A randomized study of how physicians interpret research funding disclosures.

BACKGROUND: The effects of clinical-trial funding on the interpretation of trial results are poorly understood. We examined how such support affects physicians' reactions to trials with a high, medium, or low level of methodologic rigor. METHODS: We presented 503 board-certified internists with abstracts that we designed describing clinical trials of three hypothetical drugs. The trials had high, medium, or low methodologic rigor, and each report included one of three support disclosures: funding from a pharmaceutical company, NIH funding, or none. For both factors studied (rigor and funding), one of the three possible variations was randomly selected for inclusion in the abstracts. Follow-up questions assessed the physicians' impressions of the trials' rigor, their confidence in the results, and their willingness to prescribe the drugs. RESULTS: The 269 respondents (53.5% response rate) perceived the level of study rigor accurately. Physicians reported that they would be less willing to prescribe drugs tested in low-rigor trials than those tested in medium-rigor trials (odds ratio, 0.64; 95% confidence interval [CI], 0.46 to 0.89; P=0.008) and would be more willing to prescribe drugs tested in high-rigor trials than those tested in medium-rigor trials (odds ratio, 3.07; 95% CI, 2.18 to 4.32; P<0.001). Disclosure of industry funding, as compared with no disclosure of funding, led physicians to downgrade the rigor of a trial (odds ratio, 0.63; 95% CI, 0.46 to 0.87; P=0.006), their confidence in the results (odds ratio, 0.71; 95% CI, 0.51 to 0.98; P=0.04), and their willingness to prescribe the hypothetical drugs (odds ratio, 0.68; 95% CI, 0.49 to 0.94; P=0.02). Physicians were half as willing to prescribe drugs studied in industry-funded trials as they were to prescribe drugs studied in NIH-funded trials (odds ratio, 0.52; 95% CI, 0.37 to 0.71; P<0.001). These effects were consistent across all levels of methodologic rigor. CONCLUSIONS: Physicians discriminate among trials of varying degrees of rigor, but industry sponsorship negatively influences their perception of methodologic quality and reduces their willingness to believe and act on trial findings, independently of the trial's quality. These effects may influence the translation of clinical research into practice.

Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations.

BACKGROUND: Recent years have witnessed a growing body of observational literature on the association between glucose-lowering treatments and cardiovascular disease. However, many of the studies are based on designs or analyses that inadequately address the methodological challenges involved. METHODS: We reviewed recent observational literature on the association between glucose-lowering medications and cardiovascular outcomes and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We describe and illustrate these methodological issues and their impact on observed associations, providing examples from the reviewed literature. We suggest approaches that may be employed to manage these methodological challenges. RESULTS: From the evaluation of 81 publications of observational investigations assessing the association between glucose-lowering treatments and cardiovascular outcomes, we identified the following methodological challenges: 1) handling of temporality in administrative databases; 2) handling of risks that vary with time and treatment duration; 3) definitions of the exposure risk window; 4) handling of exposures that change over time; and 5) handling of confounding by indication. Most of these methodological challenges may be suitably addressed through application of appropriate methods. CONCLUSIONS/INTERPRETATION: Observational research plays an increasingly important role in the evaluation of the clinical effects of diabetes treatment. Implementation of appropriate research methods holds the promise of reducing the potential for spurious findings and the risk that the spurious findings will mislead the medical community about risks and benefits of diabetes medications.

Validation of claims-based algorithms for identification of high-grade cervical dysplasia and cervical cancer.

BACKGROUND: High-grade cervical dysplasia or cervical intraepithelial neoplasia grade 2 or worse has been widely used as a surrogate endpoint in cervical cancer screening or prevention trials. METHODS: To identify high-grade cervical dysplasia and cervical cancer, we developed claims-based algorithms that incorporated a combination of diagnosis and procedure codes using the billing data in an electronic medical records database and assessed the validity of the algorithms in an independent administrative claims database. We calculated the positive predictive value (PPV) with the 95% confidence interval (CI) of each algorithm, using new cytologic or pathologic diagnosis of cervical intraepithelial neoplasia 2 or 3, carcinoma in situ, or cervical cancer as the gold standard. RESULTS: Having ≥1 diagnosis code for high-grade cervical dysplasia or cervical cancer had a PPV of 57.1% (95%CI, 54.7-59.5%). By requiring ≥2 diagnoses for high-grade cervical dysplasia or cervical cancer, separated by 7-30 days, the PPV increased to 60.2% (95%CI, 53.9-66.1%). At least two diagnoses and a procedure code within a month from the first diagnosis date yielded a PPV of 80.7% (95%CI, 73.6-86.2%). The algorithms had greater PPVs in identifying prevalent high-grade cervical dysplasia or cervical cancer. Overall, the PPVs of these algorithms were similar or slightly lower in the external claims data than in the sample used to derive the algorithms. CONCLUSIONS: Use of ≥2 diagnosis codes in combination with a procedure code appears to be a valid tool for studying high-grade cervical dysplasia and cervical cancer in both electronic medical record and administrative claims databases.

The Extracellular and Cytoplasmic Domains of Syndecan Cooperate Postsynaptically to Promote Synapse Growth at the Drosophila Neuromuscular Junction.

The heparan sulfate proteoglycan (HSPG) Syndecan (Sdc) is a crucial regulator of synapse development and growth in both vertebrates and invertebrates. In Drosophila, Sdc binds via its extracellular heparan sulfate (HS) sidechains to the receptor protein tyrosine phosphatase LAR to promote the morphological growth of the neuromuscular junction (NMJ). To date, however, little else is known about the molecular mechanisms by which Sdc functions to promote synapse growth. Here we show that all detectable Sdc found at the NMJ is provided by the muscle, strongly suggesting a post-synaptic role for Sdc. We also show that both the cytoplasmic and extracellular domains of Sdc are required to promote synapse growth or to rescue Sdc loss of function. We report the results of a yeast two-hybrid screen using the cytoplasmic domains of Sdc as bait, and identify several novel candidate binding partners for the cytoplasmic domains of Sdc. Together, these studies provide new insight into the mechanism of Sdc function at the NMJ, and provide enticing future directions for further exploring how Sdc promotes synapse growth.

Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011.

IMPORTANCE: Prescription and over-the-counter medicines and dietary supplements are commonly used, alone and together, among older adults. However, the effect of recent regulatory and market forces on these patterns is not known. OBJECTIVES: To characterize changes in the prevalence of medication use, including concurrent use of prescription and over-the-counter medications and dietary supplements, and to quantify the frequency and types of potential major drug-drug interactions. DESIGN, SETTING, AND PARTICIPANTS: Descriptive analyses of a longitudinal, nationally representative sample of community-dwelling older adults 62 to 85 years old. In-home interviews with direct medication inspection were conducted in 2005-2006 and again in 2010-2011. The dates of the analysis were March to November 2015. We defined medication use as the use of at least 1 prescription or over-the-counter medication or dietary supplement at least daily or weekly and defined concurrent use as the regular use of at least 2 medications. We used Micromedex to identify potential major drug-drug interactions. MAIN OUTCOMES AND MEASURES: Population estimates of the prevalence of medication use (in aggregate and by therapeutic class), concurrent use, and major drug-drug interactions. RESULTS: The study cohort comprised 2351 participants in 2005-2006 and 2206 in 2010-2011. Their mean age was 70.9 years in 2005-2006 and 71.4 years in 2010-2011. Fifty-three percent of participants were female in 2005-2006, and 51.6% were female in 2010-2011. The use of at least 1 prescription medication slightly increased from 84.1% in 2005-2006 to 87.7% in 2010-2011 (P = .003). Concurrent use of at least 5 prescription medications increased from 30.6% to 35.8% (P = .02). While the use of over-the-counter medications declined from 44.4% to 37.9%, the use of dietary supplements increased from 51.8% to 63.7% (P < .001 for both). There were clinically significant increases in the use of statins (33.8% to 46.2%), antiplatelets (32.8% to 43.0%), and omega-3 fish oils (4.7% to 18.6%) (P < .05 for all). In 2010-2011, approximately 15.1% of older adults were at risk for a potential major drug-drug interaction compared with an estimated 8.4% in 2005-2006 (P < .001). Most of these interacting regimens involved medications and dietary supplements increasingly used in 2010-2011. CONCLUSIONS AND RELEVANCE: In this study, the use of prescription medications and dietary supplements, and concurrent use of interacting medications, has increased since 2005, with 15% of older adults potentially at risk for a major drug-drug interaction. Improving safety with the use of multiple medications has the potential to reduce preventable adverse drug events associated with medications commonly used among older adults.

Addressing limitations in observational studies of the association between glucose-lowering medications and all-cause mortality: a review.

A growing body of observational literature on the association between glucose-lowering treatments and all-cause mortality has been accumulating in recent years. However, many investigations present designs or analyses that inadequately address the methodological challenges involved. We conducted a systematic search with a non-systematic extension to identify observational studies published between 2000 and 2012 that evaluated the effects of glucose-lowering medications on all-cause mortality. We reviewed these studies and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We described these methodological issues and their potential impact on observed associations, providing examples from the reviewed literature, and suggested possible approaches to manage these methodological challenges. We evaluated 67 publications of observational studies evaluating the association between glucose-lowering treatments and all-cause mortality. The identified methodological challenges included trade-offs associated with the outcome of all-cause mortality, incorrect temporal sequencing in administrative databases, inadequate treatment of time-varying hazards and treatment duration effects, unclear definition of the exposure risk window, improper handling of time-varying exposures, and incomplete accounting for confounding by indication. Most of these methodological challenges may be adequately addressed through the application of appropriate methods. Observational research plays an increasingly important role in assessing the clinical effects of diabetes therapy. The implementation of suitable research methods can reduce the potential for spurious findings, and thus the risk of misleading the medical community about benefits and harms of diabetes therapy.

Behavioral and clinical factors associated with self-reported abnormal Papanicolaou tests in rheumatoid arthritis.

BACKGROUND: Some evidence suggests that women with rheumatoid arthritis (RA) are at increased risk for the development of cervical cancer; however, it is unclear how this increase risk is conferred. We aimed to assess the factors related to abnormal Papanicolaou (Pap) tests in women with RA to determine whether they are similar to those reported for the general population. METHODS: A structured questionnaire was mailed to 503 female patients from a longitudinal RA cohort. The survey included items on sociodemographic, behavioral, and gynecological factors. Univariate and multivariable logistic regression models examined the association of self-reported abnormal Pap results with a number of potential behavioral risk factors. RESULTS: The questionnaire response rate was 57.5% (n=289). Median age was 61 years and 97% had ≥1 Pap test previously. Twenty-nine percent of respondents reported a previous abnormal Pap result. In the multivariable logistic model adjusted for age, number of lifetime sexual partners, age at menarche, birth control use, and history of sexually transmitted disease (STD), ever using birth control (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.18-4.52) and previous STD (OR 3.38, 95% CI 1.70-6.70) were associated with an increased risk of abnormal Pap result. Compared with either the state or national population, a greater proportion of the respondents was older, married, and previous smokers, and completed postsecondary education and obtained a Pap test. CONCLUSIONS: In this cross-sectional study, self-reported abnormal Pap results were associated with use of birth control and history of STD in RA patients.