The design and conduct of clinical trials to limit missing data.

This article summarizes recommendations on the design and conduct of clinical trials of a National Research Council study on missing data in clinical trials. Key findings of the study are that (a) substantial missing data is a serious problem that undermines the scientific credibility of causal conclusions from clinical trials; (b) the assumption that analysis methods can compensate for substantial missing data is not justified; hence (c) clinical trial design, including the choice of key causal estimands, the target population, and the length of the study, should include limiting missing data as one of its goals; (d) missing-data procedures should be discussed explicitly in the clinical trial protocol; (e) clinical trial conduct should take steps to limit the extent of missing data; (f) there is no universal method for handling missing data in the analysis of clinical trials - methods should be justified on the plausibility of the underlying scientific assumptions; and (g) when alternative assumptions are plausible, sensitivity analysis should be conducted to assess robustness of findings to these alternatives. This article focuses on the panel's recommendations on the design and conduct of clinical trials to limit missing data. A companion paper addresses the panel's findings on analysis methods.

Hysterectomy, endometrial ablation and Mirena® for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis.

OBJECTIVE: The aim of this project was to determine the clinical effectiveness and cost-effectiveness of hysterectomy, first- and second-generation endometrial ablation (EA), and Mirena® (Bayer Healthcare Pharmaceuticals, Pittsburgh, PA, USA) for the treatment of heavy menstrual bleeding. DESIGN: Individual patient data (IPD) meta-analysis of existing randomised controlled trials to determine the short- to medium-term effects of hysterectomy, EA and Mirena. A population-based retrospective cohort study based on record linkage to investigate the long-term effects of ablative techniques and hysterectomy in terms of failure rates and complications. Cost-effectiveness analysis of hysterectomy versus first- and second-generation ablative techniques and Mirena. SETTING: Data from women treated for heavy menstrual bleeding were obtained from national and international trials. Scottish national data were obtained from the Scottish Information Services Division. PARTICIPANTS: Women who were undergoing treatment for heavy menstrual bleeding were included. INTERVENTIONS: Hysterectomy, first- and second-generation EA, and Mirena. MAIN OUTCOME MEASURES: Satisfaction, recurrence of symptoms, further surgery and costs. RESULTS: Data from randomised trials indicated that at 12 months more women were dissatisfied with first-generation EA than hysterectomy [odds ratio (OR): 2.46, 95% confidence interval (CI) 1.54 to 3.93; p = 0.0002), but hospital stay [WMD (weighted mean difference) 3.0 days, 95% CI 2.9 to 3.1 days; p < 0.00001] and time to resumption of normal activities (WMD 5.2 days, 95% CI 4.7 to 5.7 days; p < 0.00001) were longer for hysterectomy. Unsatisfactory outcomes associated with first- and second-generation techniques were comparable [12.2% (123/1006) vs 10.6% (110/1034); OR 1.20, 95% CI 0.88 to 1.62; p = 0.2). Rates of dissatisfaction with Mirena and second-generation EA were similar [18.1% (17/94) vs 22.5% (23/102); OR 0.76, 95% CI 0.38 to 1.53; p = 0.4]. Indirect estimates suggested that hysterectomy was also preferable to second-generation EA (OR 2.32, 95% CI 1.27 to 4.24; p = 0.006) in terms of patient dissatisfaction. The evidence to suggest that hysterectomy is preferable to Mirena was weaker (OR 2.22, 95% CI 0.94 to 5.29; p = 0.07). In women treated by EA or hysterectomy and followed up for a median [interquartile range (IQR)] duration of 6.2 (2.7-10.8) and 11.6 (7.9-14.8) years, respectively, 962/11,299 (8.5%) women originally treated by EA underwent further gynaecological surgery. While the risk of adnexal surgery was similar in both groups [adjusted hazards ratio 0.80 (95% CI 0.56 to 1.15)], women who had undergone ablation were less likely to need pelvic floor repair [adjusted hazards ratio 0.62 (95% CI 0.50 to 0.77)] and tension-free vaginal tape surgery for stress urinary incontinence [adjusted hazards ratio 0.55 (95% CI 0.41 to 0.74)]. Abdominal hysterectomy led to a lower chance of pelvic floor repair surgery [hazards ratio 0.54 (95% CI 0.45 to 0.64)] than vaginal hysterectomy. The incidence of endometrial cancer following EA was 0.02%. Hysterectomy was the most cost-effective treatment. It dominated first-generation EA and, although more expensive, produced more quality-adjusted life-years (QALYs) than second-generation EA and Mirena. The incremental cost-effectiveness ratios for hysterectomy compared with Mirena and hysterectomy compared with second-generation ablation were £1440 per additional QALY and £970 per additional QALY, respectively. CONCLUSIONS: Despite longer hospital stay and time to resumption of normal activities, more women were satisfied after hysterectomy than after EA. The few data available suggest that Mirena is potentially cheaper and more effective than first-generation ablation techniques, with rates of satisfaction that are similar to second-generation techniques. Owing to a paucity of trials, there is limited evidence to suggest that hysterectomy is preferable to Mirena. The risk of pelvic floor surgery is higher in women treated by hysterectomy than by ablation. Although the most cost-effective strategy, hysterectomy may not be considered an initial option owing to its invasive nature and higher risk of complications. Future research should focus on evaluation of the clinical effectivesness and cost-effectiveness of the best second-generation EA technique under local anaesthetic versus Mirena and types of hysterectomy such as laparoscopic supracervical hysterectomy versus conventional hysterectomy and second-generation EA. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding: systematic review and meta-analysis of data from individual patients.

OBJECTIVE: To evaluate the relative effectiveness of hysterectomy, endometrial destruction (both "first generation" hysteroscopic and "second generation" non-hysteroscopic techniques), and the levonorgestrel releasing intrauterine system (Mirena) in the treatment of heavy menstrual bleeding. DESIGN: Meta-analysis of data from individual patients, with direct and indirect comparisons made on the primary outcome measure of patients' dissatisfaction. DATA SOURCES: Data were sought from the 30 randomised controlled trials identified after a comprehensive search of the Cochrane Library, Medline, Embase, and CINAHL databases, reference lists, and contact with experts. Raw data were available from 2814 women randomised into 17 trials (seven trials including 1359 women for first v second generation endometrial destruction; six trials including 1042 women for hysterectomy v first generation endometrial destruction; one trial including 236 women for hysterectomy v Mirena; three trials including 177 women for second generation endometrial destruction v Mirena). Eligibility criteria for selecting studies Randomised controlled trials comparing hysterectomy, first and second generation endometrial destruction, and Mirena for women with heavy menstrual bleeding unresponsive to other medical treatment. RESULTS: At around 12 months, more women were dissatisfied with outcome with first generation hysteroscopic techniques than with hysterectomy (13% v 5%; odds ratio 2.46, 95% confidence interval 1.54 to 3.9, P<0.001), but hospital stay (weighted mean difference 3.0 days, 2.9 to 3.1 days, P<0.001) and time to resumption of normal activities (5.2 days, 4.7 to 5.7 days, P<0.001) were longer for hysterectomy. Unsatisfactory outcomes were comparable with first and second generation techniques (odds ratio 1.2, 0.9 to 1.6, P=0.2), although second generation techniques were quicker (weighted mean difference 14.5 minutes, 13.7 to 15.3 minutes, P<0.001) and women recovered sooner (0.48 days, 0.20 to 0.75 days, P<0.001), with fewer procedural complications. Indirect comparison suggested more unsatisfactory outcomes with second generation techniques than with hysterectomy (11% v 5%; odds ratio 2.3, 1.3 to 4.2, P=0.006). Similar estimates were seen when Mirena was indirectly compared with hysterectomy (17% v 5%; odds ratio 2.2, 0.9 to 5.3, P=0.07), although this comparison lacked power because of the limited amount of data available for analysis. CONCLUSIONS: More women are dissatisfied after endometrial destruction than after hysterectomy. Dissatisfaction rates are low after all treatments, and hysterectomy is associated with increased length of stay in hospital and a longer recovery period. Definitive evidence on effectiveness of Mirena compared with more invasive procedures is lacking.

Surgery for nonarteritic anterior ischemic optic neuropathy.

BACKGROUND: Nonarteritic ischemic optic neuropathy is characterized by sudden and painless loss of vision in the eye, accompanied by pallid swelling of the optic disc. No medical therapy has been proven effective in treating this condition. OBJECTIVES: The objective of this review is to assess the safety and efficacy of surgery compared with other treatment or usual care in people with nonarteritic ischemic optic neuropathy. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Group Trials Register, in The Cochrane Library, MEDLINE, EMBASE and the UK National Research Register (NRR). The last search was on 13 July 2005. SELECTION CRITERIA: We included randomized controlled trials. DATA COLLECTION AND ANALYSIS: We obtained full copies of all potentially relevant articles. One randomized trial was eligible for inclusion. One author extracted data which was verified by another author. No synthesis was required. MAIN RESULTS: The one included trial randomized 258 participants and was stopped early. At the time of the 24-month report the follow-up rate was 95.3% for six months and 67.4% for 24 months (174 participants, 89 careful follow up and 85 surgery). There was no evidence of a benefit of surgery on visual acuity. At six months 32.0% of the surgery group had improved visual acuity by three or more lines compared with 42.6% of the careful follow up group (unadjusted risk ratio (RR) 0.75, 95% confidence interval (CI) 0.54 to 1.04). At 24 months 29.4% of the surgery group had improved compared with 31.0% of the careful follow up group (unadjusted RR 0.95, 95% CI 0.60 to 1.49). Participants who underwent surgery had a greater risk of losing three or more lines of vision. At six months 18.9% in the surgery group had worsened compared with 14.8% in the careful follow up group (RR 1.28; 95% CI 0.73 to 2.24). At 24 months 20.0% in the surgery group had worsened compared with 21.8% in the careful follow up group (RR 0.92; 95% CI 0.51 to 1.64). AUTHORS' CONCLUSIONS: Results from the single trial indicate no evidence of a beneficial effect of optic nerve decompression surgery for nonarteritic ischemic optic neuropathy.

Publication of clinical trials: accountability and accessibility.

Publication of findings from clinical trials is a necessary step in the research continuum, to provide a record of the work done, convey information to the community, and support translation of research into clinical practice. Systematic reviews of randomized controlled trials are now widely regarded as the highest level of evidence in determining the effect of an intervention on an outcome. They largely depend on internationally accessible, published reports of all trials undertaken. Investigators and their institutions or organizations have responsibility for reporting their clinical trials accurately and completely, including disclosure of potential conflicts of interest. To ensure evidence-based health care, issues relating to accessibility and accountability of clinical trial results require immediate action.

Newspaper reporting of screening mammography.

BACKGROUND: Continuing controversy surrounds screening mammography, particularly for women 40 to 49 years of age. Newspapers are potentially important sources of information on this topic, but it is not known whether they provide well-founded and objective information and recommendations. OBJECTIVE: To examine how screening mammography is reported in newspapers. DESIGN: Cross-sectional descriptive study. SETTING: 6 top-circulation U.S. newspapers, 1990 to 1997. MEASUREMENTS: Number of articles about screening mammography, issues covered by the articles, information sources, content and sources of quotes, recommendations cited in articles, and presentation of risks and benefits. RESULTS: The most common theme of newspaper articles about mammography was screening for women 40 to 49 years of age. Thirty-one percent of the articles presented information without citing a source or justification. Quotes and recommendations in the articles were approximately twice as likely to support as to express reservations about mammography for women aged 40 to 49 years. Recommendations changed little over time and rarely reflected changes in recommendations of national organizations. Of the 102 articles describing the benefits of mammography, 95% expressed them in relative terms and 11% expressed them in absolute terms. CONCLUSIONS: Newspapers tended to overrepresent support for screening mammography for women aged 40 to 49 years. Reports would have been improved by identification of all sources for information cited, less reliance on relatively few sources, and discussion of benefits in absolute as well as relative terms. Medical journalism may benefit from identification of standards similar to those used for reporting medical research.

Development and implementation of a science training course for breast cancer activists: Project LEAD (leadership, education and advocacy development).

OBJECTIVE: To develop and implement Project LEAD (leadership, education, and advocacy development), a science course for breast cancer activists. POPULATION: Students were breast cancer activists and other consumers, mainly affiliated with advocacy organizations in the United States of America. SETTING: Project LEAD is offered by the National Breast Cancer Coalition; the course takes place over 5 days and is offered 4 times a year, in various cities in the United States of America. RESULTS: The Project LEAD curriculum has developed over 5 years to include lectures, problem-based study groups, case studies, interactive critical appraisal sessions, a seminar by an 'expert' scientist, role play, and homework components. A core faculty has been valuable for evaluating and revising the course and has proved necessary to provide consistent high quality teaching. Course evaluations indicated that students gained critical appraisal skills, enhanced their knowledge and developed confidence in selected areas of basic science and epidemiology. CONCLUSIONS: Project LEAD comprises a unique curriculum for training breast cancer activists in science and critical appraisal. Course evaluations indicate that students gain confidence and skills from the course.

Purchasing oncology services. Kerr L. White Institute/American Cancer Society Task Force on Purchasing Oncology Services.

BACKGROUND: A multidisciplinary panel representing various stakeholders in the health care delivery and oncology services marketplace was convened to develop specific criteria for healthcare purchasers to consider when evaluating the structures and processes of health plans. These rank ordered criteria also can be used by oncologic service providers and health plan designers as a yardstick for the services they offer. METHODS: A multidisciplinary 31-member Task Force was assembled by the Kerr L. White Institute and the American Cancer Society in March 1997. Task Force members were selected for their ability to offer expert insight as purchasers, suppliers, policymakers, consumers, or stakeholders in the health care marketplace. A preference-weighted majority voting rule was used to identify the three most important recommendations of the 10 that were generated through a modified Delphi technique. To test the practicality of the top three recommendations, leaders of large managed care organizations (MCOs) were surveyed; the results of this survey then were compared with the results of the Task Force survey. RESULTS: The three most important recommendations from the Task Force were that health plans provide access to: 1) comprehensive cancer care, 2) preventive and screening services, and 3) second opinions and treatment options supported by scientific evidence. The difference between the responses of the Task Force and the MCOs was that MCOs placed the highest importance on evidence-based decision-making, with their next three rankings coinciding with those identified by the Task Force. CONCLUSIONS: The value of these summary recommendations will be realized through their use by both purchasers and suppliers to influence the structure and content of the delivery of oncologic services.

Surgery for nonarteritic anterior ischemic optic neuropathy.

BACKGROUND: Nonarteritic ischemic optic neuropathy is characterized by sudden and painless loss of vision in one eye, accompanied by pallid swelling of the optic disc. Although various medical interventions, such as corticosteroids and phenytoin sodium, have been used to treat nonarteritic ischemic optic neuropathy, no therapy has been proven effective. OBJECTIVES: The objective of this review is to assess the safety and efficacy of surgical treatment compared with other treatment or usual care in people with nonarteritic ischemic optic neuropathy. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register - Central and MEDLINE. The most recent searches were performed in December 1997. SELECTION CRITERIA: We included randomized trials comparing surgery to no surgery in people with nonarteritic ischemic optic neuropathy. DATA COLLECTION AND ANALYSIS: We obtained full copies of all potentially relevant articles. Only one article described a randomized trial of surgery and it was eligible for inclusion. No formal assessment of quality was done. One reviewer extracted data. No synthesis was required, as there was only one trial. MAIN RESULTS: The one trial identified randomized 258 patients. The only published report with outcomes data for that trial presents preliminary results from 244 patients who had achieved six months of follow-up at the time of the report. Participants assigned to surgery did no better than participants assigned to careful follow-up regarding improved visual acuity of three or more lines of vision at six months: 32.6% of the surgery group improved compared with 42.7% of the careful follow-up group. The adjusted odds ratio (OR), adjusted for baseline visual acuity and diabetes, comparing the two groups for three or more lines improvement was 0.74 (95% confidence interval (CI) 0.39 to 1. 38) (surgery group improvement was worse than careful follow-up). In addition, participants receiving surgery had a significantly greater risk of losing three or more lines of vision at six months: 23.9% in the surgery group worsened compared with 12.4% in the careful follow-up group. The six-month adjusted OR comparing the two groups for loss of three or more lines of vision was 1.96 (95% CI 0.87 to 4.41). Spontaneous improvement of three or more lines of vision was observed in 42.7% of participants in the careful follow-up group. REVIEWER'S CONCLUSIONS: Results from the Ischemic Optic Neuropathy Decompression Trial indicate that optic nerve decompression surgery for nonarteritic ischemic optic neuropathy is not effective.

Is there a sex bias in choosing editors? Epidemiology journals as an example.

CONTEXT: Editors, authors, and reviewers are influential in shaping science. The careers of women in public health have received less scrutiny than those of women in medicine and other branches of science. The performance of women as editors, authors, and reviewers in epidemiology has not been previously studied. OBJECTIVE: To examine changes over time in the representation of women at the editorial level in US epidemiology journals compared with the proportion of women authors and reviewers. DESIGN AND SETTING: Cross-sectional study of 4 US epidemiology journals, American Journal of Epidemiology, Annals of Epidemiology, Epidemiology, and the Journal of Clinical Epidemiology (formerly the Journal of Chronic Diseases), for 1982, 1987, 1992, and 1994. SUBJECTS: Editors, authors, and reviewers for the selected years. MAIN OUTCOME MEASURES: Sex of editors, authors, and reviewers. RESULTS: We identified 2415 reports associated with 8005 authors. One of 7 editors in chief was a woman, a position she shared with a man. For all journals, the proportion of editors who were women ranged from 5 (6.5%) of 77 in 1982 to 42 (16.3%) of 258 in 1994. Over all journals and all years, women comprised a higher proportion of authors (28.7% [2225/7743]) compared with reviewers (26.7% [796/2982]) or editors (12.8% [89/696]). CONCLUSIONS: Fewer women in public health hold editorial positions than are authors and reviewers. The reasons for this important discrepancy, including the possibility of a selection bias favoring men, should be further investigated.

Medical prophylaxis and treatment of cystoid macular edema after cataract surgery. The results of a meta-analysis.

OBJECTIVE: The study aimed to determine the effectiveness of prophylactic medical intervention in reducing the incidence of cystoid macular edema (CME) and the effectiveness of medical treatment for chronic CME after cataract surgery. DESIGN: The study design was a systematic review and meta-analysis of published reports of randomized clinical trials (RCTs). PARTICIPANTS: Sixteen RCTs involving 2898 eyes examining the effectiveness of medical prophylaxis of CME and 4 RCTs involving 187 eyes testing the effectiveness of medical treatment of chronic CME were used in the study. INTERVENTIONS: Medical prophylaxis of treatment (cyclo-oxygenase inhibitors or corticosteroids) versus control (placebo or active treatment) was performed. MAIN OUTCOME MEASURES: Incidence of angiographically diagnosed CME, incidence of clinically significant CME, and vision were measured. RESULTS: Thirty-six articles reported testing a prophylactic medical intervention for CME after cataract surgery. The incidence of CME varied extensively across studies and was related to the study design used. Summary odds ratios (OR) indicated that prophylactic intervention was effective in reducing the incidence of both angiographic CME (OR = 0.36; 95% confidence interval [CI] = 0.28-0.45) and clinically relevant CME (OR = 0.49; 95% CI = 0.33-0.73). There also was a statistically significant positive effect on improving vision (OR = 1.97; 95% CI = 1.14-3.41). A combination of the results of the four RCTs testing medical therapy for chronic CME indicated a treatment benefit in terms of improving final visual acuity by two or more Snellen lines (OR = 2.67; 95% CI = 1.35-5.30). Assessment of the quality of the 20 RCTs included in the meta-analyses indicated problems in the design, execution, and reporting of a number of trials. CONCLUSION: A combination of the results from RCTs indicates that medical prophylaxis for aphakic and pseudophakic CME and medical treatment for chronic CME are beneficial. Because most of the RCTs performed to date have problems related to quality, a well-designed RCT is needed to confirm this result, using clinical CME and vision as outcomes.

Single agent versus combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: a meta-analysis of response, toxicity, and survival.

BACKGROUND: This meta-analysis was conducted to compare the effects of single agent versus combination chemotherapy on response rate, toxicity, and survival of patients with advanced nonsmall cell lung carcinoma (NSCLC). METHODS: The authors reviewed randomized clinical trials published in the medical literature and the reference lists of relevant articles. Objective response rate, survival at 6 and 12 months, and the incidence of treatment-related death were compared among all patients receiving single agent chemotherapy and those receiving combination chemotherapy. A subgroup analysis for all outcomes was conducted for 10 trials published between 1989 and 1996 that used a platinum analogue or vinorelbine as the single agent arm. RESULTS: The authors identified 38 potentially eligible trials, 25 of which (with a total of 5156 patients) were included in the meta-analysis. Overall, combination chemotherapy produced a nearly 2-fold increase in response rate compared with single agent chemotherapy (response rate [RR], 1.93; 95% confidence interval [CI], 1.54-2.42). However, combination chemotherapy also increased toxicity significantly, including a 3.6-fold increase in the risk of treatment-related death (RR, 3.5; 95% CI, 1.8-6.7). Survival at 6 months (RR, 1.10; 95% CI, 1.02-1.19) and 12 months (RR, 1.22; 95% CI, 1.03-1.45) was modestly superior with combination chemotherapy when all trials are included. However, when a platinum analogue or vinorelbine are used as single agents, this difference was no longer statistically significant at 6 months (RR, 1.03; 95% CI, 0.92-1.15) or at 12 months (RR, 1.10; 95% CI, 0.94-1.43). CONCLUSIONS: Combination chemotherapy increased objective response and toxicity rates compared with single-agent chemotherapy. Survival was prolonged only modestly with combination chemotherapy but not significantly so when more active single agents were used.

Participation in the Ischemic Optic Neuropathy Decompression Trial: sex, race, and age.

BACKGROUND: The Ischemic Optic Neuropathy Decompression Trial (IONDT) is a randomized, single masked, multicenter trial designed to assess the safety and efficacy of optic nerve decompression surgery compared with careful follow-up in patients 50 years or older with non-arteritic anterior ischemic neuropathy (NAION). OBJECTIVES: To examine and evaluate the sex, race, and age distributions of the screened, and subsequently enrolled, IONDT population, especially the proportions of female, minority, and elderly patients, and demographic characteristics of clinical center investigators, the geographical location of IONDT Clinical Centers, and the referral patterns of local physicians. SETTING: Twenty-five U.S. clinical centers. PARTICIPANTS: There were 1,681 referrals to the Clinical Centers; an Eligibility Screening Form providing demographic information was completed for 1,152. FINDINGS: Forty-three percent (495/1,152) of screened cases were women. Seven percent (85/1,152) were minorities: 33 African-Americans, 34 Hispanics, 17 Asians, and 1 Native-American. The average age was 66 +/- 10 years with a range of 22-92 years of age. Of the 1,152 referred patients, 305 were eligible for randomization; 258 (85%) of these agreed to participate in the trial. The demographic makeup of the randomized IONDT patients was similar to that of the screened population. CONCLUSIONS: Women and the elderly are well represented in the IONDT. Because the number of participating minorities was low, we cannot reliably assess their level of participation. Both a low incidence of NAION in minorities and a low referral rate of minorities to clinical trials are plausible explanations for our findings.

Effectiveness of the 40 adolescent AIDS-risk reduction interventions: a quantitative review.

OBJECTIVE: (1) To review evaluations of Acquired Immunodeficiency Syndrome (AIDS) prevention interventions targeting adolescents to determine whether these efforts have been effective in reducing risk behaviors. (2) To examine the relation between intervention design issues and outcomes measures. METHOD: A systematic review of five electronic databases and hand-searches of 11 journals, were undertaken for articles published from January 1983 through November 1995 that reported evaluations of adolescent AIDS risk-reduction interventions conducted in the United States. Outcomes examined include: improved attitudes about AIDS risk and protective behaviors, increased intention to abstain from sexual intercourse or to use condoms, and reduced sexual risk behaviors. RESULTS: Forty studies that met preestablished inclusion criteria were found. For each outcome assessed, a majority of studies found a positive intervention impact (88% of studies assessing changes in knowledge; 58% changes in attitude, 60% changes in intention to use condoms, 73% in condom use, and 64% in decreasing number of sexual partners). Interventions that demonstrated an increase in intention to use a condom were significantly more likely to be theory-based than those that did not show any significant changes in intention (100% vs. 0%, p = .048). Interventions that increased condom use and decreased the number of sexual partners were longer in duration than those that did not improve these outcomes. CONCLUSIONS: AIDS risk reduction interventions can be effective in improving knowledge, attitudes, and behavioral intentions and in reducing risk practices. The positive relationship between improved outcomes and several elements of intervention design underscores the need for increased focus on intervention design in future studies.

How important is publication bias? A synthesis of available data.

It has long been recognized that investigators frequently fail to report their research findings (Dickersin, 1990). Chalmers (1990) has suggested that this failure represents scientific misconduct since volunteers who consent to participate in research, and agencies that provide funding support for investigations, do so with the understanding that the work will make a contribution to knowledge. Clearly, knowledge that is not disseminated is not making a "contribution". This failure to publish is not only inappropriate scientific conduct, it also influences the information available for interpretation by the scientific community. Of course, if research is left randomly unpublished, there is less information available, but that information is unbiased. We now have solid evidence that failure to publish is not a random event; rather, publication is dramatically influenced by the direction and strength of research findings (Dickersin et al., 1987, 1992; Dickersin & Min, 1993; Easterbrook et al., 1991; Simes, 1986). This tendency of editors and reviewers to accept manuscripts submitted by investigators based on the strength and direction of the research findings is termed "publication bias". The problem has been under discussion for many years and has recently been studied directly in medicine and public health. This article will review the major evidence available regarding publication bias and will suggest measures for overcoming the problem.

Identifying relevant studies for systematic reviews.

OBJECTIVE: To examine the sensitivity and precision of Medline searching for randomised clinical trials. DESIGN: Comparison of results of Medline searches to a "gold standard" of known randomised clinical trials in ophthalmology published in 1988; systematic review (meta-analysis) of results of similar, but separate, studies from many fields of medicine. POPULATIONS: Randomised clinical trials published in 1988 in journals indexed in Medline, and those not indexed in Medline and identified by hand search, comprised the gold standard. Gold standards for the other studies combined in the meta-analysis were based on: randomised clinical trials published in any journal, whether indexed in Medline or not; those published in any journal indexed in Medline; or those published in a selected group of journals indexed in Medline. MAIN OUTCOME MEASURE: Sensitivity (proportion of the total number of known randomised clinical trials identified by the search) and precision (proportion of publications retrieved by Medline that were actually randomised clinical trials) were calculated for each study and combined to obtain weighted means. Searches producing the "best" sensitivity were used for sensitivity and precision estimates when multiple searches were performed. RESULTS: The sensitivity of searching for ophthalmology randomised clinical trials published in 1988 was 82%, when the gold standard was for any journal, 87% for any journal indexed in Medline, and 88% for selected journals indexed in Medline. Weighted means for sensitivity across all studies were 51%, 77%, and 63%, respectively. The weighted mean for precision was 8% (median 32.5%). Most searchers seemed not to use freetext subject terms and truncation of those terms. CONCLUSION: Although the indexing terms available for searching Medline for randomised clinical trials have improved, sensitivity still remains unsatisfactory. A mechanism is needed to "'register" known trials, preferably by retrospective tagging of Medline entries, and incorporating trials published before 1966 and in journals not indexed by Medline into the system.