Two major goals of research in medicine and public health are to discover the causes of human diseases and establish effective therapeutic and preventive interventions. In general, no single study is sufficient to establish a cause of a disease or to prove that an intervention is effective. Rather, establishing causation relies on interpretation of all available evidence. Meta-analysis has commonly been used to pool the results of clinical trials, both to establish efficacy and safety of interventions. Because of the challenges of clinical research, it is common for individual studies to be underpowered to detect real significant effects of interventions or establish true existing causal associations Although more commonly used to pool the results of clinical trials, meta-analysis has also been used to pool the results of observational case-control studies and cohort studies.
Regardless of whether meta-analysis is used to examine data from clinical trials or observational studies, a few basic principles are applicable. All meta-analyses require a written protocol. This protocol must first identify the question to be answered. When the aim is to pool the results of all available data, the protocol specifies how the prior studies will be identified. In addition, the protocol should define inclusion and exclusion criteria, the data to be collected, and the analytic plan. Thus, in many ways conduct of a meta-analysis is similar to conducting a retrospective cohort or case-control study, except that the study subjects are prior studies rather than people.
In recent years, a major focus of research in gastroenterology has been to identify genetic determinants of disease. Numerous technical advances, such as completion of the Human Genome Project and development of high throughput techniques, have resulted in an explosion of genetic and genomic research. Many common conditions are associated with Mendelian (single gene) transmission, such as hereditary hemochromatosis, but the vast majority of common diseases involve multiple genetic and environmental factors. There are now numerous reports of associations of genetic variants with several common complex digestive and liver disorders. However, despite the scientific excitement and the predictions for personalized prevention and drug treatment, the promise for health promotion and disease prevention has yet to be fulfilled. These technical advances have brought with them new challenges. For example, the ability to examine variations among thousands of genes in a single study creates the potential for false-positive findings (type 1 errors). Thus, reproducibility is an essential in genetic research.
Because of the complexities emerging from gene discoveries and the need for a systematic epidemiologic approach to the evaluation of new genes and their variants, the Centers for Disease Control and Prevention (CDC), with many partners, launched in 1998 an open international collaborative initiative, the Human Genome Epidemiology Network (HuGENet™). The goals of HuGENet™ are to (1) establish an information exchange network that promotes global collaboration in the development and dissemination of peer-reviewed epidemiologic information on human genes; (2) develop an updated and accessible knowledge base on the worldwide web; and (3) promote the use of this resource base by health care providers, researchers, and the public for making decisions involving the use of genetic tests in health services.
Gene discoveries for various diseases continue at a fast pace using to date mostly family-based studies. Once a gene–disease association has been established, subsequent studies often focus on genotype–phenotype associations and gene–environment interactions. There are also an increasing number of epidemiologic association studies, especially case-control designs using genome-wide association approaches that assess simultaneously hundreds of thousands of genetic variants. As of December 1, 2006, >24,000 articles were indexed in the CDC HuGE Published Literature database (established in 2001). Most of these articles describe gene–disease associations (86%); fewer studies evaluated gene–gene or gene–environment interactions (17%), prevalence of DNA variants (10%), or genetic tests (3%).
Genotype–phenotype association and gene–environment interaction studies are frequently underpowered because the statistical power is determined by the subgroups being studied. Yet, these studies are potentially critical to understand the actual mechanism by which a genetic variation leads to a disease. Meta-analysis is therefore a potentially valuable tool for the field of genetics research and it may prove particularly useful in studies of genotype–phenotype associations and gene–environment interactions. It also provides a technique to test for heterogeneity between studies, which is important when examining reproducibility of findings.
Given that we anticipate increasing use of reviews and meta-analysis of genetic association studies in the field of gastroenterology, the Board of Editors has decided to standardize the way in which such studies must be conducted and reported if they are to be published in Gastroenterology or Clinical Gastroenterology and Hepatology. We have elected to adopt the HuGE guidelines that have also been used by several other medical and scientific journals. Guidelines are posted on the HuGENet™ website. These guidelines provide a standardized method for the conduct and reporting of meta-analysis of genetic studies. As of December 1, 2006, 55 HuGE reviews have been published in various journals and posted on the HuGENet™ website, few of which dealt with digestive or liver disorders
(Table 1).
Table 1: Volume of Human Genome Epidemiology Publications in Gastroenterology and Liver Diseases for Selected Conditions, 2001–2006a
(a) Query of the HuGE Published Literature Database on December 15, 2006.
Our adoption of the HuGE guidelines should only minimally affect the work of conducting such research. HuGE requires investigators to register their protocol before the study is initiated. Otherwise, the conduct of the study proceeds as would have been expected otherwise. Upon completion of the study, the work is submitted to a peer-reviewed journal, such as Gastroenterology and Clinical Gastroenterology and Hepatology. After acceptance and publication by a HuGE-participating journal, an added advantage is that the HuGENet™ posts results of the meta-analysis online, thereby furthering the public availability of the research findings.
We will gradually incorporate these requirements into the Gastroenterology and Clinical Gastroenterology and Hepatology editorial decisions. Studies initiated and conducted before January 1, 2008, are encouraged to follow the HuGENet™ guidelines. After January 1, 2008, our journals will require all meta-analyses of genetic studies to be registered and to follow the HuGENet™ guidelines. The Board of Editors feels confident that this will lead to improved quality of such studies published in our journals. |
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