Evaluating the validity of clinical codes to identify cataract and glaucoma in the UK Clinical Practice Research Datalink.

PURPOSE: The aim of this study is to determine (i) the positive predictive value (PPV) of an algorithm using clinical codes to identify incident glaucoma and cataract events in the Clinical Practice Research Datalink (CPRD) and (ii) the ability to capture the correct timing of these clinical events. METHODS: A total of 21,339 and 5349 potential cataract and glaucoma cases, respectively, were identified in CPRD between 1 January 1990 and 31 December 2010. Questionnaires were sent to the general practitioners (GP) of 1169 (5.5%) cataract and 1163 (21.7%) glaucoma cases for validation. GPs were asked to verify the diagnosis and the timing of the diagnosis and to provide other supporting information. RESULTS: A total of 986 (84.3%) valid cataract questionnaires and 863 (74.2%) glaucoma questionnaires were completed. 92.1% and 92.4% of these used information beyond EMR to verify the diagnosis. Cataract and glaucoma diagnoses were confirmed in the large majority of the cases. The PPV (95% CI) of the cataract and glaucoma Read code algorithm were 92.0% (90.3-93.7%) and 84.1% (81.7-86.6%), respectively. However, timing of diagnosis was incorrect for a substantial proportion of the cases (20.3% and 32.8% of the cataract and glaucoma cases, respectively) among whom 30.4% and 49.2% had discrepancies in diagnosis timing greater than 1 year. CONCLUSIONS: High PPV suggests that the algorithms based on the clinical Read codes are sufficient to identify the cataract and glaucoma cases in CPRD. However, these codes alone may not be able to accurately identify the timing of the diagnosis of these eye disorders. Ltd.

Identification of Stevens-Johnson syndrome and toxic epidermal necrolysis in electronic health record databases.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) carry a high mortality risk. While identifying clinical and genetic risk factors for these conditions has been hindered by their rarity, large electronic health databases hold promise for identifying large numbers of cases for study, especially with the introduction in 2008 of ICD-9 codes more specific for these conditions. OBJECTIVE: The objective of this study is to estimate the validity of ICD-9 codes for ascertaining SJS/TEN in 12 collaborating research units in the USA, covering almost 60 million lives. METHODS: From the electronic databases at each site, we ascertained potential cases of SJS/TEN using ICD-9 codes. At five sites, a subset of medical records was abstracted and standardized criteria applied by board-certified dermatologists to adjudicate diagnoses. Multivariate logistic regression was used to identify factors independently associated with validated SJS/TEN cases. RESULTS: A total of 56 591 potential cases of SJS/TEN were identified. A subset of 276 charts was selected for adjudication and 39 (of the 276) were confirmed as SJS/TEN. Patients with the ICD-9 codes introduced after 2008 were more likely to be confirmed as cases (OR 3.32; 95%CI 0.82, 13.47) than those identified in earlier years. Likelihood of case status increased with length of hospitalization. Applying the probability of case status to the 56 591 potential cases, we estimated 475-875 to be valid SJS/TEN cases. CONCLUSION: Newer ICD-9 codes, along with length of hospitalization, identified patients with a high likelihood of SJS/TEN. This is important for identification of subjects for future pharmacogenomics studies.

Cardiovascular and mortality risks in Parkinson's disease patients treated with entacapone.

The controlled trial Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) reported an unexpected increase in acute myocardial infarction (AMI) with entacapone use in patients with Parkinson's disease (PD). The authors investigated whether entacapone increased cardiovascular and mortality risk compared with the use of a non-levodopa dopamine agonist (DA) or a selective monoamine oxidase type-B inhibitor (MAOBI). Using national Medicare data, a new-user cohort of elderly patients with PD treated with entacapone was propensity score (PS) matched with new users of either DA or MAOBI. The PS model included variables for sociodemographics, cardiovascular disease, medications, prior PD treatment, and comorbidities. Cox proportional hazards regression was used to compare on-therapy time to event for AMI, stroke, and death with DA-MAOBI as a reference. Study cohorts included 8681 entacapone-treated and 17,362 DA-MAOBI-treated initators who were followed for 2569 and 5385 person-years, respectively. Cohorts were closely balanced for all covariates. During follow-up, there were 106 AMIs, 89 strokes, and 201 deaths. The hazard ratio (HR) and 95% confidence interval (CI) associated with entacapone use was 0.86 (95% CI, 0.57-1.30) for AMI, 0.85 (95% CI, 0.54-1.35) for stroke, and 0.79 (95% CI, 0.58-1.07) for death. The risk was unchanged for treatment of ≤ 6 months' and>6 months' duration and was unaffected by adjustment for time-varying levodopa use during follow-up. The risk of each endpoint was not differentially affected by diabetes, ischemic heart disease, or kidney failure status. However, the risk of stroke was modified by the presence (HR, 2.09; 95% CI, 0.98-4.45) or absence (HR, 0.51; 95% CI, 0.27-0.95) of advanced PD-related morbidities (P value for interaction=0.004). Entacapone was not associated with an increased risk of AMI, stroke, or death in elderly patients with PD.

Concomitant use of isotretinoin and contraceptives before and after iPledge in the United States.

PURPOSE: The major concern associated with isotretinoin treatment is its high teratogenic potential. Therefore, ensuring use of contraception while on therapy is an important strategy for at-risk patients and has been emphasized in all risk management programs. iPledge, the latest and most rigorous isotretinoin program, requires, among other stipulations, monthly assessments of contraceptive use for patients undergoing isotretinoin treatment. The purpose of this study is to evaluate isotretinoin usage patterns and assess concomitant use of isotretinoin and contraceptives before and after iPledge. METHODS: Female patients aged 13-45 years with a new prescription for isotretinoin products during 2004-2008 were identified in the IMS Health longitudinal prescription claims database. Monthly concomitant use of isotretinoin and contraceptives was estimated. Segmented regression analysis of interrupted time series data was used to assess changes in monthly proportion of concomitant use in the 24 months preceding versus following iPledge implementation. RESULTS: The number of isotretinoin prescriptions decreased after iPledge implementation. A small but significant increase in monthly proportion of patients concomitantly using isotretinoin and contraceptive therapies was observed immediately after iPledge implementation (1.3%, p-value = 0.02), particularly among younger patients (2.5%, p-value < 0.01). No changes in the proportion of concomitancy over time (i.e. slope) between the periods before and after iPledge implementation were observed. CONCLUSION: The findings of this pharmacy prescription claims-based study suggest a small increase in concomitant use of isotretinoin and contraceptives coincident with the time of implementation of iPledge, particularly among younger women. Published 2013. This article is a U. S. Government work and is in the public domain in the USA.

Validation of an algorithm to estimate gestational age in electronic health plan databases.

PURPOSE: To validate an algorithm that uses delivery date and diagnosis codes to define gestational age at birth in electronic health plan databases. METHODS: Using data from 225,384 live born deliveries to women aged 15-45 years in 2001-2007 within eight of the 11 health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program, we compared (1) the algorithm-derived gestational age versus the "gold-standard" gestational age obtained from the infant birth certificate file and (2) the prenatal exposure status of two antidepressants (fluoxetine and sertraline) and two antibiotics (amoxicillin and azithromycin) as determined by the algorithm-derived versus the gold-standard gestational age. RESULTS: The mean algorithm-derived gestational age at birth was lower than the mean obtained from the birth certificate file among singleton deliveries (267.9 vs 273.5 days) but not among multiple-gestation deliveries (253.9 vs 252.6 days). The algorithm-derived prenatal exposure to the antidepressants had a sensitivity and a positive predictive value of ≥95%, and a specificity and a negative predictive value of almost 100%. Sensitivity and positive predictive value were both ≥90%, and specificity and negative predictive value were both >99% for the antibiotics. CONCLUSIONS: A gestational age algorithm based upon electronic health plan data correctly classified medication exposure status in most live born deliveries, but trimester-specific misclassification may be higher for drugs typically used for short durations.

Reporting of meta-analyses of randomized controlled trials with a focus on drug safety: an empirical assessment.

BACKGROUND: Due to the sparse nature of serious drug-related adverse events (AEs), meta-analyses combining data from several randomized controlled trials (RCTs) to evaluate drug safety issues are increasingly being conducted and published, influencing clinical and regulatory decision making. Evaluation of meta-analyses involves the assessment of both the individual constituent trials and the approaches used to combine them. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting framework is designed to enhance the reporting of systematic reviews and meta-analyses. However, PRISMA may not cover all critical elements useful in the evaluation of meta-analyses with a focus on drug safety particularly in the regulatory-public health setting. PURPOSE: This work was conducted to (1) evaluate the adherence of a sample of published drug safety-focused meta-analyses to the PRISMA reporting framework, (2) identify gaps in this framework based on key aspects pertinent to drug safety, and (3) stimulate the development and validation of a more comprehensive reporting tool that incorporates elements unique to drug safety evaluation. METHODS: We selected a sample of meta-analyses of RCTs based on review of abstracts from high-impact journals as well as top medical specialty journals between 2009 and 2011. We developed a preliminary reporting framework based on PRISMA with specific additional reporting elements critical for the evaluation of drug safety meta-analyses of RCTs. The reporting of pertinent elements in each meta-analysis was reviewed independently by two authors; discrepancies in the independent evaluations were resolved through discussions between the two authors. RESULTS: A total of 27 meta-analyses, 12 from highest impact journals, 13 from specialty medical journals, and 2 from Cochrane reviews, were identified and evaluated. The great majority (>85%) of PRISMA elements were addressed in more than half of the meta-analyses reviewed. However, the majority of meta-analyses (>60%) did not address most (>80%) of the additional reporting elements critical for the evaluation of drug safety. Some of these elements were not addressed in any of the reviewed meta-analyses. LIMITATIONS: This review included a sample of meta-analyses, with a focus on drug safety, recently published in high-impact journals; therefore, we may have underestimated the extent of the reporting problem across all meta-analyses of drug safety. Furthermore, temporal trends in reporting could not be evaluated in this review because of the short time interval selected. CONCLUSIONS: While the majority of PRISMA elements were addressed by most studies reviewed, the majority of studies did not address most of the additional safety-related elements. These findings highlight the need for the development and validation of a drug safety reporting framework and the importance of the current initiative by the Council for International Organizations of Medical Sciences (CIOMS) to create a guidance document for drug safety information synthesis/meta-analysis, which may improve reporting, conduct, and evaluation of meta-analyses of drug safety and inform clinical and regulatory decision making.

Prevalence and trends in the use of antipsychotic medications during pregnancy in the U.S., 2001-2007: a population-based study of 585,615 deliveries.

This study aims to estimate the prevalence of and temporal trends in prenatal antipsychotic medication use within a cohort of pregnant women in the U.S. We identified live born deliveries to women aged 15-45 years in 2001-2007 from 11 U.S. health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program. We ascertained prenatal exposure to antipsychotics from health plan pharmacy dispensing files, gestational age from linked infant birth certificate files, and ICD-9-CM diagnosis codes from health plan claims files. We calculated the prevalence of prenatal use of atypical and typical antipsychotics according to year of delivery, trimester of pregnancy, and mental health diagnosis. Among 585,615 qualifying deliveries, 4,223 (0.72%) were to women who received an atypical antipsychotic and 548 (0.09%) were to women receiving a typical antipsychotic any time from 60 days before pregnancy through delivery. There was a 2.5-fold increase in atypical antipsychotic use during the study period, from 0.33% (95% confidence interval: 0.29%, 0.37%) in 2001 to 0.82% (0.76%, 0.88%) in 2007, while the use of typical antipsychotics remained stable. Depression was the most common mental health diagnosis among deliveries to women with atypical antipsychotic use (63%), followed by bipolar disorder (43%) and schizophrenia (13%). The number and proportion of pregnancies exposed to atypical antipsychotics has increased dramatically in recent years. Studies are needed to examine the comparative safety and effectiveness of these medications relative to other therapeutic options in pregnancy.

Secondary use of randomized controlled trials to evaluate drug safety: a review of methodological considerations.

BACKGROUND: Randomized clinical trials (RCTs) are often positioned at the top of evidence hierarchies. Meta-analyses of RCTs aim to integrate the state of knowledge on a given scientific question, particularly for rare drug-related outcomes. However, although RCTs are valuable tools in our armamentarium, they are rarely designed to evaluate drug safety and are thus susceptible to limitations that may hamper the ability of both RCTs and meta-analyses to fully characterize the safety profiles of drugs. Their potential limitations might be exacerbated in the study of rare outcomes, often encountered in drug safety assessment, when even minor deviations from the intended randomization could impact the stability of the risk estimates. PURPOSE: This article considers the methodological caveats of both RCTs and meta-analyses of RCTs pertinent to the study of drug-related harms. It is intended to stimulate discussion about the impact of these caveats on interpreting findings of RCTs and meta-analyses for drug safety, which would foster more robust, critical evaluations, and thus enhance clinical and regulatory decision-making. METHODS: Pertinent issues that can influence the interpretation of drug-related harms discussed in this article were based on authors' expertise and review of the literature. RESULTS: Investigators and clinicians should be cognizant of the potential limitations of the secondary use of RCTs and meta-analyses in the assessment of drug-related harms and, when applicable, should consider potential remedies to overcome these limitations. LIMITATIONS: Only few practical examples are included in the article due to the fact that many of the discussed caveats are not examined and/or reported in many publications. In addition, the confidential nature of data reviewed at a regulatory agency forestalls an in depth discussion of examples pertaining to specific drugs. Furthermore, our ability to quantify the extent of encountering, or the actual impact of, the caveats addressed in this review on the RCTs findings is limited. It is worth noting that the mere encounter of a given caveat does not mean that it will obviate the utility of drug safety information from a given trial. The extent of its impact is expected to vary based on the specifics of the trial, the drugs studied, the indications, and the nature of the adverse events. CONCLUSIONS: Although some of the limitations described are inherent in RCTs, some of the sources of bias highlighted in this article could be minimized by careful RCT design, planned follow-up, and improved collection of information on adverse events. As future research sheds more light on pertinent knowledge gaps and issues, the ability to maximize the use of RCTs and meta-analyses of RCTs to address drug safety questions of interest will be greatly enhanced.

Mumps and ovarian cancer: modern interpretation of an historic association.

BACKGROUND: Epidemiologic studies found childhood mumps might protect against ovarian cancer. To explain this association, we investigated whether mumps might engender immunity to ovarian cancer through antibodies against the cancer-associated antigen MUC1 abnormally expressed in the inflamed parotid gland. METHODS: Through various health agencies, we obtained sera from 161 cases with mumps parotitis. Sera were obtained from 194 healthy controls. We used an ELISA to measure anti-MUC1 antibodies and electro-chemiluminescence assays to measure MUC1 and CA 125. Log-transformed measurements were analyzed by t-tests, generalized linear models, and Pearson or Spearman correlations. We also conducted a meta-analysis of all published studies regarding mumps and ovarian cancer. RESULTS: Adjusting for assay batch, age, and sex, the level of anti-MUC1 antibodies was significantly higher in mumps cases compared to controls (p = 0.002). Free circulating levels of CA 125, but not MUC1, were also higher in cases (p = 0.02). From the meta-analysis, the pooled odds ratio estimate (and 95% CI) for the mumps and ovarian cancer association was 0.81 (0.68-0.96) (p = 0.01). CONCLUSION: Mumps parotitis may lead to expression and immune recognition of a tumor-associated form of MUC1 and create effective immune surveillance of ovarian cancer cells that express this form of MUC1.

Use of nonsteroidal antiinflammatory agents and incidence of ovarian cancer in 2 large prospective cohorts.

Epidemiologic data on the association between nonsteroidal antiinflammatory drugs (NSAIDs) and ovarian cancer risk have been inconsistent. The authors prospectively examined the association between regular use of aspirin and nonaspirin NSAIDs and ovarian cancer incidence among 197,486 participants of the Nurses' Health Study (NHS) and the Nurses' Health Study-II (NHS-II) over 24 and 16 years of follow-up, respectively. Information on aspirin was initially assessed in 1980 (NHS) and 1989 (NHS-II) and on nonaspirin NSAIDs and acetaminophen in 1990 (NHS) and 1989 (NHS-II) and updated throughout follow-up. The authors used Cox proportional hazards models adjusting for ovarian cancer risk factors. A total of 666 confirmed cases of epithelial ovarian cancer were identified over 2,790,986 person-years of follow-up. The hazard ratios associated with regular use of aspirin, nonaspirin NSAIDs, and acetaminophen were 1.11 (95% confidence interval (CI): 0.92, 1.33), 0.81 (95% CI: 0.64, 1.01), and 1.14 (95% CI: 0.92, 1.43), respectively. The authors did not observe a dose-response relation with increased frequency or duration of regular use of any of these medications and ovarian cancer incidence. The results did not differ substantially by tumor histology. In this large prospective study, the authors found no compelling evidence to support an association between regular use of aspirin, nonaspirin NSAIDs, or acetaminophen and ovarian cancer incidence.

A systematic review of validated suicide outcome classification in observational studies.

BACKGROUND: Suicidal outcomes, including ideation, attempt, and completed suicide, are an important drug safety issue, though few epidemiological studies address the accuracy of suicidal outcome ascertainment. Our primary objective was to evaluate validated methods for suicidal outcome classification in electronic health care database studies. METHODS: We performed a systematic review of PubMed and EMBASE to identify studies that validated methods for suicidal outcome classification published 1 January 1990 to 15 March 2016. Abstracts and full texts were screened by two reviewers using prespecified criteria. Sensitivity, specificity, and predictive value for suicidal outcomes were extracted by two reviewers. Methods followed PRISMA-P guidelines, PROSPERO Protocol: 2016: CRD42016042794. RESULTS: We identified 2202 citations, of which 34 validated the accuracy of measuring suicidal outcomes using International Classification of Diseases (ICD) codes or algorithms, chart review or vital records. ICD E-codes (E950-9) for suicide attempt had 2-19% sensitivity, and 83-100% positive predictive value (PPV). ICD algorithms that included events with 'uncertain' intent had 4-70% PPV. The three best-performing algorithms had 74-92% PPV, with improved sensitivity compared with E-codes. Read code algorithms had 14-68% sensitivity and 0-56% PPV. Studies estimated 19-80% sensitivity for chart review, and 41-97% sensitivity and 100% PPV for vital records. CONCLUSIONS: Pharmacoepidemiological studies measuring suicidal outcomes often use methodologies with poor sensitivity or predictive value or both, which may result in underestimation of associations between drugs and suicidal behaviour. Studies should validate outcomes or use a previously validated algorithm with high PPV and acceptable sensitivity in an appropriate population and data source.

A prospective study on habitual duration of sleep and incidence of breast cancer in a large cohort of women.

Mounting evidence suggests habitual sleep duration is associated with various health outcomes; both short and long sleep duration have been implicated in increased risk of cardiovascular disease, diabetes, and all-cause mortality. However, data on the relation between sleep duration and cancer risk are sparse and inconclusive. A link between low levels of melatonin, a hormone closely related to sleep, and increased risk of breast cancer has recently been suggested but it is unclear whether duration of sleep may affect breast cancer risk. We explored the association between habitual sleep duration reported in 1986 and subsequent risk of breast cancer in the Nurses' Health Study using Cox proportional hazards models. During 16 years of follow-up, 4,223 incident cases of breast cancer occurred among 77,418 women in this cohort. Compared with women sleeping 7 hours, covariate-adjusted hazard ratios and 95% confidence intervals for those sleeping < or =5, 6, 8, and > or =9 hours were 0.93 (0.79-1.09), 0.98 (0.91-1.06), 1.05 (0.97-1.13), and 0.95 (0.82-1.11), respectively. A moderate trend in risk increase towards longer sleep duration was observed when analyses were restricted to participants who reported same sleep duration in 1986 and 2000 (P(trend) = 0.05). In this prospective study, we found no convincing evidence for an association between sleep duration and the incidence of breast cancer.

The Effect of FDA Drug Safety Communications on Patterns of Tiotropium Dispensing: A U.S. Health Plan Claims Database Study.

BACKGROUND: The FDA issued 2 main drug safety communications (DSCs) on the cardiovascular safety of tiotropium in March 2008 (warning of a potential increased stroke risk) and January 2010 (informing of an absence of a significant increased stroke risk or cardiovascular events based on findings from a large trial). OBJECTIVE: To describe the effect of the FDA DSCs on medication dispensing of tiotropium in a large U.S. claims database. METHODS: Initiation of tiotropium products among patients with chronic obstructive pulmonary disease (COPD) aged 40 years and older was determined monthly from 2006-2012 using medication dispensing from the IMS Lifelink Health Plan Claims Database. Similarly, monthly initiation of products containing long-acting beta-agonists (LABAs) was calculated to explore product switching. The effect of the 2008 and 2010 FDA DSCs was measured using interrupted time-series analysis. Subgroups of patients with greater cardiovascular risk were also examined. RESULTS: A decreasing trend in initiation of tiotropium-containing products was present before the initial 2008 DSC. The decline in tiotropium initiation continued until January 2010, accompanied by an increased initiation of LABA-containing products in patients with COPD. In the presence of the existing decreasing trend, the initial DSC was followed by an immediate 2.8% (P = 0.02) further reduction in tiotropium initiation. Tiotropium initiation increased 2.5% (P = 0.03) immediately after the 2010 DSC, reducing the overall decline in rate and stabilizing (flattening) the trend. No significant changes in dispensing level or trend were observed among COPD patients with cardiovascular comorbidity. CONCLUSIONS: Cardiovascular safety concerns may have affected tiotropium initiation as indicated by the decrease in tiotropium dispensing shown immediately following the initial DSC. The effect was alleviated as concerns lessened following the most recent DSC. DISCLOSURES: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors are employed by the FDA and have no conflict of interest relevant to the content of this study. The views expressed herein do not necessarily represent the views of the FDA.

Use of Prescription Drug Samples in the USA: A Descriptive Study with Considerations for Pharmacoepidemiology.

INTRODUCTION: Free prescription drug samples provided in physician offices can lead to exposure misclassification in pharmacoepidemiologic studies that rely on pharmacy claims data. METHODS: We quantified drug-specific sample provision rates based on nationally projected data from a survey of over 3200 US office-based physicians for 1993-2013. RESULTS: Between 2009 and 2013, a total of 44.7 % of newly initiated brand-only sitagliptin but only 3.6 % of generically available metformin therapy was provided as samples. We observed similar discrepancies between newly initiated rosuvastatin and simvastatin, dabigatran and warfarin, atomoxetine and methylphenidate, and between oral antibiotic drugs. During continued therapy, sample use was still present though to a lesser extent (sitagliptin 17.0 %, rosuvastatin 23.9 %), and remained high for some oral contraceptives (norethindrone 55.8 %). Oral contraceptives had the longest average days of sample supply (levonorgestrel, continued use 85.1 days). The average days of supply for all other chronically used study drugs ranged from 13.4 (dabigatran, new use) to 25.3 (exenatide, continued use) per sample provided. From 1993 to 2013, we found pronounced drops in sample provisions over time coinciding with more recent generic approval dates. CONCLUSIONS: We observed markedly differential exposure to medication samples between branded and generic drugs. This can introduce bias in pharmacoepidemiologic studies, especially when adverse events that occur soon after drug initiation are of interest.

Challenges in evaluating cancer as a clinical outcome in postapproval studies of drug safety.

Pharmaceuticals approved in the United States are largely not known human carcinogens. However, cancer signals associated with pharmaceuticals may be hypothesized or arise after product approval. There are many study designs that can be used to evaluate cancer as an outcome in the postapproval setting. Because prospective systematic collection of cancer outcomes from a large number of individuals may be lengthy, expensive, and challenging, leveraging data from large existing databases are an integral approach. Such studies have the capability to evaluate the clinical experience of a large number of individuals, yet there are unique methodological challenges involved in their use to evaluate cancer outcomes. To discuss methodological challenges and potential solutions, the Food and Drug Administration and the National Cancer Institute convened a two-day public meeting in 2014. This commentary summarizes the most salient issues discussed at the meeting.

Racial differences in premenopausal endogenous hormones.

Differences in breast cancer incidence across racial groups are well documented. African Americans have the highest rates of premenopausal breast cancer and Asians have lower breast cancer rates across all age groups. We hypothesized that levels of premenopausal endogenous hormones and growth factors, risk factors that have been predictive of breast cancer, would differ by race. Using a cross-sectional study design, we tested this hypothesis in the Nurses' Health Study II. We assayed estradiol, progesterone, prolactin, sex hormone binding globulin (SHBG), insulin-like growth factor-I (IGF-I), and IGFBP-3 in 111 African American and 111 Asian American women, matched to 111 Caucasian women on age, day of luteal phase, and day, time, and fasting status at blood collection. We analyzed the association between race and hormone levels using robust linear regression methods. In multivariate models, compared with Caucasians, African Americans had 18% higher levels of estradiol (P < 0.01), 17% higher free estradiol (P < 0.01), 11% lower SHBG (P = 0.05), 11% higher IGF-I (P < 0.01), 25% higher free IGF-I (P < 0.01), and 9% lower IGFBP-3 (P < 0.01) levels. In multivariate models, compared with Caucasian women, Asian Americans had 22% higher calculated free estradiol (P < 0.01), 31% lower SHBG (P < 0.01), and 25% higher free IGF-I (P < 0.01) levels. No racial differences were found in progesterone and prolactin levels. Our study showed hormone differences consistent with breast cancer risk between Caucasians and African Americans but inconsistent with breast cancer risk between Asian Americans and Caucasians. Further research is needed to explore differences across racial groups and the link between endogenous hormones and breast cancer risk.

Off-label topical calcineurin inhibitor use in children.

OBJECTIVE: To assess off-label use of the topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, in children during periods before and after regulatory action by the US Food and Drug Administration (FDA) in 2005. METHODS: We identified new pediatric (age <20 years) users of topical tacrolimus or pimecrolimus in US Medicaid from 2001 to 2009, and examined the annual rate of drug use (pre- and postregulatory action) by age. We assessed medical claims for diagnoses consistent with an indication for a TCI, and assessed prescriptions for evidence of first-line atopic dermatitis therapy use before TCI initiation. RESULTS: There were 57,664 eligible pediatric tacrolimus users and 425,242 eligible pediatric pimecrolimus users at baseline. The rate of TCI use decreased substantially after FDA regulatory action. The proportion of new users younger than 2 years of age significantly decreased for both tacrolimus (36.7% to 22.5%, P < .001) and pimecrolimus (47.0% to 33.7%, P < .001) after regulatory actions. Previous use of topical corticosteroids increased by ≈ 7% for both TCIs from the pre- to postregulatory period. However, after regulatory actions, there was only a small increase in the proportion of tacrolimus or pimecrolimus users with an atopic dermatitis or eczema diagnosis before drug initiation, and high strength use of tacrolimus was unchanged. CONCLUSIONS: The rate of TCI use in children younger than 2 years of age fell substantially after FDA regulatory action in 2005. Off-label use of TCI as first-line therapy changed little.

Review of quality assessment tools for the evaluation of pharmacoepidemiological safety studies.

OBJECTIVES: Pharmacoepidemiological studies are an important hypothesis-testing tool in the evaluation of postmarketing drug safety. Despite the potential to produce robust value-added data, interpretation of findings can be hindered due to well-recognised methodological limitations of these studies. Therefore, assessment of their quality is essential to evaluating their credibility. The objective of this review was to evaluate the suitability and relevance of available tools for the assessment of pharmacoepidemiological safety studies. DESIGN: We created an a priori assessment framework consisting of reporting elements (REs) and quality assessment attributes (QAAs). A comprehensive literature search identified distinct assessment tools and the prespecified elements and attributes were evaluated. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the percentage representation of each domain, RE and QAA for the quality assessment tools. RESULTS: A total of 61 tools were reviewed. Most tools were not designed to evaluate pharmacoepidemiological safety studies. More than 50% of the reviewed tools considered REs under the research aims, analytical approach, outcome definition and ascertainment, study population and exposure definition and ascertainment domains. REs under the discussion and interpretation, results and study team domains were considered in less than 40% of the tools. Except for the data source domain, quality attributes were considered in less than 50% of the tools. CONCLUSIONS: Many tools failed to include critical assessment elements relevant to observational pharmacoepidemiological safety studies and did not distinguish between REs and QAAs. Further, there is a lack of considerations on the relative weights of different domains and elements. The development of a quality assessment tool would facilitate consistent, objective and evidence-based assessments of pharmacoepidemiological safety studies.

Interaction between use of non-steroidal anti-inflammatory drugs and selected genetic polymorphisms in ovarian cancer risk.

Inflammation and non-steroidal anti-inflammatory agents (NSAIDs) may play important role in ovarian cancer. However, epidemiologic data are inconsistent, possibly reflecting inter-individual genetic differences affecting the metabolism of NSAIDs. We examined whether common polymorphisms affecting the metabolism of NSAIDs modify the association between NSAIDs and ovarian cancer risk. We genotyped 1,353 DNA samples from women who developed ovarian cancer and 1,823 samples from matched controls participating in the New England Case-Control study and the Nurses' Health Studies. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with regular use of NSAIDs and with relevant polymorphisms on ovarian cancer risk. Multivariable unconditional logistic regression estimated the association of NSAID use across stratum of each genotype. Regular use of NSAIDs was not associated with ovarian cancer risk. Multivariable OR (95% CI) associated with use NSAIDs was 0.85 (95% CI: 0.71-1.02). Associations between NSAID use and ovarian cancer risk did not differ significantly across strata of genotypes. None of the studied polymorphisms was associated with ovarian cancer risk. The multivariable ORs (95% CI) associated with CYP2C9 and UGT1A6 variant genotypes were 0.99 (0.90-1.08) and 0.93 (0.82-1.05), respectively. The multivariable ORs (95% CI) associated with PPAR-γ, COX-2 -765G>C, and COX-2 Ex10+837T>C polymorphisms were 1.02 (0.87-1.20), 0.87 (0.75-1.00), and 0.97 (0.87-1.09), respectively. In this relatively large study, we found no convincing evidence supporting an association between NSAIDs use and ovarian cancer risk. Furthermore, data did not suggest interaction between selected polymorphisms and use of NSAIDs in relation to ovarian cancer risk.