Multiple Imputation Analysis Research Articles

Abstract PR08: Linking electronic health records with cancer registry data for epidemiology and health services research: Challenges and opportunities

Abstract Background: There is tremendous potential to leverage the value from electronic health records (EHRs) and population-based cancer registry data by integrating them to study the cancer continuum from screening to diagnosis and treatment. Registries provide detailed diagnosis and tumor characteristics and initial treatment summaries (even across health care systems), while EHRs contain rich clinical detail such as medical histories and preventive screenings. Moreover, to the extent that EHR systems may be comparable across health care systems, pooling EHRs from multiple health care systems can enhance the generalizability of findings. Furthermore, there is the potential to integrate neighborhood or environmental data based on geocoding patient addresses for research focusing on multilevel exposures. With patient populations frequently in the millions, the opportunities for highly powered scientific discovery are nearly unparalleled. However, the logistical complexity, cost, and possibility for systematic error to hamper findings may be considerable. Recently, we linked the EHRs of a large, multispecialty health care delivery system with the California cancer registry (CCR) and established two retrospective cohort studies. We will describe the process undertaken, some challenges and lessons learned, and the resulting cohort populations. Methods: Using a probabilistic linkage process, we combined Sutter Health EHR data with the CCR to identify incident cancer cases occurring among the EHR population. We then established two retrospective cohorts each with 13 years of follow-up time and distinct scientific objectives. The mammogram cohort is designed to study patterns of screening utilization and breast cancer-related outcomes. The lung cancer cohort will elucidate risk factors for lung cancer in never-smokers, an uncommon diagnosis that has not been successfully studied in other data sources due to lack of smoking status and/or small sample sizes. Results: From an adult EHR population of 4.5 million, we identified 306,554 unique cancers diagnosed between 2000 and 2013. Linkage efforts, including multiple institutional approvals, took 18 months to complete. We compared the identified cases with the rest of the CCR patients in the Sutter Health catchment region to evaluate external validity. Inclusion/exclusion criteria resulted in a mammogram cohort of 516,419 screened women, 11,222 of whom were diagnosed with breast cancer, and a lung cancer cohort with 1.3 million male and female never-smokers, 1,143 of whom were diagnosed with lung cancer. For the latter, we also undertook patient address geocoding and linkage with neighborhood and environmental data. Multiple imputation and sensitivity analysis will be used to explore the impact of missing EHR data, a common issue in such studies. Conclusions: Our experiences set the foundation to encourage and inform researchers interested in working with EHRs for cancer research as well as provide context for improvement and scalability. This abstract is also being presented as Poster A27. Citation Format: Caroline A. Thompson, Mindy DeRouen, Su-Ying Liang, Anqi Jin, Harold S. Luft, Daphne Lichtensztajn, Salma Shariff-Marco, Iona Cheng, Scarlett L. Gomez. Linking electronic health records with cancer registry data for epidemiology and health services research: Challenges and opportunities [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr PR08.

Accuracy of time to treatment estimates in the CRASH-3 clinical trial: impact on the trial results

BackgroundEarly treatment with tranexamic acid may reduce deaths after traumatic brain injury (TBI). In mild and moderate TBI, there is a time to treatment interaction, with early treatment being most beneficial. Time to treatment was recorded by clinicians and is subject to error. Using monitoring data from the CRASH-3 trial, we examine the impact of errors in time to treatment on estimated treatment effects.MethodsThe CRASH-3 trial was a randomised trial of the effect of tranexamic acid on death and vascular occlusive events in 12,737 TBI patients. This analysis includes the 8107 patients with a Glasgow coma scale score of 9 to 15 since previous analyses showed that these patients benefit most from early treatment. Clinician-recorded time to treatment was checked against ambulance and hospital records for 1368/12,737 (11%) patients. Patients who died were preferentially selected for monitoring and we monitored 36% of head injury deaths. We describe measurement errors using Bland-Altman graphs. We model the effect of tranexamic acid on head injury death using logistic regression with a time-treatment interaction term. We use regression calibration, multiple imputation and Bayesian analysis to estimate the impact of time to treatment errors.ResultsClinicians rounded times to the nearest half or full hour in 66% of cases. Monitored times were also rounded and were identical to clinician times in 63% of patients. Times were underestimated by an average of 9 min (95% CI − 85, 66). There was more variability between clinician-recorded and monitored times in low- and middle-income countries than in high-income countries. The treatment effect estimate at 1 h was greater for monitored times OR = 0.61 (95% CI 0.47, 0.81) than for clinician-recorded times OR = 0.63 (95% CI 0.48, 0.83). All three adjustment methods gave similar time to treatment interactions. For Bayesian methods, the treatment effect at 1 h was OR = 0.58 (95% CI 0.43, 0.78). Using monitored times increased the time-treatment interaction term from 1.15 (95% CI 1.03, 1.27) to 1.16 (95% CI 1.05, 1.28).ConclusionsAccurate estimation of time from injury to treatment is challenging, particularly in low resource settings. Adjustment for known errors in time to treatment had minimal impact on the trial results.Trial registrationClinicalTrials.gov NCT01402882. Registered on 25 July 2011

Outcomes and Challenges of Reproductive Health in Hematopoietic Stem Cell Transplantation Survivors.

Long-term therapy-related reproductive health side effects impact the quality of life of hematopoietic stem cell transplantation (HSCT) survivors. In this study, we evaluated the prevalence of gonadal dysfunction (GD) pre- and post-HSCT, analyzed factors associated with GD, and explored rates of fertility assessment (FA) and fertility preservation (FP) in a resource-limited setting. FA and outcomes of patients age ≤45 years undergoing HSCT between June 2000 and May 2018 were collected retrospectively. We included 213 patients with a median age of 26 years. Pre-HSCT FA was performed in 71.8%, with a GD rate of 17%. The rate of GD was not different between the sexes (females, 19.5% versus males, 16.1%; P=.616) and was only associated with increasing age. The rate of cryopreservation in the cohort was 3.3%. Almost one-half (47.7%) of post-HSCT patients completed FA and evidenced an increase in GD rate to 48.9%. Comparing pre-HSCT and post-HSCT GD rates, women had a significant increase (19.5% versus 81.4%; P < .001), whereas men did not (16.1% versus 20.4%; P=.76). These results were confirmed by a multiple imputation analysis accounting for missing data. Female sex, pre-HSCT cytotoxic therapy, myeloablative conditioning, and germ cell tumor (GCT) diagnosis were associated with post-HSCT GD. Reproductive health preservation can be positively impacted when FA and FP are prioritized at the initial diagnosis in HSCT candidates, particularly in women of older age and men with a diagnosis of GCT. The low FP success observed urges implementation of strategies that favor accessibility and improve quality of life of HSCT survivors in low- and middle-income countries.

Abstract A077: Examining the relationship between various informal sources of social support and the physical well-being among cancer survivors

Abstract Cancer survivors have previously reported lower quality of life scores compared to non-cancer survivors. More specifically, the quality of life domain of physical well-being has previously been shown to be significantly worse among cancer survivors compared to non-cancer survivors. Previous studies have observed that specific sources of informal social support (i.e., support from family and friends) can improve a cancer survivor's physical well-being. However, no studies to date have assessed if support from fictive kin (or individuals who are not related by marriage or blood but are considered to be an extension of the family) and church members may also play a role on the physical well-being of cancer survivors. The purpose of this study was to examine the association between four informal sources of social support (i.e., family, friends, fictive kin, and church members) and the physical well-being among cancer survivors. Findings were based on data collected from the National Survey of American Life (NSAL) dataset. Physical well-being was measured using the following item from the NSAL dataset: “How would you rate your overall physical health at the present time?” A total of 238 cancer survivors (n=70 non-Hispanic whites, n=36 Caribbean Blacks, n=132 African Americans) comprised the study sample. Multiple imputation analyses were conducted within SAS to assess the associations between the informal sources of social support and the physical well-being among cancer survivors. All multiple imputation analyses were controlled for gender, age, race, household income, years of education, marital status, employment status, length of time residing in the U.S, and insurance coverage. Neither friends (β= -0.07, SE=0.09, p=0.42) nor fictive kin (β=0.06, SE=0.13, p=0.66) were significantly associated with the physical well-being of cancer survivors. Support from family was marginally associated with physical well-being (β=0.16, SE=0.08, p=0.05). A positive association was observed between support from church members and physical well-being (β=0.22, SE=0.09, p=0.01). Findings from this study suggest that support from church members can play an important role on the physical well-being of cancer survivors. Researchers of future health promotion interventions should consider collaborating with churches as a means of improving the physical well-being among cancer survivors. Citation Format: Shaila M. Strayhorn. Examining the relationship between various informal sources of social support and the physical well-being among cancer survivors [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A077.

Sex-Specific Differences in Percutaneous Coronary Intervention Outcomes After a Cardiac Event: A Cohort Study Examining the Role of Depression, Worry and Autonomic Function

To determine whether differential all-cause hospital readmission exists for men and women 2 years after percutaneous coronary intervention (PCI) treatment for acute coronary syndrome (ACS), and to identify potential autonomic and psychological pathways contributing to this association. Four hundred and sixteen (416) patients admitted with ACS were recruited from coronary care wards. Participants attended the study centre at one (T0) and 12 (T1) months following discharge. Heart rate variability (HRV) was used to assess autonomic functioning measured via a three-lead electrocardiogram. Psychological variables of interest (pathological worry, depression and phobic anxiety) were measured using validated self-report questionnaires. Percutaneous coronary intervention treatment data were collected from hospital records. The primary outcome was 2-year all-cause hospital readmission (yes/no). Logistic regression modelling using both complete case analysis and multiple imputation analysis was applied. Men who received PCI had a significant reduction in the odds of being rehospitalised over the following 2 years, relative to women who did not (OR=0.45, 95% CI=0.20, 0.98). No other group benefited to this extent. Adjustment for age, ACS severity and Very Low Frequency (VLF) Power appeared to strengthen the association in both the complete case analysis and multiple imputation analysis models. The inclusion of depression and worry also marginally explained these associations in the multiple imputation analysis model. Men who receive PCI after ACS were less likely to be readmitted to hospital over the following 2 years than their female counterparts. The small sample size of women and observational study design limit interpretation of the findings. However, heart rate variability, specifically VLF power, requires further investigation as a driver of such sex-specific outcomes.

Combining Multiple Imputation and Hidden Markov Modeling to Obtain Consistent Estimates of Employment Status

Abstract Recently, a method was proposed that combines multiple imputation and latent class analysis (MILC) to correct for misclassification in combined data sets. A multiply imputed data set is generated which can be used to estimate different statistics of interest in a straightforward manner and can ensure that uncertainty due to misclassification is incorporated in the estimate of the total variance. In this article, MILC is extended by using hidden Markov modeling so that it can handle longitudinal data and correspondingly create multiple imputations for multiple time points. Recently, many researchers have investigated the use of hidden Markov modeling to estimate employment status rates using a combined data set consisting of data originating from the Labor Force Survey (LFS) and register data; this combined data set is used for the setup of the simulation study performed in this article. Furthermore, the proposed method is applied to an Italian combined LFS-register data set. We demonstrate how the MILC method can be extended to create imputations of scores for multiple time points and thereby show how the method can be adapted to practical situations.

Semi-parametric regression when some (expensive) covariates are missing by design

The paper deals with the scenario where some covariates are observed by design for a subset of the observations only. In the example treated in the paper this occurs with a two phase sampling scheme where in the first phase a relatively large sample is drawn to record a response variable Y and a set of (cheap) covariates x. In a second phase a smaller sample is drawn from the first phase sample where additional (usually expensive) covariates z are also recorded. The second phase can be drawn with unequal probability sampling, where the sampling weights depend on the observed Y and x. The overall intention is to fit a regression model of Y on both, x and z. Due to the design of the data collection we are faced with missing values for z for a majority of observations. We propose an approximate estimation approach using semi-parametric mean and variance regression of Y on x only and augment this fit with a full regression model of Y on x and z. The idea extends the approach of Little (1992) towards non-normal data and non-linear models. The proposed estimation is numerically rather simple and performs convincingly well in simulation studies compared to alternatives such as complete-case and multiple imputation analysis.

TXA (Tranexamic Acid) Risk Evaluation in Combat Casualties (TRECC)

BackgroundThe use of tranexamic acid (TXA) has become increasingly prevalent for hemorrhage prevention in military trauma patients due to its known survival benefits. There is concern of increased venous thromboembolism...

Severe asthma in the US population and eligibility for mAb therapy

Severe asthma in the US population and eligibility for mAb therapy

Association between dietary patterns and adult depression symptoms based on principal component analysis, reduced-rank regression and partial least-squares.

There have been inconsistent findings on the association between dietary patterns and depressive symptoms (DepS). In addition, studies have used single analysis methods to identify dietary patterns. In the current study, we aimed to determine the association between dietary patterns, derived by principal component analysis (PCA), reduced-rank regressions (RRR) and partial least-squares (PLS), and DepS among adults using a cohort study in Australia. We examined a total of 1743 study participants (≥24 years, 48.9% males) using cross-sectional and longitudinal data from the North West Adelaide Health Study (NWAHS). The Center for Epidemiological Studies-Depression (CES-D) scale was used to assess DepS and a score ≥16 was considered as having depression. Dietary data were collected using a food frequency questionnaire. Eicosapentaenoic acid (EPA)/Docosahexaenoic acid (DHA), folate, magnesium (Mg) and zinc (Zn) densities were chosen as the response variables for RRR and PLS analyses. Dietary patterns were identified by PCA, RRR and PLS. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated across quartiles (Q) using log-binomial logistic regression to assess the association between dietary patterns and DepS. Sensitivity analyses, including a longitudinal association between dietary patterns and DepS among 859 participants, were performed. Multiple imputation was performed to investigate the effect of missing data on the estimates. In this study, 16.9% (14.2% in men and 20.8% in women) of the participants had DepS. We retained two, four and four dietary patterns captured by PCA, RRR and PLS respectively. The 'prudent' pattern determined by PCA [ORQ4VsQ1=0.57; 95% CI: 0.35, 0.92] and PLS [ORQ4VsQ1=0.66; 95% CI: 0.43, 1.00] together with the 'typical Australian' pattern determined by RRR [ORQ4VsQ1=0.60; 95% CI: 0.40, 0.90] were inversely associated with DepS whereas the 'western' pattern derived by PCA [ORQ4VsQ1=2.04; 95% CI: 1.12, 3.68] and PLS [ORQ4VsQ1=1.62; 95% CI: 1.05, 2.50] was positively associated with DepS. In the longitudinal analysis, the 'prudent' pattern determined by PCA [ORQ4VsQ1=0.52; 95% CI: 0.25, 1.09] tended to be inversely associated with DepS whereas 'western' patterns determined by PCA [ORQ4VsQ1=3.47; 95% CI: 1.37, 8.78] and PLS [ORQ4VsQ1=2.47; 95% CI: 1.24, 4.91] were positively associated with DepS. We found that a dietary pattern characterized by high intakes of fruits, vegetables, medium fat dairy, nuts, legumes, and fish was inversely associated with DepS in this population-based study. Contrary to this, a dietary pattern characterized by high intakes of processed and red meat, fast foods (snacks and takeaway foods), soft drinks, white bread and high-fat dairy products were significantly associated with DepS. Multiple imputation and sensitivity analysis identified similar patterns of association between dietary pattern and DepS. The findings indicate that the 'western' pattern was consistently associated with an increased risk, and the 'prudent' pattern tended to be associated with a reduced risk of DepS. This suggests that dietary interventions may assist with the treatment of DepS. However, current evidence on the impact of diet on DepS should be supported using further longitudinal studies with extended follow up, larger sample sizes and repeated measures.

Abstract A028: Clinical and analytic validation of FoundationOne CDx™ for NTRK fusion-positive solid tumors in patients treated with entrectinib

Abstract Introduction: Patients whose tumors harbor NTRK gene fusions represent an extremely small proportion of the overall cancer population (i.e., ~0.32-1%). While adult and pediatric cancer patients with NTRK fusion-positive solid tumors are rare, they comprise a patient population with a targetable alteration for whom there is currently no accepted standard of care. Comprehensive genomic profiling assays are a critical component in the identification of this sub-population, and herein we describe the clinical validation and analytic performance of FoundationOne CDx™ (F1CDx) as the companion diagnostic for entrectinib, a potent inhibitor of ROS1 and TRK A/B/C kinases. F1CDx and entrectinib were approved in Japan for the respective diagnosis and treatment of adult and pediatric patients with NTRK fusion-positive advanced recurrent solid tumors. Methods: Analytical concordance was determined by comparing F1CDx to a validated RNA NGS fusion panel using 28 NTRK fusion-positive and 53 NTRK fusion-negative samples. Concordance was defined as the overall percent agreement (OPA) between the two assays. Positive and negative percent agreement (PPA, NPA) were calculated using the RNA assay as the reference. Analytical sensitivity was calculated from representative gene fusions based on the 95% probability of detection, and intermediate precision was assessed from NTRK-positive samples run at and slightly above the platform limit of detection. Clinical validation for F1CDx as a companion diagnostic for entrectinib in Japan was estimated based upon patients in the primary efficacy population who had samples remaining for F1CDx testing using multiple imputation and sensitivity analysis of the concordance of F1CDx to the various enrollment assays. Results: OPA between F1CDx and an orthogonally validated RNA NGS fusion panel was 92.6% (95% CI: 84.6-97.2%). PPA and NPA values were 85.7% (95% CI: 67.3-96.0%) and 96.2% (95% CI: 87.0-99.5%), respectively. Platform sensitivity for rearrangements was between 6.4-11.3% tumor purity. Repeatability for NTRK fusions was 100% (95% CI: 73.5-100.0%) and reproducibility was 100% (95% CI: 90.3-100.0%). OPA, PPA and NPA values comparing F1CDx to the multiple enrollment assays utilized for the STARTRK-2 trial were 95.7% (95% CI: 87.8-99.1%), 84.2% (95% CI: 60.4-96.6%), and 100.0% (95% CI: 92.9-100.0%), respectively. The previously reported overall response rate (ORR) for the primary efficacy population in the STARTRK-2 trial was 57.4% (95% CI: 42.3-70.7%)1. Bridging analysis estimated that the ORR for the F1CDx NTRK-positive population was 50.0% (95% CI: 24.7-75.4%), with acceptable balance between co-variates in the F1CDx evaluable and non-evaluable populations. Conclusions: The DNA-based F1CDx assay demonstrated strong concordance compared to an externally validated RNA NGS fusion panel (92.6% OPA) for the detection of NTRK fusions. Furthermore, an analysis of the clinical efficacy demonstrated comparable results between F1CDx NTRK-positive patients (ORR of 50%; 95% CI: 24.7-75.4%) and the overall NTRK fusion-positive population (ORR of 57%; 95% CI: 42.3-70.7%) from the STARTRK-2 clinical trial evaluating entrectinib in patients with solid tumors. 1. ESMO [https://www.esmo.org/Oncology-News/Entrectinib-NTRK-Fusion-Positive-Tumours-Demetri] Citation Format: David Fabrizio, Coren Milbury, Wai-Ki Yip, Bahar Yilmazel, Xiaobo Bai, Juan Liao, David Smith, Christine Burns, Christine Vietz. Clinical and analytic validation of FoundationOne CDx™ for NTRK fusion-positive solid tumors in patients treated with entrectinib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A028. doi:10.1158/1535-7163.TARG-19-A028

REACTIVITY TO THE MEASUREMENT OF PSYCHOLOGICAL WELL-BEING IN OLDER ADULTS

Although it is known that measurement reactivity can yield medium-sized effects (Cohen’s d = .50) on anxiety, its effects on psychological well-being (PWB) measures (e.g., purpose in life, personal growth) are unknown. The aim of this study was to evaluate reactivity to the measurement of PWB in older adults. Ninety-four adults aged 60 ≥ years (mean = 75) were recruited from a fitness center, retirement home and community center in Indiana. All participants received a questionnaire via postal mail at baseline (T1) and 2-3 weeks later (T2). Using block randomization (block size = 16), older adults were randomly allocated (1:1 ratio) to one of two conditions: PWB measures assessed at T1 and T2; and PWB measures were at T2 only. Purpose in life and personal growth were assessed using Ryff’s PWB scales. Multiple imputation analysis was conducted to account for attrition at T2 (18%), and all participants were analyzed according to the condition they were originally assigned. ANCOVA, controlling for recruitment sites, revealed that purpose in life (p = .03), but not personal growth (p = .08), T2 scores were on average lower when PWB was measured twice compared to those when PWB was measured once. The detected difference in purpose in life T2 scores was of medium size (d [95%CI] = - .50 [-.95, -.04]). This finding suggests that initial or later scores might be biased – a problematic finding because if ignored, measurement reactivity has the potential to affect conclusions drawn from gerontological research that focuses on PWB.

Speed of processing training and depression in assisted and independent living: A randomized controlled trial.

Late life depression is widely associated with lower quality of life and greater disability, making it an important target for prevention. Earlier randomized controlled trials [RCTs] demonstrated that speed of processing training [SOPT] led to reductions in depressive symptoms and clinical depression in community-dwelling adults. Our purpose was to evaluate depression outcomes related to SOPT among older adults who live in supported senior living settings. This two-arm, parallel RCT included 351 participants aged 55–102 years who resided in assisted and independent settings in 31 senior living communities. Participants were randomized within sites to computerized SOPT vs. computerized crossword puzzles with a targeted dose of 10 hours of playtime at baseline plus 4 hours of booster training at five and eleven months. Depression outcomes included the 9-item Patient Health Questionnaire [PHQ-9] scores, categorical levels, and dichotomous indicators. Random effects linear mixed effect models estimated SOPT effects in intention-to-treat complete case and multiple imputation analyses. Mean age of the sample was 81.0 years, 72.2% were women, and 41.0% resided in assisted living. At baseline 65.7% had no depression [PHQ-9 scores < 5] and 6.6% had clinically meaningful depression [PHQ-9 scores ≥ 10]. At 12 months we found significantly increased PHQ-9 scores [p = 0.006] and categorical levels [p = 0.003], and higher percentages of PHQ-2 scores > 3 [p = 0.016] and major depressive syndrome [p = 0.045] among the assisted living SOPT group. No significant change in depression was observed in the independent living SOPT or attention control groups. In summary, the SOPT known as Road Tour/Double Decision significantly increased, rather than decreased, the burden of depressive symptoms among participants residing in assisted living. Given these risks, this SOPT program should be avoided among older people in assisted living settings, and other SOPT interventions should be combined with systematic depression monitoring.

Time-Varying Outcomes With the Absorb Bioresorbable Vascular Scaffold During 5-Year Follow-up

Bioresorbable scaffolds were designed to provide clinical benefits after their complete bioresorption. Prior studies demonstrated early risks with the Absorb polymeric bioresorbable vascular scaffold (BVS). Whether this risk profile changes over time during the course of its bioresorption is unknown. To examine outcomes of the first-generation BVS before and after 3 years, the point of its complete bioresorption in animals. We searched MEDLINE and the Cochrane database, conference proceedings, and public websites for relevant studies. Eligible studies were randomized clinical trials of BVS vs metallic drug-eluting stents in patients with coronary artery disease with at least 5-year follow-up. Four trials of BVS vs everolimus-eluting stents (EES) with 3384 patients met criteria. Individual patient data from the 4 trials were pooled, and summary-level meta-analysis was performed. The major effectiveness and safety measures were target lesion failure (TLF; cardiac death, target vessel-related myocardial infarction, or ischemia-driven target lesion revascularization) and device thrombosis. Outcomes were examined through 5-year follow-up and between 0 to 3 and 3 to 5 years. Mean age for the 3384 patients was 62.8 years; 2452 patients were men (72.5%), and diabetes was present in 1020 patients (30.2%). Through 5-year follow-up, treatment with BVS compared with EES was associated with higher rates of TLF (14.9% vs 11.6%; HR, 1.26; 95% CI, 1.03-1.54; P = .03) and device thrombosis (2.5% vs 0.8%; HR, 2.87; 95% CI, 1.46-5.65; P = .002). Target lesion failure occurred in 11.6% of BVS-treated patients vs 7.9% of EES-treated patients between 0 to 3 years (HR, 1.42; 95% CI, 1.12-1.80), and 4.3% of BVS-treated patients vs 4.5% of EES-treated patients between 3 to 5 years (HR, 0.92; 95% CI, 0.64-1.31) (P for interaction = .046). Device thrombosis occurred in 2.4% of BVS-treated patients vs 0.6% of EES-treated patients between 0 to 3 years (HR, 3.86; 95% CI, 1.75-8.50) and 0.1% of BVS-treated patients vs 0.3% of EES-treated patients between 3 to 5 years (HR, 0.44; 95% CI, 0.07-2.70) (P for interaction = .03). These results were consistent by spline analysis and after multiple imputation and multivariable analysis. The period of excess risk for the first-generation Absorb BVS ends at 3 years. These data provide mechanistic insights into the timing of adverse events after BVS and identify the hurdles to be overcome for bioresorbable technology to be accepted as a valid alternative for patients with coronary artery disease. ClinicalTrials.gov identifiers: NCT01751906, NCT01844284, NCT01923740, and NCT01425281.

The 13-Valent Pneumococcal Conjugate Vaccine Is Effective Against Hypoxic Pneumonia in Children in Lao PDR: A Novel Method Using a Hospital-Based Observational Study

Background: Pneumococcal pneumonia is a leading cause of childhood mortality. Pneumococcal conjugate vaccines (PCVs) have been shown to reduce hypoxic pneumonia in children. However, there are no 13-valent PCV (PCV13) vaccine effectiveness (VE) studies on hypoxic pneumonia from Asia. We describe a novel approach to determine the effectiveness of PCV13 against hypoxic pneumonia in children admitted with pneumonia in the Lao People's Democratic Republic, a low-resource setting. Methods: A prospective hospital-based observational study of children up to 59 months old admitted with pneumonia to a single tertiary hospital in Vientiane was undertaken over 54 months. Pneumonia was defined using the 2013 WHO definition. Hypoxia was defined as an oxygen saturation <90% in room air or requiring oxygen supplementation during hospitalisation. PCV13 status was determined by written record. VE was calculated using logistic regression comparing the odds of hypoxia between vaccinated and undervaccinated pneumonia cases. To handle potential confounders a propensity score (PS) analysis using inverse probability of treatment weighting was used; for missing data, multiple imputation (MI) analysis was undertaken. Findings: There were 826 children admitted with pneumonia, 285 had hypoxic pneumonia and 377 were PCV13-vaccinated. The unadjusted, PS adjusted and MI adjusted VE against hypoxic pneumonia were 23% (95% confidence interval [CI]: -9, 46%; p=0·14); 37% ([CI]: 6, 57%; p=0·02) and 35% ([CI]: 7, 55%; p=0·02) respectively. Interpretation: This is the first apparent study to show PCV13 is effective against hypoxic pneumonia in Asia. This single hospital-based approach will enable other similar settings to test for VE. Funding Statement: This study received funding from the Bill & Melinda Gates Foundation (OPP1115490). Declaration of Interests: KM and CN receive grants from Pfizer, outside the submitted work. The Institute of Research for Development (IRD) and Aix-Marseille University funds both ADP and the HRSV testing. PN receives grants from the Wellcome Trust. JL receives funding from Bill and Melinda Gates foundation. All other authors declare no competing interests. The opinion presented in this paper is that of the authors and does not reflect Pfizer. We have not been paid by a pharmaceutical company to write this article. Ethics Approval Statement: This study was conducted according to the study protocol approved by the Oxford Tropical Research Ethics Committee (OxTREC reference:1050-13), Laos Ministry of Health National Ethics Committee for Health Research (No 061NECHR), the Ethics Review Committee of the WHO Regional Office for the Western Pacific Region (WPRO-ERC) (reference ID:2013.30.LAO.2.EPI) and by The Royal Children’s Hospital Human Resources Ethics Committee (HREC) (reference number:33177B).

Identifying psychosocial characteristics that predict outcome to the UPLIFT programme for people with persistent back pain: protocol for a prospective cohort study

IntroductionPrognostic screening of people with low back pain (LBP) improves utilisation of primary healthcare resources. Whether this also applies to secondary healthcare remains unclear. Therefore, this study aims to develop...

Quality of Life, Fatigue, and Sleep Problems in Pancreatic Cancer Patients—A Randomized Trial on the Effects of Exercise

Improving quality of life (QoL) is an important treatment goal in pancreatic cancer patients. Although the beneficial effects of exercise on QoL are well understood, few studies have investigated more aggressive cancers such as pancreatic cancer. Within a randomized trial, we assessed the efficacy of 6-month resistance training on physical functioning (primary outcome) and further QoL-related outcomes. 65 pancreatic cancer patients were assigned to home-based training, supervised training, or a usual care control group. Analysis-of-covariance models on changes from baseline to 6 and 3 months were ap- plied. 47 patients completed the intervention period. After 6 months, no effects of resistance training were observed. However, after 3 months, explorative analyses showed significant between-group mean differences (MD) in favor for resistance training for physical functioning (pooled group: MD=11.0; p=0.016; effect size[ES]=0.31), as well as for global QoL (MD=12.1; p=0.016; effect size=0.56), and other outcomes, such as sleep problems and fatigue. Multiple imputation analyses yielded similar results. Home-based and supervised training performed similarly. This first randomized resistance training trial in pancreatic cancer patients indicated clinically relevant improve- ments in QoL after 3 but not after 6 months. Given the severity of pancreatic cancer, exercise recommendations may already commence at surgery.

Efficacy of a tailored PCR-guided triple therapy in the treatment of Helicobacter pylori infection

IntroductionResistance to clarithromycin and fluoroquinolones is increasing in many countries. We aimed to assess the efficacy of a tailored PCR-guided triple therapy versus an empirical triple therapy in the treatment of H. pylori infection. Patients and methodsFrench multicenter prospective open-label randomized study to assess H. pylori and resistance to clarithromycin and levofloxacin with GenoType HelicoDR® test. Patients of the control group were treated with empirical therapy of proton pump inhibitor (PPI), amoxicillin, and clarithromycin for 7 days. Patients of the experimental group with clarithromycin-susceptible strains, clarithromycin-resistant/levofloxacin-susceptible strains, and with clarithromycin-resistant/levofloxacin-resistant strains received tailored therapy of PPI, amoxicillin, and clarithromycin for 7 days, PPI, amoxicillin, and levofloxacin for 10 days, and PPI, amoxicillin, and metronidazole for 14 days, respectively. H. pylori eradication was assessed by 13C urea breath test at least 28 days after the end of treatment. ResultsWe included 526 patients: 260 (49.4%) were randomly assigned to empirical triple therapy and 266 (50.6%) to tailored therapy. Clarithromycin and levofloxacin resistances were 23.3% and 12.8%, respectively. Follow-up urea breath test was available for 415 (78.9%) patients. Tailored therapy was superior to empirical therapy in terms of eradication (85.5% vs. 73.1%, RR=1.85, 95%CI [1.25–2.78], p=0.003). Findings were consistent in the susceptibility analysis using multiple imputation (RR=1.61, 95%CI [1.14–2.27], P=0.003) and per-protocol analysis (RR=1.89, 95%CI [0.25–2.78], p=0.003). ConclusionIn a country with a high level of clarithromycin resistance, tailored PCR-guided therapy was superior to empirical triple therapy for H. pylori eradication (https://www.ClinicalTrials.gov: NCT01168063).

Multilevel Reliability Measures of Latent Scores Within an Item Response Theory Framework

This paper evaluated multilevel reliability measures in two-level nested designs (e.g., students nested within teachers) within an item response theory framework. A simulation study was implemented to investigate the behavior of the multilevel reliability measures and the uncertainty associated with the measures in various multilevel designs regarding the number of clusters, cluster sizes, and intraclass correlations (ICCs), and in different test lengths, for two parameterizations of multilevel item response models with separate item discriminations or the same item discrimination over levels. Marginal maximum likelihood estimation (MMLE)-multiple imputation and Bayesian analysis were employed to evaluate the accuracy of the multilevel reliability measures and the empirical coverage rates of Monte Carlo (MC) confidence or credible intervals. Considering the accuracy of the multilevel reliability measures and the empirical coverage rate of the intervals, the results lead us to generally recommend MMLE-multiple imputation. In the model with separate item discriminations over levels, marginally acceptable accuracy of the multilevel reliability measures and empirical coverage rate of the MC confidence intervals were found in a limited condition, 200 clusters, 30 cluster size, .2 ICC, and 40 items, in MMLE-multiple imputation. In the model with the same item discrimination over levels, the accuracy of the multilevel reliability measures and the empirical coverage rate of the MC confidence intervals were acceptable in all multilevel designs we considered with 40 items under MMLE-multiple imputation. We discuss these findings and provide guidelines for reporting multilevel reliability measures.

Behavioral therapy for urinary symptoms in Parkinson's disease: A randomized clinical trial.

Determine the efficacy of behavioral therapy for urinary symptoms in Parkinson's disease. Randomized trial of behavioral therapy compared with control condition among adults (aged 54-85 years, 74% male, 10% Black/ 83% White) with Parkinson's and greater than or equal to 4 incontinence episodes weekly. Behavioral therapy included pelvic floor muscle exercises, bladder training, fluid and constipation management. Both groups completed bladder diary self-monitoring. Outcomes included diary-derived incontinence and ICIQ-overactive bladder (OAB) score (range, 0-16) with bother and quality of life questionnaires (higher scores = worse outcomes). Fifty-three participants randomized and 47 reported 8-week outcomes including 26 behavioral therapy and 21 control. Behavioral vs control participants were similar with respect to age (71.0 ± 6.1 vs 69.7 ± 8.2 years), sex (70% vs 78% male), motor score, cognition, mean weekly incontinence episodes (13.9 ± 9.6 vs 15.1 ± 11.1) and OAB symptoms (8.9 ± 2.4 vs 8.3 ± 2.2). Weekly incontinence reduction was similar between behavioral (-6.2 ± 8.7) and control participants (-6.5 ± 13.8) (P = 0.89). After multiple imputation analysis, behavioral therapy participants reported statistically similar reduction in OAB symptoms compared to control (-3.1 ± 2.8 vs -1.9 ± 2.2, P = 0.19); however quality of life (-22.6 ± 19.1 vs -7.0 ± 18.4, P = 0.048) and bother (-12.6 ± 17.2 vs - 6.7 ± 8.8, P = 0.037) improved significantly more with behavioral therapy. Self-monitoring resulted in fewer urinary symptoms; however, only multicomponent behavioral therapy was associated with reduced bother and improved quality of life. Providers should consider behavioral therapy as initial treatment for urinary symptoms in Parkinson's disease.