Reporting of Sex Effects by Systematic Reviews on Interventions for Depression, Diabetes, and Chronic Pain

Differences in disease prevalence, clinical manifestations, and health outcomes exist between men and women. Sources for this variation range from biological differentiation at the cellular level to behavioral differences influenced by societal gender norms. Typically, biologically based differences between men and women are called sex differences, whereas gender differences describe health differences related, at least in part, to societal constructs of gender (13). For example, biological events unique to women, such as pregnancy and menopause, are probably associated with sex differences in occurrence of certain conditions or in response to some medical therapies (48). Gender differences probably exist in health-related perceptions and behaviors for women and men with medical conditions that are prevalent for both sexes (for example, heart disease and chronic pain) (9 –16). Although sex and gender differences are theoretically distinct, they remain difficult to disentangle when differences between men and women in health outcomes and treatment effectiveness are being examined. For this reason, and for brevity, we hereafter refer to sex and gender differences collectively as sex effects. In the past 2 decades, recognition of the importance of sex effects for health outcomes and treatment heterogeneity has been growing. Beginning in 1993, the National Institutes of Health has issued policies requiring the inclusion of women and minorities in all clinical research and trial designs with valid analysis of sex effects or differences between racial and ethnic groups (17, 18). Since then, the inclusion of women in clinical trials has increased (19, 20), and sex effects have been identified for medications, such as nicotine replacement therapy, analgesics, and aspirin (13, 14, 21). Recently, sex effects in adverse reactions led to sex-specific dosage recommendations for a widely used sedative (7). Despite this progress, representation of women in clinical studies remains inadequate for many conditions (22). Further, published clinical trials infrequently report sex effects or discuss the appropriateness of sex-specific analyses (19, 20, 23). To advance the clinical evidence base and improve health outcomes for women, clinical research must include adequate numbers of women, appropriately conduct sex-specific analyses, and consistently report sex effects. Systematic reviews (SRs) are a key source of information for clinicians, researchers, and guideline panels. By synthesizing the overall body of evidence for key clinical and research questions, SRs could potentially make a unique contribution to the evaluation of sex effects. To our knowledge, however, the reporting of sex effects by SRs has not been previously examined. Here, we use evidence mapping to systematically evaluate the reporting of sex effects by SRs examining a diverse set of interventions for chronic conditions common to women (that is, depression, diabetes, and chronic pain). Evidence mapping is an emerging approach that describes key characteristics of studies for a broad area of medicine (2426). Our evidence map addresses the volume and characteristics of eligible SRs, including the representation of women in primary studies, whether and how reviews reported sex effects, and findings about sex effects. Methods This work was part of a larger report for the Veterans Health Administration (VHA) Evidence-based Synthesis Program (ESP). The complete technical report is available online (www.hsrd.research.va.gov/publications/esp) and includes additional information on our methods. We focused on SRs to determine the reporting of sex effects, provide high-level information about the volume of current clinical evidence, and summarize information about actual sex effects. Prioritization of Conditions for Inclusion We used forced-ranking prioritization (27) with our VHA stakeholders to determine our conditions of interest. These stakeholders included representatives from the Health Services Research & Development Center for the Study of Healthcare Innovation, Implementation and Policy; Health Services Research & Development Women's Health Research Network; Women's Health Research in the Office of Research & Development; Women's Health Services; and Mental Health Services. We initially selected 34 conditions (Appendix Table 1) based on disease prevalence in women, disease burden in women, availability and breadth of effective treatments for men or women, and women veterans' priorities for gender-specific care. Stakeholders ranked this initial set of conditions, discussed the rankings, and reranked conditions that initially received intermediate priority rankings. After 2 rounds of iterative prioritization, the following conditions were selected: depressive disorders, type 2 diabetes mellitus, and chronic pain (that is, chronic low back pain, fibromyalgia, and chronic knee pain due to osteoarthritis). Appendix Table 1. Conditions Presented to Stakeholders for Prioritization* Data Sources and Searches In collaboration with an expert reference librarian, we searched PubMed and Cochrane Database of Systematic Reviews to identify eligible SRs published after 1 October 2009 through 31 October 2014 for depression, 13 February 2015 for diabetes, and 27 February 2015 for chronic pain. Search strategies used Medical Subject Headings and free-text terms for the conditions of interest, eligible interventions, and SRs (Appendix Table 2). We restricted the search to the past 6 years because SRs are typically outdated within 5 years of publication (28), and our goal was to describe the current state of the clinical literature. In addition to electronic searching, we screened published reviews of reviews for eligible articles. Appendix Table 2. Search Strategies Study Selection and Quality Assessment Eligible SRs evaluated interventions in several broad categories (that is, medications, behavioral interventions, supervised exercise, and quality improvement or organizational interventions). We also included condition-specific interventions, such as bariatric surgery for diabetes. Reviews that evaluated mixed conditions or multiple interventions must have reported results separately for at least 1 eligible condition or intervention. We included reviews of interventions in any setting, with any type of active or inactive comparator, and with any duration of follow-up. Detailed inclusion and exclusion criteria are provided in Appendix Table 3. Appendix Table 3. Detailed Inclusion and Exclusion Criteria for Review Eligibility Two investigators screened citations for eligibility, and citations that were considered to be relevant by either person were retained for full-text review. Full-text articles were reviewed by 2 investigators, and disagreements were resolved through discussion or adjudicated by a third person. Formal assessment of review quality was beyond the scope of this project. However, we noted whether reviews originated from organizations known for high-quality reviews (that is, Cochrane Collaboration, Agency for Healthcare Research and Quality Evidence-based Practice Centers, and VHA ESP). For reviews reporting sex effects, we also assessed industry funding and whether statistical power was considered. Data Abstraction Data were abstracted by 1 investigator and reviewed by a second person. Disagreements were resolved by discussion or by a third reviewer. Abstracted data included the analysis method (that is, qualitative synthesis, meta-analysis, network meta-analysis, or individual-patient data [IPD] meta-analysis); clinical conditions; interventions; main outcomes; number and design of primary studies (for example, randomized, controlled trials [RCTs] or observational cohorts); proportion of women in the included primary studies; and if sex effects were part of the study aims, analysis plan, or results. For reviews reporting sex effects, we also recorded the number of primary studies used for sex-specific analyses, effect estimates, and the method used (for example, metaregression, subgroup analysis, or IPD meta-analysis). All eligible reviews on depressive disorders and chronic pain conditions were fully abstracted. All diabetes reviews of nonpharmacologic interventions were also fully abstracted. For eligible diabetes medication reviews (n= 120), we applied an additional prioritization procedure before full abstraction. We prioritized reviews that examined multiple classes of medications or evaluated a single class of medications when 6 or fewer eligible reviews were identified. For SRs evaluating a single class (>6 eligible reviews were identified), we used additional prioritization criteria (for example, the most recent review published in a high-impact journal or work done by an organization known for high-quality reviews). The remaining unselected but eligible reviews (n= 58) had a keyword text search for sex effects and were fully abstracted only when this search yielded positive results (n= 13). Data Synthesis and Analysis of SRs We grouped eligible reviews by intervention category and described the overall volume of clinical literature for interventions addressing each condition of interest. We also determined the number of reviews reporting sex effects and summarized these results. Time trends for the proportion of these reviews were examined for depression and diabetes. Examination of Primary RCTs for Selected Interventions We anticipated that some interventions for each condition would have few or no eligible SRs that addressed sex effects. Thus, for a subset of interventions for each condition, we evaluated primary RCTs to determine the feasibility of conducting a future review to evaluate sex effects. Specifically, we examined quality improvement interventions and psychotherapy for depression; diet, physical activity, and culturally tailored psychoeducation for diabetes; behavioral interventions for chronic low back pain; and exercise interventions for