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1.  Support of personalized medicine through risk-stratified treatment recommendations - an environmental scan of clinical practice guidelines 
BMC Medicine  2013;11:7.
Risk-stratified treatment recommendations facilitate treatment decision-making that balances patient-specific risks and preferences. It is unclear if and how such recommendations are developed in clinical practice guidelines (CPGs). Our aim was to assess if and how CPGs develop risk-stratified treatment recommendations for the prevention or treatment of common chronic diseases.
We searched the United States National Guideline Clearinghouse for US, Canadian and National Institute for Health and Clinical Excellence (United Kingdom) CPGs for heart disease, stroke, cancer, chronic obstructive pulmonary disease and diabetes that make risk-stratified treatment recommendations. We included only those CPGs that made risk-stratified treatment recommendations based on risk assessment tools. Two reviewers independently identified CPGs and extracted information on recommended risk assessment tools; type of evidence about treatment benefits and harms; methods for linking risk estimates to treatment evidence and for developing treatment thresholds; and consideration of patient preferences.
We identified 20 CPGs that made risk-stratified treatment recommendations out of 133 CPGs that made any type of treatment recommendations for the chronic diseases considered in this study. Of the included 20 CPGs, 16 (80%) used evidence about treatment benefits from randomized controlled trials, meta-analyses or other guidelines, and the source of evidence was unclear in the remaining four (20%) CPGs. Nine CPGs (45%) used evidence on harms from randomized controlled trials or observational studies, while 11 CPGs (55%) did not clearly refer to harms. Nine CPGs (45%) explained how risk prediction and evidence about treatments effects were linked (for example, applying estimates of relative risk reductions to absolute risks), but only one CPG (5%) assessed benefit and harm quantitatively and three CPGs (15%) explicitly reported consideration of patient preferences.
Only a small proportion of CPGs for chronic diseases make risk-stratified treatment recommendations with a focus on heart disease and stroke prevention, diabetes and breast cancer. For most CPGs it is unclear how risk-stratified treatment recommendations were developed. As a consequence, it is uncertain if CPGs support patients and physicians in finding an acceptable benefit- harm balance that reflects both profile-specific outcome risks and preferences.
PMCID: PMC3565912  PMID: 23302096
Cancer; cardiovascular disease; chronic disease; COPD; diabetes; guidelines; randomized trials; risk assessment; stroke; treatment
2.  Network meta-analysis-highly attractive but more methodological research is needed 
BMC Medicine  2011;9:79.
Network meta-analysis, in the context of a systematic review, is a meta-analysis in which multiple treatments (that is, three or more) are being compared using both direct comparisons of interventions within randomized controlled trials and indirect comparisons across trials based on a common comparator. To ensure validity of findings from network meta-analyses, the systematic review must be designed rigorously and conducted carefully. Aspects of designing and conducting a systematic review for network meta-analysis include defining the review question, specifying eligibility criteria, searching for and selecting studies, assessing risk of bias and quality of evidence, conducting a network meta-analysis, interpreting and reporting findings. This commentary summarizes the methodologic challenges and research opportunities for network meta-analysis relevant to each aspect of the systematic review process based on discussions at a network meta-analysis methodology meeting we hosted in May 2010 at the Johns Hopkins Bloomberg School of Public Health. Since this commentary reflects the discussion at that meeting, it is not intended to provide an overview of the field.
PMCID: PMC3159133  PMID: 21707969
3.  High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease 
BMC Medicine  2011;9:73.
The complexity of chronic diseases is a challenge for investigators conducting randomized trials. The causes for this include the often difficult control for confounding, the selection of outcomes from many potentially important outcomes, the risk of missing data with long follow-up and the detection of heterogeneity of treatment effects. Our aim was to assess such aspects of trial design and analysis for four prevalent chronic diseases.
We included 161 randomized trials on drug and non-drug treatments for chronic obstructive pulmonary disease, type 2 diabetes mellitus, stroke and heart failure, which were included in current Cochrane reviews. We assessed whether these trials defined a single outcome or several primary outcomes, statistically compared baseline characteristics to assess comparability of treatment groups, reported on between-group comparisons, and we also assessed how they handled missing data and whether appropriate methods for subgroups effects were used.
We found that only 21% of all chronic disease trials had a single primary outcome, whereas 33% reported one or more primary outcomes. Two of the fifty-one trials that tested for statistical significance of baseline characteristics adjusted the comparison for a characteristic that was significantly different. Of the 161 trials, 10% reported a within-group comparison only; 17% (n = 28) of trials reported how missing data were handled (50% (n = 14) carried forward last values, 27% (n = 8) performed a complete case analysis, 13% (n = 4) used a fixed value imputation and 10% (n = 3) used more advanced methods); and 27% of trials performed a subgroup analysis but only 23% of them (n = 10) reported an interaction test. Drug trials, trials published after wide adoption of the CONSORT (CONsolidated Standards of Reporting Trials) statement (2001 or later) and trials in journals with higher impact factors were more likely to report on some of these aspects of trial design and analysis.
Our survey showed that an alarmingly large proportion of chronic disease trials do not define a primary outcome, do not use appropriate methods for subgroup analyses, or use naïve methods to handle missing data, if at all. As a consequence, biases are likely to be introduced in many trials on widely prescribed treatments for patients with chronic disease.
PMCID: PMC3141538  PMID: 21663701
4.  Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: a network meta-analysis 
BMC Medicine  2009;7:2.
Most patients with chronic obstructive pulmonary disease (COPD) receive inhaled long-acting bronchodilators and inhaled corticosteroids. Conventional meta-analyses established that these drugs reduce COPD exacerbations when separately compared with placebo. However, there are relatively few head-to-head comparisons and conventional meta-analyses focus on single comparisons rather than on a simultaneous analysis of competing drug regimens that would allow rank ordering of their effectiveness. Therefore we assessed, using a network meta-analytic technique, the relative effectiveness of the common inhaled drug regimes used to reduce exacerbations in patients with COPD.
We conducted a systematic review and searched existing systematic reviews and electronic databases for randomized trials of ≥ 4 weeks' duration that assessed the effectiveness of inhaled drug regimes on exacerbations in patients with stable COPD. We extracted participants and intervention characteristics from included trials and assessed their methodological quality. For each treatment group we registered the proportion of patients with ≥ 1 exacerbation during follow-up. We used treatment-arm based logistic regression analysis to estimate the absolute and relative effects of inhaled drug treatments while preserving randomization within trials.
We identified 35 trials enrolling 26,786 patients with COPD of whom 27% had ≥ 1 exacerbation. All regimes reduced exacerbations statistically significantly compared with placebo (odds ratios ranging from 0.71 (95% confidence interval [CI] 0.64 to 0.80) for long-acting anticholinergics to 0.78 (95% CI 0.70 to 0.86) for inhaled corticosteroids). Compared with long-acting bronchodilators alone, combined treatment was not more effective (comparison with long-acting beta-agonists: odds ratio 0.93 [95% CI 0.84 to 1.04] and comparison with long-acting anticholinergics: odds ratio 1.02 [95% CI 0.90 to 1.16], respectively). If FEV1 was ≤ 40% predicted, long-acting anticholinergics, inhaled corticosteroids, and combination treatment reduced exacerbations significantly compared with long-acting beta-agonists alone, but not if FEV1 was > 40% predicted. This effect modification was significant for inhaled corticosteroids (P = 0.02 for interaction) and combination treatment (P = 0.01) but not for long-acting anticholinergics (P = 0.46). A limitation of this analysis is its exclusive focus on exacerbations and lack of FEV1 data for individual patients.
We found no evidence that one single inhaled drug regimen is more effective than another in reducing exacerbations. Inhaled corticosteroids when added to long-acting beta-agonists reduce exacerbations only in patients with COPD with FEV1 ≤ 40%.
PMCID: PMC2636836  PMID: 19144173
5.  Where is the supporting evidence for treating mild to moderate chronic obstructive pulmonary disease exacerbations with antibiotics? A systematic review 
BMC Medicine  2008;6:28.
Randomised trials comparing different drugs head-to-head are extremely valuable for clinical decision-making. However, it is scientifically and ethically sensible to demand strong evidence that a drug is effective by showing superiority over a placebo before embarking on head-to-head comparisons of potentially ineffective drugs. Our aim was to study the evolvement of evidence from placebo-controlled and head-to-head trials on the effects of antibiotics for the treatment of mild to moderate exacerbations of chronic obstructive pulmonary disease.
We conducted a historical systematic review. Through electronic databases and hand-searches, we identified placebo-controlled and head-to-head antibiotic trials for the treatment of mild to moderate chronic obstructive pulmonary disease exacerbations. We compared the numbers of patients recruited in placebo-controlled and head-to-head trials between 1957 and 2005. Using cumulative meta-analysis of placebo-controlled trials, we determined when, if ever, placebo-controlled trials had shown convincing evidence that antibiotics are effective in preventing treatment failure in patients with mild to moderate chronic obstructive pulmonary disease exacerbations.
The first head-to-head trial was published in 1963. It was followed by another 100 trials comparing different antibiotics in a total of 34,029 patients with mild to moderate chronic obstructive pulmonary disease exacerbations. Over time, the cumulative odds ratio in placebo-controlled trials remained inconclusive throughout with odds ratios ranging from 0.39 (95% confidence intervals 0.04–4.22) to the most recent estimate (1995) of 0.81 (95% confidence intervals 0.52–1.28, P = 0.37).
Placebo-controlled trials do not support the use of antibiotics in chronic obstructive pulmonary disease patients with mild to moderate exacerbations. Conducting head-to-head trials is, therefore, scientifically and ethically questionable. This underscores the requirement to perform or study systematic reviews of placebo-controlled trials before conducting head-to-head trials.
PMCID: PMC2569060  PMID: 18847478
6.  Do citizens have minimum medical knowledge? A survey 
BMC Medicine  2007;5:14.
Experts defined a "minimum medical knowledge" (MMK) that people need for understanding typical signs and/or risk factors of four relevant clinical conditions: myocardial infarction, stroke, chronic obstructive pulmonary disease and HIV/AIDS. We tested to what degree Swiss adult citizens satisfy this criterion for MMK and whether people with medical experience have acquired better knowledge than those without.
Questionnaire interview in a Swiss urban area with 185 Swiss citizens (median age 29 years, interquartile range 23 to 49, 52% male). We obtained context information on age, gender, highest educational level, (para)medical background and specific health experience with one of the conditions in the social surrounding. We calculated the proportion of MMK and examined whether citizens with medical background (personal or professional) would perform better compared to other groups.
No single citizen reached the full MMK (100%). The mean MMK was as low as 32% and the range was 0 -72%. Surprisingly, multivariable analysis showed that participants with a university degree (n = 84; β (95% CI) +3.7% MMK (0.4–7.1) p = 0.03), (para)medical background (n = 34; +6.2% MMK (2.0–10.4), p = 0.004) and personal illness experience (n = 96; +4.9% MMK (1.5–8.2), p = 0.004) had only a moderately higher MMK than those without, while age and sex had no effect on the level of MMK. Interaction between university degree and clinical experience (personal or professional) showed no effect suggesting that higher education lacks synergistic effect.
This sample of Swiss citizens did not know more than a third of the MMK. We found little difference within groups with medical experience (personal or professional), suggesting that there is a consistent and dramatic lack of knowledge in the general public about the typical signs and risk factors of relevant clinical conditions.
PMCID: PMC1894984  PMID: 17540024

Results 1-6 (6)