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Biomedical subjects

Julian P T Higgins

Publications and source records attributed to Julian P T Higgins.

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

Bayesian synthesis of epidemiological evidence with different combinations of exposure groups: application to a gene-gene-environment interaction.

Meta-analysis to investigate the joint effect of multiple factors in the aetiology of a disease is of increasing importance in epidemiology. This task is often challenging in practice, because studies typically concentrate on studying the effect of only one exposure, sometimes may report the interaction between two exposures, but rarely address more complex interactions that involve more than two exposures. In this paper, we develop a meta-analysis framework that combines estimates from studies of multiple exposures. A key development is an approach to combining results from studies that report information on any subset or combination of the full set of exposures. The model requires assumptions to be made about the prevalence of the specific exposures. We discuss several possible model specifications and prior distributions, including information internal and external to the meta-analysis data set, and using fixed-effect and random-effects meta-analysis assumptions. The methodology is implemented in an original meta-analysis of studies relating the risk of bladder cancer to two N-acetyltransferase genes, NAT1 and NAT2, and smoking status.

Arylamine N-Acetyltransferase↗
PubMed2006

Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review.

OBJECTIVE: To review systematically the evidence for an effect of long chain and shorter chain omega 3 fatty acids on total mortality, cardiovascular events, and cancer. DATA SOURCES: Electronic databases searched to February 2002; authors contacted and bibliographies of randomised controlled trials (RCTs) checked to locate studies. REVIEW METHODS: Review of RCTs of omega 3 intake for (3) 6 months in adults (with or without risk factors for cardiovascular disease) with data on a relevant outcome. Cohort studies that estimated omega 3 intake and related this to clinical outcome during at least 6 months were also included. Application of inclusion criteria, data extraction, and quality assessments were performed independently in duplicate. RESULTS: Of 15,159 titles and abstracts assessed, 48 RCTs (36,913 participants) and 41 cohort studies were analysed. The trial results were inconsistent. The pooled estimate showed no strong evidence of reduced risk of total mortality (relative risk 0.87, 95% confidence interval 0.73 to 1.03) or combined cardiovascular events (0.95, 0.82 to 1.12) in participants taking additional omega 3 fats. The few studies at low risk of bias were more consistent, but they showed no effect of omega 3 on total mortality (0.98, 0.70 to 1.36) or cardiovascular events (1.09, 0.87 to 1.37). When data from the subgroup of studies of long chain omega 3 fats were analysed separately, total mortality (0.86, 0.70 to 1.04; 138 events) and cardiovascular events (0.93, 0.79 to 1.11) were not clearly reduced. Neither RCTs nor cohort studies suggested increased risk of cancer with a higher intake of omega 3 (trials: 1.07, 0.88 to 1.30; cohort studies: 1.02, 0.87 to 1.19), but clinically important harm could not be excluded. CONCLUSION: Long chain and shorter chain omega 3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer.

Cardiovascular Diseases↗
PubMed2006

Five glutathione s-transferase gene variants in 23,452 cases of lung cancer and 30,397 controls: meta-analysis of 130 studies.

BACKGROUND: Glutathione S-transferases (GSTs) are known to abolish or reduce the activities of intracellular enzymes that help detoxify environmental carcinogens, such as those found in tobacco smoke. It has been suggested that polymorphisms in the GST genes are risk factors for lung cancer, but a large number of studies have reported apparently conflicting results. METHODS AND FINDINGS: Literature-based meta-analysis was supplemented by tabular data from investigators of all relevant studies of five GST polymorphisms (GSTM1 null, GSTT1 null, I105V, and A114V polymorphisms in the GSTP1 genes, and GSTM3 intron 6 polymorphism) available before August, 2005, with investigation of potential sources of heterogeneity. Included in the present meta-analysis were 130 studies, involving a total of 23,452 lung cancer cases and 30,397 controls. In a combined analysis, the relative risks for lung cancer of the GSTM1 null and GSTT1 null polymorphisms were 1.18 (95% confidence interval [CI]: 1.14-1.23) and 1.09 (95% CI: 1.02-1.16), respectively, but in the larger studies they were only 1.04 (95% CI: 0.95-1.14) and 0.99 (95% CI: 0.86-1.11), respectively. In addition to size of study, ethnic background was a significant source of heterogeneity among studies of the GSTM1 null genotype, with possibly weaker associations in studies of individuals of European continental ancestry. Combined analyses of studies of the 105V, 114V, and GSTM3*B variants showed no significant overall associations with lung cancer, yielding per-allele relative risks of 1.04 (95% CI: 0.99-1.09), 1.15 (95% CI: 0.95-1.39), and 1.05 (95% CI: 0.89-1.23), respectively. CONCLUSIONS: The risk of lung cancer is not strongly associated with the I105V and A114V polymorphisms in the GSTP1 gene or with GSTM3 intron 6 polymorphism. Given the non-significant associations in the larger studies, the relevance of the weakly positive overall associations with the GSTM1 null and the GSTT1 null polymorphisms is uncertain. As lung cancer has important environmental causes, understanding any genetic contribution to it in general populations will require the conduct of particularly large and comprehensive studies.

Carcinogens↗
PubMed2006

Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls.

BACKGROUND: Variants of certain haemostatic genes (such as that encoding factor V Leiden) are involved in the development of venous thrombosis, but studies of such variants in coronary disease have reported apparently conflicting results. We did meta-analyses on seven such haemostatic genetic variants for which the available evidence on each comprises at least 5000 coronary disease cases and at least 5000 controls. METHODS: Meta-analyses were done of 191 studies in relation to factor V G1691A (ie, factor V Leiden), factor VII G10976A, prothrombin G20210A, plasminogen activator inhibitor-1 (PAI-1) [-675] 4G/5G, and three platelet glycoprotein (GP) receptor variants (GPIa C807T, GPIbalpha T[-5]C, GPIIIa C1565T), involving a total of 66 155 coronary disease cases and 91 307 controls. We explored potential sources of heterogeneity. FINDINGS: In a combined analysis of all studies, the per-allele relative risks (RR) for coronary disease of factor V 1691A and of prothrombin 20210A were 1.17 (95% CI 1.08-1.28) and 1.31 (1.12-1.52), respectively. Combined analyses of studies of the PAI-1 [-675] 4G variant yielded a per-allele relative risk for coronary disease of 1.06 (1.02-1.10), but there was an indication of publication bias in these studies. Combined analyses of the factor VII 10976A, GPIa 807T, GPIbalpha [-5]C, and GPIIIa 1565T variants showed no significant overall associations with coronary disease, yielding per-allele RRs of 0.97 (0.91-1.04), 1.02 (0.97-1.08), 1.05 (0.96-1.13), and 1.03 (0.98-1.07), respectively. INTERPRETATION: The 1691A variant of the factor V gene and the 20210A variant of the prothrombin gene, both of which increase circulating thrombin generation, might each be moderately associated with the risk of coronary disease. Further studies are merited to assess these associations in greater detail (including any gene-gene and gene-environment interactions) and to determine any implications with regard to potential therapies designed to reverse patients' prothrombotic phenotype, such as selective plasma factor V or factor Xa inhibition.

Blood Coagulation Factors↗
PubMed2006

A road map for efficient and reliable human genome epidemiology.

Networks of investigators have begun sharing best practices, tools and methods for analysis of associations between genetic variation and common diseases. A Network of Investigator Networks has been set up to drive the process, sponsored by the Human Genome Epidemiology Network. A workshop is planned to develop consensus guidelines for reporting results of genetic association studies. Published literature databases will be integrated, and unpublished data, including 'negative' studies, will be captured by online journals and through investigator networks. Systematic reviews will be expanded to include more meta-analyses of individual-level data and prospective meta-analyses. Field synopses will offer regularly updated overviews.

Databases, Factual↗
PubMed2005

Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis.

Accurate risk estimates for individuals with a family history of colorectal cancer are important for surveillance strategies. We systematically reviewed the literature on familial risks of colorectal cancer to determine relative risk estimates for categories of family history and translated these relative risk estimates into absolute risk estimates. A random-effects meta-analysis pooled the effect estimates from individual studies and actuarial life-table methods converted relative into absolute risks. Fifty-nine studies were identified including 47 that estimated the relative risk of developing colorectal cancer given at least one affected first-degree relative. The pooled risk estimate was 2.24 (95% CI 2.06 to 2.43) which rose to 3.97 (95% CI 2.60 to 6.06) with at least two affected relatives. A population lifetime risk of 1.8% for a 50-year old increased to 3.4% (95% CI 2.8 to 4.0) with at least one affected relative or 6.9% (95% CI 4.5 to 10.4) with two or more. Accurate absolute risk estimates show how cancer risks vary over time, particularly by pattern of family history and age of individual at-risk.

Age Factors↗
PubMed2005

A network of investigator networks in human genome epidemiology.

The task of identifying genetic determinants for complex, multigenetic diseases is hampered by small studies, publication and reporting biases, and lack of common standards worldwide. The authors propose the creation of a network of networks that include groups of investigators collecting data for human genome epidemiology research. Twenty-three networks of investigators addressing specific diseases or research topics and representing several hundreds of teams have already joined this initiative. For each field, the authors are currently creating a core registry of teams already participating in the respective network. A wider international registry will include all other teams also working in the same field. Independent investigators are invited to join the registries and existing networks and to join forces in creating additional ones as needed. The network of networks aims to register these networks, teams, and investigators; be a resource for information about or connections to the many networks; offer methodological support; promote sound design and standardization of analytical practices; generate inclusive overviews of fields at large; facilitate rapid confirmation of findings; and avoid duplication of effort.

Databases, Genetic↗
PubMed2005

Obstacles and opportunities in meta-analysis of genetic association studies.

Genetic association studies have the potential to advance our understanding of genotype-phenotype relationships, especially for common, complex diseases where other approaches, such as linkage, are less powerful. Unfortunately, many reported studies are not replicated or corroborated. This lack of reproducibility has many potential causes, relating to study design, sample size, and power issues, and from sources of true variability among populations. Genetic association studies can be considered as more similar to randomized trials than other types of observational epidemiological studies because of "Mendelian randomization" (Mendel's second law). The rationale and methodology for synthesizing randomized trials is highly relevant to the meta-analysis of genetic association studies. Nevertheless, there are a number of obstacles to overcome when performing such meta-analyses. In this review, the impacts of Type I error, lack of power, and publication and reporting biases are explored, and the role of multiple testing is discussed. A number of special features of association studies are especially pertinent, because they may lead to true variability among study results. These include population dynamics and structure, linkage disequilibrium, conformity to Hardy-Weinberg Equilibrium, bias, population stratification, statistical heterogeneity, epistatic and environmental interactions, and the choice of statistical models used in the analysis. Approaches to dealing with these issues are outlined. The supreme importance of complete and consistent study reporting and of making data readily available is also highlighted as a prerequisite for sound meta-analysis. We believe that systematic review and meta-analysis has an important role to play in understanding genetic association studies and should help us to separate the wheat from the chaff.

Epistasis, Genetic↗
PubMed2005

Meta-analysis of individual patient data from randomized trials: a review of methods used in practice.

BACKGROUND: Meta-analyses based on individual patient data (IPD) are regarded as the gold standard for systematic reviews. However, the methods used for analysing and presenting results from IPD meta-analyses have received little discussion. METHODS: We review 44 IPD meta-analyses published during the years 1999-2001. We summarize whether they obtained all the data they sought, what types of approaches were used in the analysis, including assumptions of common or random effects, and how they examined the effects of covariates. RESULTS: Twenty-four out of 44 analyses focused on time-to-event outcomes, and most analyses (28) estimated treatment effects within each trial and then combined the results assuming a common treatment effect across trials. Three analyses failed to stratify by trial, analysing the data is if they came from a single mega-trial. Only nine analyses used random effects methods. Covariate-treatment interactions were generally investigated by subgrouping patients. Seven of the meta-analyses included data from less than 80% of the randomized patients sought, but did not address the resulting potential biases. CONCLUSIONS: Although IPD meta-analyses have many advantages in assessing the effects of health care, there are several aspects that could be further developed to make fuller use of the potential of these time-consuming projects. In particular, IPD could be used to more fully investigate the influence of covariates on heterogeneity of treatment effects, both within and between trials. The impact of heterogeneity, or use of random effects, are seldom discussed. There is thus considerable scope for enhancing the methods of analysis and presentation of IPD meta-analysis.

Data Interpretation, Statistical↗
PubMed2004

Controlling the risk of spurious findings from meta-regression.

Meta-regression has become a commonly used tool for investigating whether study characteristics may explain heterogeneity of results among studies in a systematic review. However, such explorations of heterogeneity are prone to misleading false-positive results. It is unclear how many covariates can reliably be investigated, and how this might depend on the number of studies, the extent of the heterogeneity and the relative weights awarded to the different studies. Our objectives in this paper are two-fold. First, we use simulation to investigate the type I error rate of meta-regression in various situations. Second, we propose a permutation test approach for assessing the true statistical significance of an observed meta-regression finding. Standard meta-regression methods suffer from substantially inflated false-positive rates when heterogeneity is present, when there are few studies and when there are many covariates. These are typical of situations in which meta-regressions are routinely employed. We demonstrate in particular that fixed effect meta-regression is likely to produce seriously misleading results in the presence of heterogeneity. The permutation test appropriately tempers the statistical significance of meta-regression findings. We recommend its use before a statistically significant relationship is claimed from a standard meta-regression analysis.

BCG Vaccine↗
PubMed2004

Meta-analysis in occupational epidemiology: a review of practice.

OBJECTIVES: To describe past practice in meta-analyses found in occupational epidemiology, identifying the major issues that should be considered by researchers planning a meta-analysis in this setting. METHODS: An electronic search of relevant online databases was undertaken. Papers were included in the review if they contained a statistical synthesis of risks in an occupational health setting. RESULTS: Sixty reports of meta-analyses were identified, mostly in cancer. The number of meta-analyses has increased consistently over the last 20 years. A majority of studies focused on a mean overall effect, although more than half of them also investigated heterogeneity of results. Both fixed effect and random effects meta-analysis models were employed, the former more often, and in eight studies used despite a statistically significant test for heterogeneity. A large proportion of the meta-analyses included different effect measures in the statistical synthesis, for example, including standardized mortality ratios (SMRs) and standardized incidence ratios. Most meta-analyses limited to a single type of effect measure focused on SMRs. The vast majority of meta-analyses combined all studies regardless of variation in the extent of information on exposures. CONCLUSIONS: Meta-analyses in occupational epidemiology should properly explore and incorporate heterogeneity among studies. The meta-SMR is an important construct in this field, evidenced by a large proportion of cohort studies in the meta-analyses we identified. Controversy remains over the definition and validity of the meta-SMR. In addition, several other issues, notably dealing with heterogeneity in exposure, warrant further consideration.

Bias↗
PubMed2003

Relative efficacy of differential methods of dietary advice: a systematic review.

BACKGROUND: Dietary advice to lower blood cholesterol may be given by a variety of means. The relative efficacy of the different methods is unknown. OBJECTIVE: The objective was to assess the effects of dietary advice given by dietitians compared with advice from other health professionals, or self-help resources, in reducing blood cholesterol in adults. DESIGN: We performed a systematic review, identifying potential studies by searching the electronic databases of the Cochrane Library, MEDLINE, EMBASE, CINAHL, Human Nutrition, Science Citation Index, and Social Sciences Citation Index. We also hand-searched relevant conference proceedings, reference lists in trial reports, and review articles. Finally, we contacted experts in the field. The selection criteria included randomized trials of dietary advice given by dietitians compared with advice given by other health professionals or self-help resources. The main outcome was difference in blood cholesterol between the dietitian group compared with other intervention groups. Inclusion decisions and data extraction were duplicated. RESULTS: Eleven studies with 12 comparisons met the inclusion criteria. Four studies compared dietitians with doctors, 7 with self-help resources, and 1 with nurses. Participants receiving advice from dietitians experienced a greater reduction in blood total cholesterol than those receiving advice from doctors (-0.25 mmol/L, 95% CI -0.37, -0.12 mmol/L). There was no statistically significant difference in change in blood cholesterol between dietitians and self-help resources (-0.10 mmol/L, 95% CI -0.22, 0.03 mmol/L). CONCLUSIONS: Dietitians appeared to be better than doctors at lowering blood cholesterol in the short to medium term, though the difference was small (about 4%), but there was no evidence that they were better than self-help resources or nurses.

Cholesterol↗
PubMed2003

Systematic review of controlled trials on the effectiveness of fluoride gels for the prevention of dental caries in children.

Fluoride gels have been widely used since the 1970s. The aim of this review was to assess the effectiveness and safety of fluoride gels in the prevention of dental caries in children and to examine factors potentially modifying their effectiveness. Relevant randomized or quasi-randomized trials were identified without language restrictions by searching multiple databases, reference lists of articles, and journals and by contacting selected authors and manufacturers. Trials with blind outcome assessment comparing fluoride gel with placebo or no treatment for at least one year and involving children under seventeen years of age were selected. Inclusion decisions, quality assessment, and data extraction were duplicated in a random sample of one third of studies, and consensus was achieved by discussion or a third party. Random effects meta-analyses were performed where data could be pooled. Potential sources of heterogeneity were examined in random effects meta-regression analyses. The main outcome was caries increment measured by the change in decayed, missing, and filled permanent tooth surfaces (D(M)FS). The primary measure of effect was the prevented fraction (PF) that is the difference in mean caries increment between the treatment and control groups expressed as a percentage of the mean increment in the control group. Potential adverse effects and unacceptability of treatment were also recorded. Twenty-five studies were included, involving 7,747 children. For the twenty-three that contributed data for meta-analysis, the D(M)FS pooled prevented fraction estimate was 28 percent (95 percent CI, 19 percent to 37 percent; p < 0.0001). There was clear heterogeneity, confirmed statistically (p < 0.0001). The effect of fluoride gel varied according to type of control group used, with D(M)FS PF on average being 19 percent (95 percent CI, 5 percent to 33 percent; p < 0.009) higher in non-placebo controlled trials. Only two trials reported on adverse events. There is clear evidence of a caries-inhibiting effect of fluoride gel. The best estimate of the magnitude of this effect, based on the fourteen placebo-controlled trials, is a 21 percent reduction (95 percent CI, 14 to 28 percent) in D(M)FS. This corresponds to an NNT of two (95 percent CI, 1 to 3) to avoid one D(M)FS in a population with a caries increment of 2.2 D(M)FS/year, or an NNT of twenty-four (95 percent CI, 18 to 36) based on an increment of 0.2 D(M)FS/year. However, further work is needed to identify and quantify potential harmful effects of fluoride gels.

Adolescent↗
PubMed2002

Quantifying heterogeneity in a meta-analysis.

The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity.

Albumins↗
PubMed2002

How should meta-regression analyses be undertaken and interpreted?

Appropriate methods for meta-regression applied to a set of clinical trials, and the limitations and pitfalls in interpretation, are insufficiently recognized. Here we summarize recent research focusing on these issues, and consider three published examples of meta-regression in the light of this work. One principal methodological issue is that meta-regression should be weighted to take account of both within-trial variances of treatment effects and the residual between-trial heterogeneity (that is, heterogeneity not explained by the covariates in the regression). This corresponds to random effects meta-regression. The associations derived from meta-regressions are observational, and have a weaker interpretation than the causal relationships derived from randomized comparisons. This applies particularly when averages of patient characteristics in each trial are used as covariates in the regression. Data dredging is the main pitfall in reaching reliable conclusions from meta-regression. It can only be avoided by prespecification of covariates that will be investigated as potential sources of heterogeneity. However, in practice this is not always easy to achieve. The examples considered in this paper show the tension between the scientific rationale for using meta-regression and the difficult interpretative problems to which such analyses are prone.

Adrenergic beta-Antagonists↗