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HuGENet Researchers Publish Advice on GWAS Systematic Reviews

NEW YORK (GenomeWeb News) – A trio of researchers involved with the Human Genome Epidemiology Network (HuGENet) have published a new guidance paper for systematic reviews of genetic association studies. The article, based on HuGENet's HuGE Review Handbook, appeared online last night in PLoS Medicine.

"The principal value of a well-conducted systematic review of genetic association studies is in establishing reliably the presence and magnitude of individual gene-disease associations," senior author Julian Higgins, a statistician at the Medical Research Council Biostatistics Unit in Cambridge, and colleagues wrote.

"By complementing both consortium-based pooled analyses and larger-scale attempts to collate genetic association evidence across whole fields, they play an important role alongside other research designs in the integration of evidence on genetic association."

Among their recommendations, the team suggested writing a protocol and stating the objectives and criteria before starting review studies, searching several literature databases and online data sources, and having more than one person extract data. They also urged reviewers to assess the validity of studies and consider doing a meta-analysis looking at the effect sizes reported in genetic association studies.

In contrast to narrative reviews, which can be somewhat subjective, systematic reviews involve compiling and actually analyzing data analysis from many sources, including published papers, supplementary material, online databases, correspondence with study authors, and more.

Such reviews "are designed as rigorous research studies" and "allow a more objective appraisal of the evidence than a narrative review by aiming to identify, critique, and synthesize evidence from all relevant existing studies on the topic in question using predefined methods," Higgins and his co-authors explained.

The goal of systematic reviews is to look at everything in the literature — and sometimes beyond — and combine the information in a systematic and scientific way, Higgins told GenomeWeb Daily News. That, in turn, not only pulls together data but also improves the transparency and interpretation of these results and highlights areas where more research is necessary.

For instance, HuGENet was established to assess how genetic epidemiology can inform human health. And systematic reviews and higher level analyses feed into this process, said Higgins. In 2007, HuGENet published the HuGE Review Handbook — guidance that Higgins says has been evolving over time.

HuGE Reviews are a "cornerstone of an online resource containing the cumulative and changing information on epidemiologic aspects of human genes," the authors wrote. These sorts of systematic reviews are proving valuable in other fields as well, Higgins noted.

For genome-wide association studies, where effects are often small and large samples are needed to make sense of and validate potential associations, meta-analyses and other amalgamations of data are becoming increasingly important, the trio explained.

Those undertaking systematic reviews of genetic association studies have to deal with many of the same concerns as researchers in other fields. But issues such as biases related to population stratification, genotyping errors, and so on are particularly important in GWAS reviews, Higgins explained.

The paper also emphasized the need to consider research protocols, eligibility criteria, study validity, controls, sample size, replication in multiple studies, and possible sources of selection, publication, and other bias.

In general, systematic reviews rely heavily on databases, such as GenBank, that house the majority of published literature and online resources such as dbGAP, Higgins explained. But they also tend to involve correspondence and data sharing with study authors, he added.

Although online supplementary data and other online sources are helping to facilitate systematic reviews, Higgins said doing an adequate systematic review still takes a good deal of footwork and interaction with study authors. "It's becoming easier," he said. "We're not there yet."

In terms of presenting the results of such reviews, the authors suggest including information on everything from evidence available to biases to public health implications of the research. "A systematic summary of all available evidence should allow the strengths and gaps in the evidence base to be identified and allow recommendations to be made in order to stimulate research to address such gaps," Higgins and his co-authors wrote.

The authors urged those interested in learning more about systematic review guidelines to check out the HuGE Review Handbook. They also noted that there are additional resources available, including the Cochrane Handbook for Systematic Reviews of Interventions and The Handbook of Research Synthesis.

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