.46 surgeries, if they first underwent operation at 6 vs 24 vs 48 months, respectively. Children at 8 years are expected to have stereopsis at the rate of 36.1% vs 17.2% vs 5.1%, respectively. Operation at 6 months instead of 48 months is expected to yield an additional 9% of total follow-up time in health states with eye alignment and 11% in health states with stereopsis, per 5% increase in risk for extra operations (5% and 7%, respectively, per 5% increase in risk for operation at 6 vs 24 months). Wide-range sensitivity analyses and long-term projections point to the same direction. CONCLUSION: Given the benefit/risk tradeoffs, it is probably warranted to attempt to correct large-angle infantile esotropia as early as possible.

Child↗
PubMed2005

Comparison of the diagnostic accuracy of lymphatic endothelium markers: Bayesian approach.

Tumor lymphatic density is evaluated by means of specific lymphatic endothelium markers, and is a potential predictor of clinically meaningful outcomes. There are many claims on the postulated superiority of some of these markers to identify lymphatics, always in the absence of quantitative data. We therefore compared the diagnostic accuracy of the antibody against podoplanin and the commercially available D2-40, employing Bayesian statistics to account for the absence of a gold standard. We used the pan-endothelial marker CD34 to identify 23,542 distinct blood and lymphatic vessels in sections from 30 formalin-fixed, paraffin-embedded archival tissue blocks of head and neck squamous cell carcinoma specimens. We stained two adjacent sections with podoplanin and D2-40 and identified the continuum of each stained vessel in the sections with a comprehensive method. Overall, 1,864 vessels were stained with both markers, 119 only with podoplanin and 391 only with D2-40. Significantly more vessels with intraluminal red blood cells were stained with D2-40 compared to podoplanin (McNemar's P<0.0001). Both antibodies had extremely high specificity (99.7% (95% credible interval (CrI): 99.5-99.9%) and 98.8% (95% CrI: 98.3-99.5%) for podoplanin and D2-40, respectively) and very high sensitivity (92.6% (95% CrI: 86.1-97.9%) and 97.3% (95% CrI: 94.9-99.2%) for podoplanin and D2-40, respectively). Inferences were qualitatively similar when we took into account in the analyses the possibility that the two tests (antibodies) may be correlated. We calculated that 96.3% (95% CrI: 94.2-98.6%) of the vessels stained with podoplanin and 88.9% (95% CrI: 83.9-95.7%) of the vessels stained with D2-40 were truly lymphatics. These numbers were in agreement with the observed number of stained vessels without intraluminal red blood cells. Our results suggest that both antibodies are excellent lymphatic endothelium markers and that there may be little reason to prefer either of them in most settings.

Antibodies, Monoclonal↗
PubMed2005

Unavailability of online supplementary scientific information from articles published in major journals.

Printed articles increasingly rely on online supplements to store critical scientific information, but such data may eventually become unavailable. We checked the current availability of online supplementary scientific information published in six top-cited scientific journals (Science, Nature, Cell, New England Journal of Medicine, Lancet, Proceedings of the National Academy of Sciences USA). Here we show that in 4.7% and 9.6% of articles with online supplementary material, some of the supplements became unavailable within 2 and 5 years of their publication, respectively.

Access to Information↗
PubMed2005

Comparison of large versus smaller randomized trials for mental health-related interventions.

OBJECTIVE: The extent of disagreement between large and smaller randomized, controlled trials on mental health issues is unknown. The authors aimed to compare the results of large versus smaller trials on mental health-related interventions. METHOD: The authors screened 161 Cochrane and 254 Database of Abstracts of Reviews of Effectiveness systematic reviews on mental health-related interventions. They identified 16 meta-analyses with at least one "large" randomized trial with sample size >800 and at least one "smaller" trial. Effect sizes were calculated separately for large and smaller trials. Heterogeneity was assessed between all studies, within each group (large and smaller studies), and between large and smaller studies. RESULTS: Significant between-study heterogeneity was seen in five meta-analyses. By random-effects calculations, the results of large and smaller trials differed beyond chance in four meta-analyses (25%). In three of these disagreements (effect of day care on IQ, discontinuation of antidepressants, risperidone versus typical antipsychotics for schizophrenia), the smaller trials showed greater effect sizes than the large trials. The inverse was seen in one case (olanzapine versus typical antipsychotics for schizophrenia). With fixed-effects models, disagreements beyond chance occurred in five cases (31%). In four meta-analyses, the effect size differed over twofold between large and smaller trials. Various quality and design parameters were identified as potential explanations for some disagreements. CONCLUSIONS: Large trials are uncommon in mental health. Their results are usually comparable with the results of smaller studies, but major disagreements do occur. Both large and smaller trials should be scrutinized as they offer a continuum of randomized evidence.

Adult↗
PubMed2005

Patellar resurfacing in total knee arthroplasty. A meta-analysis.

BACKGROUND: Patellar resurfacing during total knee arthroplasty remains controversial. We aimed to evaluate the effectiveness of this technique through an evaluation of the current literature. METHODS: We performed a meta-analysis of randomized controlled trials comparing total knee arthroplasties performed with and without patellar resurfacing. Outcomes of interest included the number of reoperations, the prevalence of postoperative anterior knee pain, and the improvement in various knee scores. RESULTS: Ten trials assessing 1223 knees were eligible. The absolute risk of reoperation was reduced by 4.6% (95% confidence interval, 1.9% to 7.3%) in the patellar resurfacing arm (between-study heterogeneity, p < 0.01; I(2) = 60%), implying that one would have to resurface twenty-two patellae (95% confidence interval, fourteen to fifty-two patellae) in order to prevent one reoperation. Patellar resurfacing reduced the absolute risk of postoperative anterior knee pain by 13.8% (95% confidence interval, 6.4% to 21.2%), implying that one would have to resurface seven patellae (95% confidence interval, five to sixteen patellae) in order to prevent one case of postoperative anterior knee pain. Only four trials provided adequate data for a quantitative synthesis of the changes in the various knee scores; on the basis of those four trials, there was no difference in the mean improvement in the knee scores (standardized mean difference, 0.03; 95% confidence interval, -0.50 to 0.56). CONCLUSIONS: The available evidence indicates that patellar resurfacing reduces the risks of reoperation and anterior knee pain after total knee arthroplasty. The observed effects are clinically important despite their modest magnitude. Additional, carefully designed randomized trials are required to strengthen this claim.

Aged↗
PubMed2004

'Racial' differences in genetic effects for complex diseases.

'Racial' differences are frequently debated in clinical, epidemiological and molecular research and beyond. In particular, there is considerable controversy regarding the existence and importance of 'racial' differences in genetic effects for complex diseases influenced by a large number of genes. An important question is whether ancestry influences the impact of each gene variant on the disease risk. Here, we addressed this question by examining the genetic effects for 43 validated gene-disease associations across 697 study populations of various descents. The frequencies of the genetic marker of interest in the control populations often (58%) showed large heterogeneity (statistical variability) between 'races'. Conversely, we saw large heterogeneity in the genetic effects (odds ratios) between 'races' in only 14% of cases. Genetic markers for proposed gene-disease associations vary in frequency across populations, but their biological impact on the risk for common diseases may usually be consistent across traditional 'racial' boundaries.

Gene Frequency↗
PubMed2004

Limited benefit of antiretroviral resistance testing in treatment-experienced patients: a meta-analysis.

OBJECTIVE: To estimate the effectiveness of resistance assessments based on viral sequencing (genotypic antiretroviral resistance testing, GART), phenotypic antiretroviral resistance testing (PART) or virtual PART (vPART) in the management of treatment-experienced HIV-1-infected patients. DESIGN: Meta-analysis of randomized controlled trials comparing treatments aided by GART, PART and vPART, and controls. METHODS: The meta-analysis synthesized data on the proportion of patients with undetectable plasma viral load, the decrease in viral load, and the increase in CD4 cell count at 3 and 6 months after randomization. RESULTS: Ten trials were analyzed (total 2258 participants). Compared with controls, at 3 and 6 months GART increased the proportion of patients with viral load below detection by 11% [95% confidence interval (CI), 6-16], and 10% (95% CI, 5-16), respectively. The difference in viral load change was 0.27 log10 copies/ml (95% CI, 0.11-0.43) and 0.21 log10 copies/ml (95% CI, 0.09-0.34), respectively. However, no improvement was observed in the CD4 cell count at either time point: the difference in CD4 cell count -5.7 x 10(6) cells/l (95% CI, -18.8 to 7.3) and 1.2 x 10(6) cells/l (95% CI, -15.0 to 17.4), respectively, at 3 and 6 months. For PART, there was no clear evidence for any benefit versus no testing (three trials). vPART conferred a small benefit in indirect comparisons versus no testing. CONCLUSION: Evidence for benefit of antiretroviral resistance testing is sparse and limited to small short-term improvements of virologic response, mostly with GART and less with vPART. Current guidelines widely recommending the use of antiretroviral resistance testing in clinical practice are not commensurate with the available evidence.

Anti-HIV Agents↗