Search

Daina B Esposito,1 Vibha CA Desai,1 Judith J Stephenson,1 M Soledad Cepeda,2 Jennifer G Lyons,1 Crystal N Holick,1 Gregory P Wedin,3 Stephan Lanes1 On behalf of members of the REMS Program Companies Metrics Subteam1HealthCore, Inc., Wilmington, DE, USA; 2Janssen Research and Development, Titusville, NJ, USA; 3Upsher-Smith Laboratories, LLC, Maple Grove, MN, USACorrespondence: Judith J StephensonHealthCore Inc, 123 Justison Street, Suite 200, Wilmington, DE, 19801, USATel +1 302-547-5770Email jstephenson@healthcore.comBackground/Rationale: The US Food and Drug Administration (FDA) approved a Risk Evaluation and Mitigation Strategy (REMS) for extended release/long-acting (ER/LA) opioids in 2012. The purpose of this study was to assess patient knowledge of the safe use of these products following implementation of the REMS and to determine possible effects of the REMS, including impact on medication access.Objective: To assess patient knowledge of safe use of ER/LA opioids and use of REMS patient education tools such as the Medication Guide (MG) and Patient Counseling Document (PCD).Methods: This was a cross-sectional survey of commercially insured (Commercial) and Medicare Advantage-insured (Medicare) adults with ≥ 1 pharmacy claim for an ER/LA opioid (10/01/2015 – 02/28/2017) in the HealthCore Integrated Research Database and Medicaid-insured (Medicaid) adult members of a research panel, about their knowledge of safe use of ER/LA opioids and receipt/comprehension of the MG and PCD.Results: Survey respondents consisted of 382 Commercial, 43 Medicare and 40 Medicaid adults. While ≥ 95% of respondents received and read the MG, fewer were aware of the PCD (Commercial: 47%, Medicare: 65%, Medicaid: 53%). Almost 75% of the knowledge questions were answered correctly by ≥ 80% of all respondents; fewer respondents recognized that use of opioids as directed can lead to death (Commercial: 73%, Medicare: 56%, Medicaid: 63%), the MG should be read at each dispensing (Commercial: 78%, Medicare: 53%, Medicaid: 75%), opioids should not be stored in the medicine cabinet (Commercial: 77%, Medicare: 79%, Medicaid: 58%), missed doses should not be taken as soon as possible (Commercial: 56%, Medicare: 51%, Medicaid: 50%), and pills should not be crushed (Commercial: 85%, Medicare: 67%, Medicaid: 52%).Conclusion: Although most respondents reported reading and understanding the MG and exhibited knowledge of safe use of ER/LA opioids, providers’ use of the PCD and increased understanding of safe use core messages need reinforcement.Keywords: Risk Evaluation and Mitigation Strategy, opioids, patient knowledge

Daina B Esposito, 1 M Soledad Cepeda, 2 Crystal N Holick, 1 Caitlin Knox, 1 Vibha CA Desai, 1 Nianya Liu, 1 Shiva-Krishna Vojjala, 1 Jennifer G Lyons, 1 Gregory P Wedin, 3 Stephan Lanes 1 On Behalf of the REMS Program Companies Metrics Subteam 1HealthCore, Inc, Andover, MA, USA; 2Janssen Research and Development, Titusville, NJ, USA; 3Upsher-Smith Laboratories, LLC, Maple Grove, MN, USACorrespondence: Stephan LanesSafety and Epidemiology, HealthCore, Inc., 300 Brickstone Square, 8th Floor, Suite 801A, Andover, MA 01810, USATel +1 302-384-0673Fax +1 978-247-6650Email slanes@healthcore.comIntroduction: The United States (US) Food and Drug Administration (FDA) required a Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting (ER/LA) opioid analgesics on 09 July 2012.Methods: This study compared the incidence of opioid overdose before (July 2010-June 2012) and after (July 2013-September 2016) the initiation of the Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting (ER/LA) opioid analgesics. We identified patients with ≥ 1 ER/LA opioid dispensing in either time period in national data from the HealthCore Integrated Research DatabaseSM (HIRD) and in United States (US) Medicaid claims data from four states. We described each population, calculated the incidence rate (IR) of opioid overdose, and assessed crude and propensity score adjusted incidence rate ratios (IRR) comparing the overdose rate after vs before implementation of the REMS.Results: A total of 121,229 commercially insured and 11,488 Medicaid patients were included in the analysis. Rates of overdose were substantially higher in Medicaid patients than in the commercially insured patients (IR 192.0, 95% confidence interval [CI] 162.60– 225.18 versus 102.60, 95% CI 93.0– 112.93 in the active period). The IRRs for opioid overdose were 1.01 (95% CI 0.87– 1.17) in the commercially insured population and 0.70 (95% CI 0.52– 0.93) in Medicaid.Conclusion: This leveling off of overdose rates among commercially insured patients and decline among Medicaid patients is encouraging, but it is difficult to disentangle the specific impact of the REMS from many other ongoing initiatives with similar goals.Keywords: opioid, overdose, REMS, Medicaid, claims

Temozolomide (TMZ) is used to treat adult patients with glioblastoma multiforme (GBM). Cases of hepatotoxicity have been reported among patients using TMZ. The objective of the study was to assess the relation, if any, between exposure to TMZ and serious acute liver injury (SALI). We used the HealthCore Integrated Research Database to perform a case-control study nested within a retrospective cohort of adult patients aged 18-100 years with at least two diagnoses of brain cancer anytime between 2006 and 2014. Patients without continuous eligibility or with a SALI diagnosis within 6 months prior to the date of incident brain cancer diagnosis were excluded. Medical records were sought for potential SALI cases and reviewed by two hepatologists. Five controls were selected for each case using incidence density sampling, matched on age and calendar year of index date. The analysis included 61 confirmed SALI cases and 305 selected controls. Exposure to TMZ was classified according to dispensing date and days supply of medication dispensed. We estimated odds ratios using conditional logistic regression models. The odds ratio for any exposure to TMZ was 0.91 (95% CI 0.44-1.91), for recent exposure to TMZ was 0.62 (95% CI 0.21-1.85). There was no increased risk of SALI with increasing duration of exposure to TMZ. When patients with unconfirmed SALI were included in the analysis, results were similar (OR 1.04; 95% CI 0.70-1.54). In conclusion, this study did not find an association between TMZ and SALI risk among patients with brain cancer.

Purpose We validated procedure codes used in health insurance claims for reimbursement of rotavirus vaccination by comparing claims for monovalent live-attenuated human rotavirus vaccine (RV1) and live, oral pentavalent rotavirus vaccine (RV5) to medical records. Methods Using administrative data from two commercially insured United States populations, we randomly sampled vaccination claims for RV1 and RV5 from a cohort of infants aged less than 1 year from an ongoing post-licensure safety study of rotavirus vaccines. The codes for RV1 and RV5 found in claims were confirmed through medical record review. The positive predictive value (PPV) of the Current Procedural Terminology codes for RV1 and RV5 was calculated as the number of medical record-confirmed vaccinations divided by the number of medical records obtained. Results Medical record review confirmed 92 of 104 RV1 vaccination claims (PPV: 88.5%; 95% CI: 80.7–93.9%) and 98 of 113 RV5 vaccination claims (PPV: 86.7%; 95% CI: 79.1–92.4%). Among the 217 medical records abstracted, only three (1.4%) of vaccinations were misclassified in claims—all were RV5 misclassified as RV1. The medical records corresponding to 9 RV1 and 15 RV5 claims contained insufficient information to classify the type of rotavirus vaccine. Conclusions Misclassification of rotavirus vaccines is infrequent within claims. The PPVs reported here are conservative estimates as those with insufficient information in the medical records were assumed to be incorrectly coded in the claims. Copyright © 2016 John Wiley & Sons, Ltd.

Purpose The aim of this study was to develop and validate an insurance claims-based algorithm for identifying urinary retention (UR) in epilepsy patients receiving antiepileptic drugs to facilitate safety monitoring. Methods Data from the HealthCore Integrated Research DatabaseSM in 2008–2011 (retrospective) and 2012–2013 (prospective) were used to identify epilepsy patients with UR. During the retrospective phase, three algorithms identified potential UR: (i) UR diagnosis code with a catheterization procedure code; (ii) UR diagnosis code alone; or (iii) diagnosis with UR-related symptoms. Medical records for 50 randomly selected patients satisfying ≥1 algorithm were reviewed by urologists to ascertain UR status. Positive predictive value (PPV) and 95% confidence intervals (CI) were calculated for the three component algorithms and the overall algorithm (defined as satisfying ≥1 component algorithms). Algorithms were refined using urologist review notes. In the prospective phase, the UR algorithm was refined using medical records for an additional 150 cases. Results In the retrospective phase, the PPV of the overall algorithm was 72.0% (95%CI: 57.5–83.8%). Algorithm 3 performed poorly and was dropped. Algorithm 1 was unchanged; urinary incontinence and cystitis were added as exclusionary diagnoses to Algorithm 2. The PPV for the modified overall algorithm was 89.2% (74.6–97.0%). In the prospective phase, the PPV for the modified overall algorithm was 76.0% (68.4–82.6%). Upon adding overactive bladder, nocturia and urinary frequency as exclusionary diagnoses, the PPV for the final overall algorithm was 81.9% (73.7–88.4%). Conclusions The current UR algorithm yielded a PPV > 80% and could be used for more accurate identification of UR among epilepsy patients in a large claims database. Copyright © 2016 John Wiley & Sons, Ltd.

Inflammatory bowel disease (IBD) is a chronic condition commonly requiring lifelong care. Both IBD and IBD-related treatments can cause significant morbidity, and it is often difficult to differentiate their relative etiologic contribution to adverse events (AEs). The objectives of this study were to assess the rates of select AEs among patients with IBD as a function of disease severity and of the use of anti-tumor necrosis factor alpha (anti-TNFα) medications.We conducted a retrospective cohort study of IBD patients in the HealthCore Integrated Research Database (HIRD(TM)) between January 2004 and January 2011 to determine rates of AEs in patients with mild and moderate to severe IBD. Key study endpoints were select prespecified malignant neoplasms, infections, and other AEs of interest.A total of 33,386 IBD patients (52.7% ulcerative colitis; 47.3% Crohn's disease) met the inclusion criteria, and 60% had been followed for ≥1 year. Patients with moderate to severe IBD had increased rates of infections, lymphatic and digestive tract cancers, gastrointestinal (GI) perforations, and myocardial infarctions versus patients with mild IBD. Patients with IBD who used anti-TNFα therapies during the study had increased incidence of many types of infections, certain GI cancers (including rectal and anal cancer), intestinal perforations, and kidney stones compared with patients who had never used anti-TNFα therapies.Results from this large US cohort provide descriptive information on AE rates in a population of IBD patients undergoing routine care, estimating background incidence rates of AEs that are not readily available in the published literature. Our study findings may be limited owing to a lack of generalizability and potential for misclassification due to reliance on medical diagnosis and treatment and procedure codes to identify disease, comorbidities, and treatments. Further research and validation of our findings in other populations and databases are needed.

Background We measured birth prevalence of major congenital malformations (MCMs) after topiramate use during pregnancy to screen for a possible signal of increased risk. Methods Using four healthcare databases, we identified three cohorts of pregnant women: cohort 1, used topiramate during the first trimester; cohort 2, used topiramate or another antiepileptic drug previously but not during pregnancy; and cohort 3, were pregnant and did not use topiramate but had indications for use individually matched to those of users. Cohort 1 was compared with cohorts 2 and 3. MCMs were a code for any major congenital malformation dated within 30 days of the delivery date on the mother's claims or within 365 days after infant birth date, excluding a genetic or syndromic basis, and with procedure or healthcare usage consistent with the MCM diagnosis code in the 365 days after infant birth. Results Of the 10 specific common MCMs evaluated, 1 (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both primary comparisons, and 4 (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio greater than 1.5 for one of the two comparisons. Following screening of organ systems with elevated MCMs, the prevalence ratio was greater than 1.5 for patent ductus arteriosus in both comparisons and for obstructive genitourinary defects in one comparison. Conclusion To evaluate a large number of MCMs across many pregnancies, we used crude methods for detecting potential signals. Therefore, these results should be seen as potential signals, not causal. Birth Defects Research (Part A) 103:269–275, 2015. © 2015 Wiley Periodicals, Inc.

Purpose First marketed in the USA in 1996, topiramate (TPM) is an antiepileptic drug later approved for migraine prophylaxis, and in 2012 for weight loss in combination with phentermine. Some studies indicate an elevated prevalence of oral cleft (OC) in infants exposed to TPM in utero. We evaluated the association between TPM use in early pregnancy and the risk of OC. Methods This retrospective cohort study used 1997–2011 automated data from four sources: HealthCore and OptumInsight (commercial insurance claims), Truven Health (Medicaid claims), and Kaiser Permanente Northern California Region (electronic medical records). We compared the prevalence of OCs in infants of women exposed to TPM in the first trimester (TPM cohort) with the prevalence in infants of women formerly exposed to TPM or other antiepileptic drugs (formerly exposed [FE] cohort) and infants of women with similar medical profiles (SMPs) to the TPM cohort that were not exposed to TPM (SMP cohort). To control for confounding, we used stratification and standardization for individual variables and propensity score deciles. Results The birth prevalence of OCs was 0.36% (7/1945) in the TPM cohort, 0.14% (20/13 512) in the FE cohort, and 0.07% (9/13 614) in the SMP cohort. Standardized by site, the prevalence ratio (PR) for TPM versus FE was 2.5 (95% CI: 1.0–6.0) and for TPM versus SMP was 5.4 (95% CI: 2.0–14.6). Adjustment for covariates one at a time or by propensity score yielded similar results. Conclusion Consistent with other recent epidemiologic research, first-trimester TPM exposure was associated with an elevated birth prevalence of OC. Copyright © 2014 John Wiley & Sons, Ltd.

Study Objective To estimate the incidence and relative risk of a hospitalization or emergency visit for noninfectious liver injury in users of eight oral antimicrobials—amoxicillin, amoxicillin-clavulanic acid, clarithromycin, cefuroxime, doxycycline, levofloxacin, moxifloxacin, telithromycin—compared with nonusers of these antimicrobials. Design Retrospective, observational cohort study with a nested case-control analysis. Data Source HealthCore Integrated Research Database. Patients Adults with continuous health plan enrollment for at least 6 months before study entry who had a new dispensing of a study antimicrobial between July 1, 2001, and March 31, 2009. Cases had diagnoses indicating noninfectious liver injury during follow-up. To control for potentially confounding risk factors, 10 controls at risk for liver injury during follow-up were matched to each case by age, sex, and event date (liver injury date of the case), and analyses were adjusted for medical history, concomitant drugs, and health care service use. Measurements and Main Results Two physician reviewers (blind to exposure) validated the cases. Among 1.3 million antimicrobial users, we identified 607 cases of liver injury, including 82 cases of severe hepatocellular injury and 11 cases of liver failure. Liver injury incidence in nonusers of study antimicrobials was 35/100,000 person-years (95% confidence interval [CI] 29–42/100,000 person-years). For valid cases, the adjusted relative risk among current users of multiple antimicrobials was 3.2 (95% CI 1.6–6.7). Levofloxacin had the highest relative risk for current single use (3.2, 95% CI 1.8–5.8). Relative risks were also elevated for amoxicillin-clavulanic acid (2.5, 95% CI 1.3–5.0), doxycycline (2.5, 95% CI 1.2–5.2), moxifloxacin (2.3, 95% CI 1.1–4.7), and amoxicillin (2.3, 95% CI 1.1–4.7). Conclusion The results support a comparatively high adjusted relative risk of liver injury among patients exposed concurrently to multiple antimicrobials and modest elevations in the risk for several antimicrobials used alone; however, we found little evidence of any strong effect of commonly used antimicrobials on the risk of liver injury.

Background Health insurance claims databases can provide data for studies of vaccine-related Guillain–Barre’ Syndrome (GBS), but not all patients with a diagnostic ICD-9-CM code for GBS have the disease. The objective of this study was to evaluate the positive predictive values (PPVs) of claims-based algorithms for identifying GBS cases in 4 claims database environments. Methods Potential cases were adolescents ages 11–21 with at least one claim for GBS (ICD-9-CM code 357.0). Medical record reviews by a panel of 3 neurologists were conducted for case confirmation. Claims data considered for inclusion in the case-ascertainment algorithm included coding position, physician specialty, visit type, diagnostic tests. PPVs were used to assess the contribution of study factors in predicting case status. Results Among 361 individuals with a GBS diagnosis code, 106 were confirmed overall (PPV = 0.29), varying from 0.24 to 0.56 across the 4 sites. Requiring the GBS code to be associated with a neurologist visit (PPV = 0.53) or to be in a primary position on an inpatient claim (0.56) improved the performance. A composite algorithm including a primary inpatient GBS code and a neurologist visit associated with any GBS code gave the highest PPV (0.70). Incorporating claims for diagnostic testing had little impact on the PPV. Findings were generally similar across study sites. Conclusions Algorithms were able to identify GBS cases better than the single occurrence of the diagnostic code for GBS, and these algorithms may perform similarly in different claims environments.

PURPOSE To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings. METHODS We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database(SM) ) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions. RESULTS Forthcoming. CONCLUSIONS This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations.

Little is known about the effects of diet after breast cancer diagnosis on survival. We prospectively examined the relation between post-diagnosis dietary factors and breast cancer and all-cause survival in women with a history of invasive breast cancer diagnosed between 1987 and 1999 (at ages 20–79 years). Diet after breast cancer diagnosis was measured using a 126-item food frequency questionnaire. Among 4,441 women without a history of breast cancer recurrence prior to completing the questionnaire, 137 subsequently died from breast cancer within 7 years of enrollment. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for intake of macronutrients as well as selected micronutrients and food groups from Cox proportional hazards regression models. After adjustment for factors at diagnosis (age, state of residence, menopausal status, smoking, breast cancer stage, alcohol, history of hormone replacement therapy), interval between diagnosis and diet assessment, and at follow-up (energy intake, breast cancer treatment, body mass index, and physical activity), women in the highest compared to lowest quintile of intake of saturated fat and trans fat had a significantly higher risk of dying from any cause (HR = 1.41, 95% CI = 1.06 to 1.87, P-trend = 0.03) for saturated fat; (HR = 1.78, 95% CI = 1.35 to 2.32, P-trend = 0.01) for trans fat intake. Associations were similar, though did not achieve statistical significance, for breast cancer survival. This study suggests that lower intake of saturated and trans fat in the post-diagnosis diet is associated with improved survival after breast cancer diagnosis.

Current data suggest that caffeinated beverages may be associated with lower risk of glioma. Caffeine has different effects on the brain, some of which could play a role in brain carcinogenesis, and coffee has been consistently associated with reduced risk of liver cancer, thus suggesting a potential anticarcinogenic effect. A total of 335 incident cases of gliomas (men, 133; women, 202) were available from three independent cohort studies. Dietary intake was assessed by food frequency questionnaires obtained at baseline and during follow-up. Cox proportional hazard models were used to estimate incidence rate ratios (RR) and 95% confidence intervals (CI) between consumption of coffee, tea, carbonated beverages, caffeine, and glioma risk adjusting for age and total caloric intake. Estimates from each cohort were pooled using a random-effects model. Consumption of five or more cups of coffee and tea daily compared with no consumption was associated with a decrease risk of glioma (RR, 0.60; 95% CI, 0.41-0.87; Ptrend = 0.04). Inverse, although weaker, associations were also observed between coffee, caffeinated coffee, tea, and carbonated beverages and glioma risk. No association was observed between decaffeinated coffee and glioma risk. Among men, a statistically significant inverse association was observed between caffeine consumption and risk of glioma (RR, 0.46; 95% CI, 0.26-0.81; Ptrend = 0.03); the association was weaker among women. Our findings suggest that consumption of caffeinated beverages, including coffee and tea, may reduce the risk of adult glioma, but further research is warranted to confirm these findings in other populations. Cancer Epidemiol Biomakers Prev; 19(1);39–47

Study Objective. To estimate the risk of upper gastrointestinal complications associated with use of cyclooxygenase-2 (COX-2) selective (celecoxib and rofecoxib) and individual nonselective nonsteroidal antiinflammatory drugs (NSAIDs) compared with nonuse of these drugs. Design. Nested case-control study. Data Source. Administrative health care databases of Saskatchewan, Canada. Patients. Among a population of men and women aged 20–89 years who were covered by public health insurance with prescription drug benefits between November 15, 1999, and December 31, 2001, 726 case patients with first hospitalization for upper gastrointestinal complications (with validation of cases through review of hospital medical records) were confirmed from 1,054,532 person-years of follow-up, and 20,002 control patients were randomly selected from all eligible controls, frequency matched to cases on their index date (± 3 mo). Measurements and Main Results. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between upper gastrointestinal complications and use of NSAIDs. Current rofecoxib and naproxen users had the highest risk for upper gastrointestinal complications with adjusted ORs of 3.6 (95% CI 2.2–5.7) and 3.4 (95% CI 1.8-6.7), respectively. No association was found between the risk of upper gastrointestinal complications and use of celecoxib (OR 1.1, 95% CI 0.7-1.8) or the use of diclofenac plus misoprostol (OR 0.7, 95% CI 0.3-1.8). A dose-response relationship was observed for rofecoxib and naproxen with ORs for high dose of 5.2 (95% CI 2.5–10.6) and 5.1 (95% CI 2.1–12.3), respectively. Short-term users of celecoxib and naproxen had a higher risk than long-term users, whereas among users of rofecoxib the risk was higher among long-term than short-term users. Conclusion. These findings support the variability of individual NSAIDs in the elevated risk of upper gastrointestinal complications. Our results suggest that the risk for rofecoxib is similar to that for naproxen. Celecoxib users appear to have a similar risk for upper gastrointestinal complications as nonusers; however, the risk may be increased at the start of treatment with celecoxib.

Objective: The aim of this study was to estimate the association between atomoxetine and cerebrovascular accident (CVA) and transient ischemic attack (TIA) in adults. Methods: This cohort study conducted within a health insurance database included 21,606 atomoxetine initiators matched to 21,606 stimulant attention-deficit/hyperactivity disorder (ADHD) medication initiators on the basis of propensity scores and a sample from the source population (N = 42,993). Outcomes were confirmed through a medical record review or a National Death Index search. Poisson regression was used to estimate the rate ratio and 95% confidence interval (CI) of CVA or TIA according to the treatment. Cox regression was used to estimate the hazards ratio (HR) and 95% CI for comparisons across cohorts. Results: Forty-four CVAs and 21 TIAs occurred during a mean follow-up of 1.5 years. The rate ratio of the current atomoxetine compared with the current stimulant ADHD medication was 1.38 for CVA (95% CI, 0.42-4.54) and 0.31 for TIA (95% CI, 0.04-2.63). Results for atomoxetine compared with the stimulant ADHD medication according to initial cohort assignment were consistent, with no increased risk for CVA or TIA. An increased risk of TIA was observed between initiation of an ADHD medication compared with the general population (HR, 3.44; 95% CI, 1.13-10.60); however, a similar pattern was not observed for CVA (HR, 0.71; 95% CI, 0.34-1.47). Conclusions: These results do not support an increased risk of CV events with atomoxetine compared with the stimulant ADHD medication. Users of ADHD medications may be at an increased risk of TIA compared with the general population.

We validated procedure codes used in health insurance claims for reimbursement of rotavirus vaccination by comparing claims for monovalent live-attenuated human rotavirus vaccine (RV1) and live, oral pentavalent rotavirus vaccine (RV5) to medical records.Using administrative data from two commercially insured United States populations, we randomly sampled vaccination claims for RV1 and RV5 from a cohort of infants aged less than 1 year from an ongoing post-licensure safety study of rotavirus vaccines. The codes for RV1 and RV5 found in claims were confirmed through medical record review. The positive predictive value (PPV) of the Current Procedural Terminology codes for RV1 and RV5 was calculated as the number of medical record-confirmed vaccinations divided by the number of medical records obtained.Medical record review confirmed 92 of 104 RV1 vaccination claims (PPV: 88.5%; 95% CI: 80.7-93.9%) and 98 of 113 RV5 vaccination claims (PPV: 86.7%; 95% CI: 79.1-92.4%). Among the 217 medical records abstracted, only three (1.4%) of vaccinations were misclassified in claims-all were RV5 misclassified as RV1. The medical records corresponding to 9 RV1 and 15 RV5 claims contained insufficient information to classify the type of rotavirus vaccine.Misclassification of rotavirus vaccines is infrequent within claims. The PPVs reported here are conservative estimates as those with insufficient information in the medical records were assumed to be incorrectly coded in the claims. Copyright © 2016 John WileySons, Ltd.

Genetic variation in vitamin D–related genes has not been investigated comprehensively and findings are equivocal. We studied the association between polymorphisms across the entire vitamin D receptor (VDR) gene and genes encoding for vitamin D activating enzyme 1-α-hydroxylase (CYP27B1) and deactivating enzyme 24-hyroxylase (CYP24A1) and prostate cancer risk among middle-aged men using a population-based case-control study design. DNA samples and survey data were obtained from incident cases (n = 630), 40 to 64 years old, identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry from 1993 to 1996 and from random controls (n = 565) of similar age without a history of prostate cancer. We selected and genotyped tag single-nucleotide polymorphisms to predict common variants across VDR (n = 22), CYP27B1 (n = 2), and CYP24A1 (n = 14). Haplotypes of VDR and CYP24A1 were not associated with prostate cancer risk. In the genotype analysis, homozygotes at two VDR loci (rs2107301 and rs2238135) were associated with a 2- to 2.5-fold higher risk of prostate cancer compared with the homozygote common allele [odds ratio, 2.47 (95% confidence interval, 1.52-4.00; P = 0.002) and 1.95 (95% confidence interval, 1.17-3.26; P = 0.007), respectively; P value corrected for multiple comparisons for VDR = 0.002]. We found no evidence that the two associated VDR single-nucleotide polymorphisms were modified by age at diagnosis, prostate cancer aggressiveness, first-degree family history of prostate cancer, or vitamin D intake. Genotypes of CYP27B1 and CYP24A1 were not associated with prostate cancer risk. Our findings suggest that polymorphisms in the VDR gene may be associated with prostate cancer risk and, therefore, that the vitamin D pathway might have an etiologic role in the development of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(10):1990–9)

Background Nutrients in dietary fruit and vegetables have been hypothesized to lower the risk of glioma by reducing the endogenous formation of N-nitroso compounds. Studies examining fruit and vegetable consumption and brain tumors have relied on case-control study designs, with one exception, and results have been inconsistent. Objective We prospectively examined the relation between consumption of fruit and vegetables (and specifically carotenoids) and the risk of glioma among men and women in 3 large US cohort studies: the Health Professionals Follow-Up Study (HPFS), the Nurses' Health Study I (NHS I), and NHS II. Design Dietary intake was assessed by food-frequency questionnaires obtained at baseline and updated every 4 y through 2002 (HPFS and NHS I) or 2003 (NHS II). We identified 296 incident adult gliomas during 3 669 589 person-years of follow-up. Cox proportional hazard models were used to estimate incidence rate ratios (RR) and 95% CIs between intake of fruit, vegetables, and carotenoids and glioma risk, with adjustment for age and total caloric intake. Results Updated average consumption of total fruit and vegetables was not significantly associated with glioma risk in the men and women (pooled multivariate RR in a comparison of the highest with the lowest quintile: 1.12; 95% CI: 0.74, 1.69). Other fruit and vegetable subgroups, individual fruit and vegetables, and 5 major carotenoids were not significantly associated with risk of glioma. Conclusion Our findings suggest that fruit, vegetable, and carotenoid consumption is not likely associated strongly with the risk of adult glioma.

Estimates of idiopathic pulmonary fibrosis (IPF) incidence and prevalence from electronic databases without case validation may be inaccurate.Develop claims algorithms to identify IPF and assess their positive predictive value (PPV) to estimate incidence and prevalence in the United States.We developed three algorithms to identify IPF cases in the HealthCore Integrated Research Database. Sensitive and specific algorithms were developed based on literature review and consultation with clinical experts. PPVs were assessed using medical records. A third algorithm used logistic regression modeling to generate an IPF score and was validated using a separate set of medical records. We estimated incidence and prevalence of IPF using the sensitive algorithm corrected for the PPV.We identified 4,598 patients using the sensitive algorithm and 2,052 patients using the specific algorithm. After medical record review, the PPVs of these algorithms using the treating clinician's diagnosis were 44.4 and 61.7%, respectively. For the IPF score, the PPV was 76.2%. Using the clinical adjudicator's diagnosis, the PPVs were 54 and 57.6%, respectively, and for the IPF score, the PPV was 83.3%. The incidence and period prevalences of IPF, corrected for the PPV, were 14.6 per 100,000 person-years and 58.7 per 100,000 persons, respectively.Sensitive algorithms without correction for false positive errors overestimated incidence and prevalence of IPF. An IPF score offered the greatest PPV, but it requires further validation.

The aim of this study was to develop and validate an insurance claims-based algorithm for identifying urinary retention (UR) in epilepsy patients receiving antiepileptic drugs to facilitate safety monitoring.Data from the HealthCore Integrated Research Database(SM) in 2008-2011 (retrospective) and 2012-2013 (prospective) were used to identify epilepsy patients with UR. During the retrospective phase, three algorithms identified potential UR: (i) UR diagnosis code with a catheterization procedure code; (ii) UR diagnosis code alone; or (iii) diagnosis with UR-related symptoms. Medical records for 50 randomly selected patients satisfying ≥1 algorithm were reviewed by urologists to ascertain UR status. Positive predictive value (PPV) and 95% confidence intervals (CI) were calculated for the three component algorithms and the overall algorithm (defined as satisfying ≥1 component algorithms). Algorithms were refined using urologist review notes. In the prospective phase, the UR algorithm was refined using medical records for an additional 150 cases.In the retrospective phase, the PPV of the overall algorithm was 72.0% (95%CI: 57.5-83.8%). Algorithm 3 performed poorly and was dropped. Algorithm 1 was unchanged; urinary incontinence and cystitis were added as exclusionary diagnoses to Algorithm 2. The PPV for the modified overall algorithm was 89.2% (74.6-97.0%). In the prospective phase, the PPV for the modified overall algorithm was 76.0% (68.4-82.6%). Upon adding overactive bladder, nocturia and urinary frequency as exclusionary diagnoses, the PPV for the final overall algorithm was 81.9% (73.7-88.4%).The current UR algorithm yielded a PPV 80% and could be used for more accurate identification of UR among epilepsy patients in a large claims database.

Background:Nitrosamines,whichareknownbladdercarcinogens, or their precursors are found in certain meat items, and concentrationsofthesecompoundsareespeciallyhighinbacon.Only3cohort studies, all with 100 case subjects, have examined the relation between meat intake and bladder cancer, and few studies have examined the relation of different meat types with bladder cancer. Objective:Theaimwastoexaminetheassociationbetweenspecific meat items and bladder cancer in 2 large prospective studies. Design: We analyzed data from 2 cohorts with up to 22 y of follow-up and 808 incident bladder cancer cases. Detailed data on meat were obtained from multiple food-frequency questionnaires administered over time. Multivariate relative risks (RRs) and 95% CIs were estimated by using Cox proportional hazards models with control for potential confounders, including detailed smoking history. Results:Menandwomenwithahighintakeofbacon(5servings/ wk)hadanelevatedriskofbladdercancercomparedwiththosewho never ate bacon (multivariate RR 1.59; 95% CI 1.06, 2.37), although the overall association was not statistically significant (P fortrend0.06).However,theassociationwithbaconwasstronger and became statistically significant after the removal of individuals who indicated having “greatly” changed their red meat (men) or bacon (women) intake during the 10 y before baseline (multivariate RR 2.10; 95% CI 1.24, 3.55; P for trend 0.006). A positive association was also detected for intake of chicken without skin, but not for chicken with skin or for other meats, including processed meats, hot dogs, and hamburgers. Conclusions:Inthese2cohortscombined,frequentconsumptionof bacon was associated with an elevated risk of bladder cancer. Other studieswithdataonspecificmeatitemsarenecessarytoconfirmour findings. Am J Clin Nutr 2006;84:1177–83.

To evaluate prospectively the association between intakes of fish, marine fatty acids, and bladder cancer risk in two ongoing cohorts, the Health Professionals Follow-up Study and the Nurses’ Health Study. During 16 and 18 years of follow-up, 501 and 235 incident cases of bladder cancer were diagnosed among men and women, respectively. Cox proportional hazard models were used to estimate incidence rate ratios (RR) and 95% confidence intervals (CI) between fish intake and bladder cancer risk adjusting for age, total caloric intake, pack-years of cigarette smoking, and current smoking. We observed no significant overall association between total fish intake and bladder cancer risk, even when we compared ≥1 servings of fish per day to fish intake ≤1–3 servings per month. Among men, a statistically significant lower risk of bladder cancer was observed among men consuming fish or high marine fatty acid, after excluding the first 4 years of follow-up (MV RR = 0.60; 95% CI, 0.38–0.94, for ≥1 total fish servings per day compared to ≤1–3 servings per month). Overall, these findings suggest that fish intake is not likely to be appreciably associated with the risk of bladder cancer.

Objectives We examined post-diagnostic diet and risk of cancer progression in a cohort of men with prostate cancer from the Health Professionals Follow-up Study. Methods We observed 392 progression outcomes among 1,202 men diagnosed with incident localized/regional prostate cancer between 1986 and 1996. Men completed prospective dietary surveys before and after diagnosis and were followed through 2000. We examined post-diagnostic consumption of red meat, grains, vegetables, fruits, milk, tomatoes, tomato sauce, and fish as predictors of progression using Cox proportional hazard regression models adjusted for total energy, age, clinical factors, and pre-diagnostic diet. Results Men in the highest versus lowest quartile of post-diagnostic fish consumption had a multivariate hazard ratio (HR) of progression of 0.73 (95% CI 0.52–1.02); the comparable HR for tomato sauce was 0.56 (95% CI 0.38–0.82). We observed inverse linear relationships for fish and tomato sauce and risk of progression (HR = 0.83, p-value = 0.006 and HR = 0.80, p-value = 0.04 for a two serving/week increase of fish and tomato sauce, respectively). Milk and fresh tomato consumption were associated with small elevations in risk. Conclusions These data suggest that diet after diagnosis may influence the clinical course of prostate cancer, and fish and tomato sauce may offer some protection against disease progression.

Objective: To examine the relation between fruits and vegetables, carotenoids, folate, and vitamins A, C, E and the risk of bladder cancer in a prospective study of women Methods: A total of 237 incident bladder cancer cases were documented during 20 years of follow-up among 88,796 women enrolled in the Nurses’ Health Study. Dietary intake was assessed by food-frequency questionnaires every two to four years and incident diagnosis of bladder cancer was ascertained every two years. Cox proportional hazard models were used to estimate incidence rate ratios (RR) and 95% confidence intervals (CI) for bladder cancer risk, adjusting for age, pack-years of smoking, current smoking, and total caloric intake. Results: Consumption of total fruits and vegetables was not associated with bladder cancer risk (RR = 1.08, 95% CI = 0.70–1.65, for > 5.5 compared to < 2.5 servings per day). Similarly, dietary intakes of carotenoids, folate, and vitamins A, C, E, were not related to bladder cancer risk. No association was observed between supplemental intake of multivitamins, vitamins A, C, E and bladder cancer risk. Conclusions: We did not observe any association for fruit and vegetable consumption or vitamin intake and bladder cancer risk among women.

We examined prospectively the relation between regular aspirin use and lung cancer risk in the Health Professionals Follow-Up Study. Of 49,383 US men aged 40-75 years who completed biennial self-administered questionnaires that assessed aspirin use beginning in 1986, 328 developed lung cancer during 601,453 person-years of follow-up through 31 December 2000. No information on aspirin dose was available. Controlling for current age, smoking status, and age at starting to smoke regularly, the relative risk (RR) of total lung cancer for regular users of aspirin (twice or more per week) at baseline compared to nonusers was 1.13 (95% confidence interval (CI) =0.89-1.43). Results were similar for non-small-cell lung cancer (RR=1.16; 95% CI=0.88-1.54). No apparent dose-dependent association was observed for the frequency of aspirin use and lung cancer risk (P for trend=0.64), and results remained null when consistent use of aspirin over time was examined. These findings do not suggest that regular aspirin use is associated with a reduced lung cancer risk.

The patterns and determinants of saxagliptin use among patients with type 2 diabetes mellitus (T2DM) are unknown in real-world settings. We compared the characteristics of T2DM patients who were new initiators of saxagliptin to those who were new initiators of non-dipeptidyl peptidase-4 (DPP-4) inhibitor oral anti-diabetic drugs (OADs) and identified factors associated with saxagliptin use. We conducted a cross-sectional study within the Clinical Practice Research Datalink (CPRD), The Health Improvement Network (THIN), US Medicare, and the HealthCore Integrated Research Database (HIRDSM) across the first 36 months of saxagliptin availability (29 months for US Medicare). Patients were included if they were: 1) ≥18 years old, 2) newly prescribed saxagliptin or a non-DPP-4 inhibitor OAD, and 3) enrolled in their respective database for 180 days. For each saxagliptin initiator, we randomly selected up to ten non-DPP-4 inhibitor OAD initiators matched on age, sex, and geographic region. Conditional logistic regression was used to identify determinants of saxagliptin use. We identified 64,079 saxagliptin initiators (CPRD: 1,962; THIN: 2,084; US Medicare: 51,976; HIRDSM: 8,057) and 610,660 non-DPP-4 inhibitor OAD initiators (CPRD: 19,484; THIN: 19,936; US Medicare: 493,432; HIRDSM: 77,808). Across all four data sources, prior OAD use, hypertension, and hyperlipidemia were associated with saxagliptin use. Saxagliptin initiation was also associated with hemoglobin A1c results >8% within the UK data sources, and a greater number of hemoglobin A1c measurements in the US data sources. In these UK and US data sources, initiation of saxagliptin was associated with prior poor glycemic control, prior OAD use, and diagnoses of hypertension and hyperlipidemia. ClinicalTrials.gov identifiers NCT01086280 , NCT01086293 , NCT01086319 , NCT01086306 , and NCT01377935

Background The accuracy of vaccine administration information recorded in administrative claims databases is uncertain. Methods We conducted a retrospective cohort study using the HealthCore Integrated Research Database SM among infants who received at least 1 RotaTeq ® (RV5) dose during the first year of life between February 1, 2006 and November 30, 2012 and were enrolled in the health plan at birth. We reviewed medical records for a sample of infants to validate vaccine administration information. Results We identified 169,560 infants who received at least 1 RV5 dose. Medical records were obtained for 85 infants, of which 74 (PPV1 87.1%; 95% CI 78.0–93.4%) had a corresponding first RV5 vaccination in the medical record with the same or similar administration date. Conclusions Administrative claims contained inaccuracies in dose number or administration date for 13% of RV5 first doses identified.

We measured birth prevalence of major congenital malformations (MCMs) after topiramate use during pregnancy to screen for a possible signal of increased risk.Using four healthcare databases, we identified three cohorts of pregnant women: cohort 1, used topiramate during the first trimester; cohort 2, used topiramate or another antiepileptic drug previously but not during pregnancy; and cohort 3, were pregnant and did not use topiramate but had indications for use individually matched to those of users. Cohort 1 was compared with cohorts 2 and 3. MCMs were a code for any major congenital malformation dated within 30 days of the delivery date on the mother's claims or within 365 days after infant birth date, excluding a genetic or syndromic basis, and with procedure or healthcare usage consistent with the MCM diagnosis code in the 365 days after infant birth.Of the 10 specific common MCMs evaluated, 1 (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both primary comparisons, and 4 (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio greater than 1.5 for one of the two comparisons. Following screening of organ systems with elevated MCMs, the prevalence ratio was greater than 1.5 for patent ductus arteriosus in both comparisons and for obstructive genitourinary defects in one comparison.To evaluate a large number of MCMs across many pregnancies, we used crude methods for detecting potential signals. Therefore, these results should be seen as potential signals, not causal.

We conducted a cohort study of acute, noninfectious liver injury among oral antimicrobial users. Potential cases were identified in the HealthCore Integrated Research Database (HIRD(SM)) population between July 1, 2001, and March 31, 2009, using ICD-9-CM codes primarily for acute and subacute necrosis of the liver, hepatic coma, and unspecified hepatitis. Liver test results were used to confirm case status according to published criteria. Two physician reviewers experienced in studying acute liver injury (blinded to study drug exposures) evaluated data abstracted from hospital and emergency department records to validate potential cases. Of 715 potential cases having claims associated with any of the primary screening codes, 312 (44%) were valid cases, 108 (15%) were not cases, and 295 (41%) were of uncertain status (records inadequate for validation). Among potential cases with adequate medical records, the PPV for presence of any of the primary codes was 74% (95% CI, 70%-78%). The highest PPV for a single code was for acute and subacute necrosis of the liver (84%; 95% CI, 77%-90%). Evaluation of cases of noninfectious liver injury using hospital and emergency department medical records continues to represent the preferred approach in studies using insurance claims data.

First marketed in the USA in 1996, topiramate (TPM) is an antiepileptic drug later approved for migraine prophylaxis, and in 2012 for weight loss in combination with phentermine. Some studies indicate an elevated prevalence of oral cleft (OC) in infants exposed to TPM in utero. We evaluated the association between TPM use in early pregnancy and the risk of OC.This retrospective cohort study used 1997-2011 automated data from four sources: HealthCore and OptumInsight (commercial insurance claims), Truven Health (Medicaid claims), and Kaiser Permanente Northern California Region (electronic medical records). We compared the prevalence of OCs in infants of women exposed to TPM in the first trimester (TPM cohort) with the prevalence in infants of women formerly exposed to TPM or other antiepileptic drugs (formerly exposed [FE] cohort) and infants of women with similar medical profiles (SMPs) to the TPM cohort that were not exposed to TPM (SMP cohort). To control for confounding, we used stratification and standardization for individual variables and propensity score deciles.The birth prevalence of OCs was 0.36% (7/1945) in the TPM cohort, 0.14% (20/13 512) in the FE cohort, and 0.07% (9/13 614) in the SMP cohort. Standardized by site, the prevalence ratio (PR) for TPM versus FE was 2.5 (95% CI: 1.0-6.0) and for TPM versus SMP was 5.4 (95% CI: 2.0-14.6). Adjustment for covariates one at a time or by propensity score yielded similar results.Consistent with other recent epidemiologic research, first-trimester TPM exposure was associated with an elevated birth prevalence of OC.

To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings.We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database(SM) ) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions.Forthcoming.This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations.

Background: Factors related to improving outcomes in breast cancer survivors are of increasing public health significance. We examined postdiagnosis weight change in relation to mortality risk in a cohort of breast cancer survivors. Methods: We analyzed data from a cohort of 3,993 women with ages 20 to 79 years living in New Hampshire, Massachusetts, or Wisconsin with invasive nonmetastatic breast cancers diagnosed in 1988 to 1999 identified through state registries. Participants completed a structured telephone interview 1 to 2 years after diagnosis and returned a mailed follow-up questionnaire in 1998 to 2001 that addressed postdiagnosis weight and other factors. Vital status information was obtained from the National Death Index through December 2005. Hazard ratios and 95% confidence intervals were estimated from Cox proportional hazards models and adjusted for prediagnosis weight, age, stage, smoking, physical activity, and other important covariates. Results: During an average 6.3 years of follow-up from the postdiagnosis questionnaire, we identified 421 total deaths, including 121 deaths from breast cancer and 95 deaths from cardiovascular disease. Increasing postdiagnosis weight gain and weight loss were each associated with greater all-cause mortality. Among women who gained weight after breast cancer diagnosis, each 5-kg gain was associated with a 12% increase in all-cause mortality (P = 0.004), a 13% increase in breast cancer–specific mortality (P = 0.01), and a 19% increase in cardiovascular disease mortality (P = 0.04). Associations with breast cancer mortality were not modified by prediagnosis menopausal status, cigarette smoking, or body mass index. Conclusion: These findings suggest that efforts to minimize weight gain after a breast cancer diagnosis may improve survival. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1403–9)

Purpose We describe a multi-center post-marketing safety study that uses distributed data methods to minimize the need for covered entities to share protected health information (PHI). Implementation has addressed several issues relevant to creation of a large scale post-marketing drug safety surveillance system envisioned by the FDA's Sentinel Initiative. Methods This retrospective cohort study of Guillain-Barre syndrome (GBS) following meningococcal conjugate vaccination incorporates the data and analytic expertise of five research organizations closely affiliated with US health insurers. The study uses administrative claims data, plus review of full text medical records to adjudicate the status of individuals with a diagnosis code for GBS (ICD9 357.0). A distributed network approach is used to create the analysis files and to perform most aspects of the analysis, allowing nearly all of the data to remain behind institutional firewalls. Pooled analysis files transferred to a central site will contain one record per person for approximately 0.2% of the study population, and contain PHI limited to the month and year of GBS onset for cases or the index date for matched controls. Results The first planned data extraction identified over 9 million eligible adolescents in the target age range of 11–21 years. They contributed an average of 14 months of eligible time on study over 27 months of calendar time. MCV4 vaccination coverage levels exceeded 20% among 17–18-year olds and 16% among 11–13 and 14–16-year-old age groups by the second quarter of 2007. Conclusion This study demonstrates the feasibility of using a distributed data network approach to perform large scale post-marketing safety analyses and is scalable to include additional organizations and data sources. We believe these results can inform the development of a large national surveillance system. Copyright © 2008 John Wiley & Sons, Ltd.

Previous studies suggest that increased physical activity may lower the risk of breast cancer incidence, but less is known about whether levels of physical activity after breast cancer diagnosis can influence survival. We prospectively examined the relation between postdiagnosis recreational physical activity and risk of breast cancer death in women who had a previous invasive breast cancer diagnosed between 1988 and 2001 (at ages 20-79 years). All women completed a questionnaire on recent postdiagnosis physical activity and other lifestyle factors. Among 4,482 women without history of recurrence at the time of completing the questionnaire, 109 died from breast cancer within 6 years of enrollment. Physical activity was expressed as metabolic equivalent task-hours per week (MET-h/wk); hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression. After adjusting for age at diagnosis, stage of disease, state of residence, interval between diagnosis and physical activity assessment, body mass index, menopausal status, hormone therapy use, energy intake, education, family history of breast cancer, and treatment modality compared with women expending

Tobacco products are major contributors of exogenous N-nitroso compounds, a group of potent neurocarcinogens. Overall results from studies of smoking and brain tumors have been null, but have provided little information on duration, age at smoking initiation, and latency. We prospectively examined the relation between cigarette smoking and glioma risk among men and women in three large U.S. cohort studies: the Health Professionals Follow-up Study (HPFS), the Nurses’ Health Study I (NHS), and NHS II. Information on smoking history was obtained at baseline (1986 for HPFS, 1976 for NHS, and 1989 for NHS II) and updated biennially through 2002 in the HPFS and the NHS and 2003 in the NHS II. We confirmed 110 incident gliomas among men and 255 gliomas among women during 667,673 and 4,388,515 person-years of follow-up, respectively. Cox proportional hazard models were used to estimate incidence rate ratios and 95% confidence intervals between smoking and glioma risk adjusting for age, total meat intake, and alcohol and coffee consumption. Estimates from each cohort were pooled using a random-effects model after determining that there was no heterogeneity by sex. No association with glioma risk was observed between baseline or updated smoking status, intensity, duration, or age at smoking initiation among men and women. Furthermore, no association with glioma risk was observed after allowing for an induction period between smoking and glioma diagnosis. These findings provide strong evidence that cigarette smoking is not associated with an appreciably elevated risk of adult glioma.

We evaluated prospectively the association between body mass index (BMI), height, recreational physical activity and the risk of bladder cancer among US adults. Data were used from 2 ongoing cohorts, the Health Professionals Follow-up Study and the Nurses' Health Study, with 3,542,012 years of follow-up and 866 incident bladder cancer cases (men = 507; women = 359) for the anthropometric analysis and 1,890,476 years of follow-up and 706 incident bladder cancer cases (men = 502; women = 204) for the physical activity analysis. Cox proportional hazard models were used to estimate incidence rate ratios (RR) and 95% confidence intervals (CI) between BMI, height, physical activity and bladder cancer risk adjusting for age, pack-years of cigarette smoking and current smoking. Estimates from each cohort were pooled using a random-effects model. We observed no association between baseline BMI and bladder cancer risk, even when we compared a BMI of > or =30 kg/m(2) to a BMI of 18-22.9 kg/m(2) [pooled multivariate (MV) RR, 1.16; 95% CI: 0.89-1.52]. A weak, but statistically significant, association was observed for the same comparison after excluding bladder cancer cases diagnosed within the first 4 years of follow-up (pooled MV RR, 1.33; 95% CI: 1.01-1.76). Height was not related to bladder cancer risk (pooled MV RR, 0.82; 95% CI: 0.65-1.03, top vs. bottom quintile). Total recreational physical activity also was not associated with the risk of bladder cancer (pooled MV RR, 0.97; 95% CI: 0.77-1.24, top vs. bottom quintile). Our findings do not support a role for BMI, height or physical activity in bladder carcinogenesis.

Findings from several beta-carotene supplementation trials were unexpected and conflicted with most observational studies. Carotenoids other than beta-carotene are found in a variety of fruits and vegetables and may play a role in this important malignancy, but previous findings regarding the five major carotenoids are inconsistent. The authors analyzed the associations between dietary beta-carotene, beta-carotene, lutein/zeaxanthin, lycopene, beta-cryptoxanthin, vitamin A, serum beta-carotene, and serum retinol and the lung cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of male smokers conducted in southwestern Finland between 1985 and 1993. Of the 27,084 male smokers aged 50-69 years who completed the 276-food item dietary questionnaire at baseline, 1,644 developed lung cancer during up to 14 years of follow-up. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals. Consumption of fruits and vegetables was associated with a lower lung cancer risk (relative risk = 0.73, 95% confidence interval: 0.62, 0.86, highest vs. lowest quintile). Lower risks of lung cancer were observed for the highest versus the lowest quintiles of lycopene (28%), lutein/zeaxanthin (17%), beta-cryptoxanthin (15%), total carotenoids (16%), serum beta-carotene (19%), and serum retinol (27%). These findings suggest that high fruit and vegetable consumption, particularly a diet rich in carotenoids, tomatoes, and tomato-based products, may reduce the risk of lung cancer.

Background RotaTeq® pentavalent human rotavirus vaccine (RV5) is effective against rotavirus illness and rotavirus-related hospitalizations and death. Effectiveness depends on adherence to the dosing schedule, which includes 3 doses at ages 2, 4 and 6 months. Two studies have used automated claims databases to estimate the proportion of vaccinated infants who complete the dosing schedule, but excluded from analysis vaccinated infants who were not enrolled in the database for a sufficient period to observe all 3 doses. Restricting study populations based on duration of follow-up can introduce bias if a large number of subjects are excluded due to insufficient follow-up, and if their outcomes differ from subjects who are included. To address the possibility that exclusions may have been extensive and led to biased estimates of completion rates, we conducted a claims database analysis in the HealthCore Integrated Research DatabaseSM to evaluate the proportion of rotavirus vaccinated infants who completed the 3 dose series of RV5. We evaluated potential error introduced by restricting analyses to infants with complete follow-up by estimating completion rates among infants with complete follow-up, and using Kaplan-Meier analyses to estimate completion rates including infants with incomplete follow-up. Results The inclusion criterion requiring continuous enrollment for the first year of life resulted in only 108,533 (40%) of 233,143 vaccinated infants from 2006–2012 being included in the analysis. After relaxing inclusion criteria, we were able to include 86% of vaccinated infants. The estimated completion rate among infants with continuous enrollment from birth through the first year of life was 78.1% (95% confidence limits [CLs] 77.8%, 78.3%), and among the expanded population the estimated completion rate was 77.4% (95% CLs 77.2%, 77.6%). Conclusions These results indicate that most infants were not followed in the database through the first year of life, but the impact of excluding infants with incomplete follow-up was negligible when assessing RV5 completion rates for this commercially insured population. Nonetheless, to increase the size of study populations and reduce the potential for bias, it is preferable to include subjects with incomplete follow-up in automated database analyses, and adopt more robust approaches to defining and analyzing study populations that account for missing data.