Dimension reduction and shrinkage methods for high dimensional disease risk scores in historical data

Abstract Background Multivariable confounder adjustment in comparative studies of newly marketed drugs can be limited by small numbers of exposed patients and even fewer outcomes. Disease risk scores (DRSs) developed in historical comparator drug users before the new drug entered the market may improve adjustment. However, in a high dimensional data setting, empirical selection of hundreds of potential confounders and modeling of DRS even in the historical cohort can lead to over-fitting and reduced predictive performance in the study cohort. We propose the use of combinations of dimension reduction and shrinkage methods to overcome this problem, and compared the performances of these modeling strategies for implementing high dimensional (hd) DRSs from historical data in two empirical study examples of newly marketed drugs versus comparator drugs after the new drugs’ market entry—dabigatran versus warfarin for the outcome of major hemorrhagic events and cyclooxygenase-2 inhibitor (coxibs) versus nonselective non-steroidal anti-inflammatory drugs (nsNSAIDs) for gastrointestinal bleeds. Results Historical hdDRSs that included predefined and empirical outcome predictors with dimension reduction (principal component analysis; PCA) and shrinkage (lasso and ridge regression) approaches had higher c-statistics (0.66 for the PCA model, 0.64 for the PCA + ridge and 0.65 for the PCA + lasso models in the warfarin users) than an unreduced model (c-statistic, 0.54) in the dabigatran example. The odds ratio (OR) from PCA + lasso hdDRS-stratification [OR, 0.64; 95 % confidence interval (CI) 0.46–0.90] was closer to the benchmark estimate (0.93) from a randomized trial than the model without empirical predictors (OR, 0.58; 95 % CI 0.41–0.81). In the coxibs example, c-statistics of the hdDRSs in the nsNSAID initiators were 0.66 for the PCA model, 0.67 for the PCA + ridge model, and 0.67 for the PCA + lasso model; these were higher than for the unreduced model (c-statistic, 0.45), and comparable to the demographics + risk score model (c-statistic, 0.67). Conclusions hdDRSs using historical data with dimension reduction and shrinkage was feasible, and improved confounding adjustment in two studies of newly marketed medications

International Comparison of Approaches to Common Data Models for Comparative Effectiveness Research

Over the past decade, characterizing the safety and effectiveness of drugs has advanced through distributed networks of data repositories where investigators implement the same procedures to address the same topic using a common data model. Distributed networks for pharmacoepidemiology have now been established in the United States (US), Globally/Europe Canada, and Asian countries. Sentinel in the US was developed in response to legislation and is funded by the US Food and Drug Administration to address their safety queries. The Observational Medical Outcomes Partnership (OMOP) is an international collaborative with a growing European data network that developed a common data model through a public-private partnership. The Canadian Network of Observational Drug Effect Studies (CNODES) receives funding and study queries from Health Canada and dissemination is directly back to the regulator as well as through the peer-reviewed literature. The Asian Pharmacoepidemiology Network (AsPEN) is an investigator-initiated multi-national research network formed to support the safety and effectiveness assessment of medications and other therapeutics and to facilitate the prompt identification and validation of emerging safety issues among the countries in Asia and Pacific regions. While these networks have implemented two different common data models (CNODES with Sentinel, ASPEN with OMOP), each network differs from the others in the aims, stage and implementation, operational approach, data quality assurance mechanisms, funding, and dissemination. The objectives of this session are to compare and contrast the role and goals, design principles, implementation approaches, and analytic conventions and procedures between common data models implemented by SENTINEL, OMOP, CNODES, ands AsPEN. Divided into seven 15-minute segments the session begins with an overview of distributed networks of common data models for pharmacoepidemiology. In four slides, each presenter then characterizes their network by describing the following: • number of data holders, lives covered, and records, data holdings, data access model, network governance. • process for transforming a repository’s data into the common data model • target audience(s), process of identifying queries and knowledge dissemination plan • two key challenges faced by the network and the lessons learned In identifying similarities and meaningful differences between the networks, in the next segment the discussant will articulate the relative strengths of the different approaches taken. This will lead into the last segment in which the floor will be opened for questions and comments from the audience. The session would be of benefit to researchers seeking to better understand or join an existing distributed network as well as researchers interested in broadening their understanding of global comparative effectiveness research

Lifestyle Changes in Relation to Initiation of Antihypertensive and Lipid-Lowering Medication : A Cohort Study

Background--Lifestyle modification is a key component of cardiovascular disease prevention before and concurrently with pharmacologic interventions. We evaluated whether lifestyle factors change in relation to the initiation of antihypertensive or lipidlowering medication (statins). Methods and Results--The study population comprised 41 225 participants of the FPS (Finnish Public Sector) study aged =40 years who were free of cardiovascular disease at baseline and responded to =2 consecutive surveys administered in 4-year intervals in 2000-2013. Medication use was ascertained through pharmacy-claims data. Using a series of pre-post data sets, we compared changes in body mass index, physical activity, alcohol consumption, and smoking between 8837 initiators and 46 021 noninitiators of antihypertensive medications or statins. In participants who initiated medication use, body mass index increased more (difference in change 0.19; 95% CI, 0.16-0.22) and physical activity declined (-0.09 metabolic equivalent of task hour/day; 95% CI, -0.16 to -0.02) compared with noninitiators. The likelihood of becoming obese (odds ratio: 1.82; 95% CI, 1.63-2.03) and physically inactive (odds ratio: 1.08; 95% CI, 1.01-1.17) was higher in initiators. However, medication initiation was associated with greater decline in average alcohol consumption (-1.85 g/week; 95% CI, -3.67 to -0.14) and higher odds of quitting smoking (odds ratio for current smoking in the second survey: 0.74; 95% CI, 0.64-0.85). Conclusions--These findings suggest that initiation of antihypertensive and statin medication is associated with lifestyle changes, some favorable and others unfavorable. Weight management and physical activity should be encouraged in individuals prescribed these medications.Peer reviewe

Impact of Baseline Heart Failure Burden on Post-Implantable Cardioverter-Defibrillator Mortality Among Medicare Beneficiaries

ObjectivesThis study sought to assess the impact of baseline heart failure (HF) burden on survival with primary implantable cardioverter-defibrillator (ICD) among Medicare recipients.BackgroundSurvival after primary ICD implantation may differ between trial and Medicare populations.MethodsLinking data from the CMS (Centers for Medicare and Medicaid Services) ICD registry and the Medicare files (2005 to 2009), we identified primary ICD recipients age ≥66 years with ejection fraction ≤35%. Number of previous HF hospitalizations (prev-HF-hosp) and length of hospitalization prior to implantation were used to define HF burden. Crude all-cause mortality was estimated. Adjusted hazard ratios (HR) were derived from Cox models.ResultsOf 66,974 ICD recipients (73% men, 88% white, mean age 75 years), 11,876 died (average follow-up = 1.4 years), with 3-year mortality of 31%. Among patients with no prev-HF-hosp, 3-year mortality was 27% compared with 63% in those with ≥3 prev-HF-hosp (adjusted HR: 1.8). Among patients with same-day implantation, 3-year mortality was 25% compared with 53% in those with >1-week hospitalization days prior to implantation (adjusted HR: 1.9). Mortality at 3-year follow-up among the 31,685 ICD recipients with no prev-HF-hosp and same-day implantation (low HF burden) was similar to that in trials (22%).ConclusionsNearly one-third of Medicare ICD recipients died within 3 years, reflecting a population with more advanced age and disease than seen in trial populations for primary prevention ICD. Nearly one-half of Medicare recipients had a low HF burden and had a survival similar to trial ICD recipients. Future research is warranted to understand the effectiveness of primary ICD implantation among Medicare beneficiaries with heavy HF burdens

Risk of Pneumonia in New Users of Cholinesterase Inhibitors for Dementia

To compare the risk of pneumonia among older patients receiving donepezil, galantamine, or rivastigmine for dementia

Harnessing the Medicaid Analytic eXtract (MAX) to Evaluate Medications in Pregnancy: Design Considerations

Background: In the absence of clinical trial data, large post-marketing observational studies are essential to evaluate the safety and effectiveness of medications during pregnancy. We identified a cohort of pregnancies ending in live birth within the 2000–2007 Medicaid Analytic eXtract (MAX). Herein, we provide a blueprint to guide investigators who wish to create similar cohorts from healthcare utilization data and we describe the limitations in detail. Methods: Among females ages 12–55, we identified pregnancies using delivery-related codes from healthcare utilization claims. We linked women with pregnancies to their offspring by state, Medicaid Case Number (family identifier) and delivery/birth dates. Then we removed inaccurate linkages and duplicate records and implemented cohort eligibility criteria (i.e., continuous and appropriate enrollment type, no private insurance, no restricted benefits) for claim information completeness. Results: From 13,460,273 deliveries and 22,408,810 child observations, 6,107,572 pregnancies ending in live birth were available after linkage, cleaning, and removal of duplicate records. The percentage of linked deliveries varied greatly by state, from 0 to 96%. The cohort size was reduced to 1,248,875 pregnancies after requiring maternal eligibility criteria throughout pregnancy and to 1,173,280 pregnancies after further applying infant eligibility criteria. Ninety-one percent of women were dispensed at least one medication during pregnancy. Conclusions: Mother-infant linkage is feasible and yields a large pregnancy cohort, although the size decreases with increasing eligibility requirements. MAX is a useful resource for studying medications in pregnancy and a spectrum of maternal and infant outcomes within the indigent population of women and their infants enrolled in Medicaid. It may also be used to study maternal characteristics, the impact of Medicaid policy, and healthcare utilization during pregnancy. However, careful attention to the limitations of these data is necessary to reduce biases

Use of antidepressants near delivery and risk of postpartum hemorrhage: cohort study of low income women in the United States

Objective: To determine whether use of serotonin or non-serotonin reuptake inhibitors near to delivery is associated with postpartum hemorrhage. Design Cohort study. Setting 2000-07 nationwide Medicaid data (Medicaid Analytic eXtract). Population 106 000 pregnant women aged 12-55 with a diagnosis of mood or anxiety disorder. Women were categorized into four mutually exclusive exposure groups according to pharmacy dispensing data: current (delivery date), recent (1-30 days before delivery date), past (1-5 months before delivery date), and no exposure (reference group). Main outcome measures Risk of postpartum hemorrhage by timing of exposure and by serotonin or non-serotonin reuptake inhibitors, classes of antidepressant, and antidepressant types. Relative risks and 95% confidence intervals adjusted for delivery year, risk factors for postpartum hemorrhage, indicators of severity of mood/anxiety disorder, other indications for antidepressants, and other drugs. High dimensional propensity score (hdPS) methods were used to empirically identify and adjust for additional factors. Results: 12 710 (12%) women had current exposure to serotonin reuptake inhibitor monotherapy, and 1495 (1.4%) women had current exposure to non-serotonin reuptake inhibitor monotherapy. The risk of postpartum hemorrhage was 2.8% among women with mood/anxiety disorders but no exposure to antidepressants, 4.0% in the current users of serotonin reuptake inhibitors, 3.8% in the current users of non-serotonin reuptake inhibitors, 3.2% in the recent users of serotonin reuptake inhibitors, 3.1% in the recent users of non-serotonin reuptake inhibitors, 2.5% in the past users of serotonin reuptake inhibitors, and 3.4% in the past users of non-serotonin reuptake inhibitors. Compared with no exposure, women with current exposure to serotonin reuptake inhibitors had a 1.47-fold increased risk of postpartum hemorrhage (95% confidence interval 1.33 to 1.62) and women with current non-serotonin reuptake inhibitor exposure had a 1.39-fold increased risk (1.07 to 1.81). Results were similar with hdPS adjustment. Women with current exposure to serotonin reuptake inhibitors had an adjusted excess risk of 1.26% (0.90% to 1.62%), with a number needed to harm of 80, and for women with current exposure to non-serotonin reuptake inhibitors the excess risk was 1.03% (0.07% to 1.99%), with a number needed to harm of 97. For exposure to serotonin reuptake inhibitors the relative risk was 1.19 (1.03 to 1.38) for recent exposure and 0.93 (0.82 to 1.06) for past exposure; for non-serotonin reuptake inhibitors the figures were 1.17 (0.80 to 1.70) and 1.26 (1.00 to 1.59), respectively. Current exposure to selective serotonin reuptake inhibitor monotherapy was also associated with postpartum hemorrhage (1.42, 1.27 to 1.57), as was current serotonin norepinephrine (noradrenaline) reuptake inhibitor (1.90, 1.37 to 2.63) and tricyclic monotherapy (1.77, 0.90 to 3.47). All types of selective serotonin reuptake inhibitors available for analysis and venlafaxine, a serotonin norepinephrine reuptake inhibitor, were significantly associated with postpartum hemorrhage. Conclusions: Exposure to serotonin and non-serotonin reuptake inhibitors, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclics, close to the time of delivery was associated with a 1.4 to 1.9-fold increased risk for postpartum hemorrhage. While potential confounding by unmeasured factors cannot be ruled out, these findings suggest that patients treated with antidepressants during late pregnancy are more likely to experience postpartum hemorrhage

Potential contribution of lifestyle and socioeconomic factors to healthy user bias in antihypertensives and lipidlowering drugs

Objectives Healthy user bias arises when users of preventive medications such as lipid-lowering drugs (LLDs), hormone replacement therapy and antihypertensive (AH) medications are healthier than non-users due to factors other than medication effects, making the medications appear more beneficial in observational studies of effectiveness and safety. The purpose of the study is to examine factors contributing to healthy user effect in patients taking AHs or LLDs.Methods: Among patients with hypertension or hyperlipidaemia in a population-based sample from the National Health and Nutrition Examination Survey (1999–2010), we assessed the association between socioeconomic and lifestyle factors and the use of AHs/LLDs by logistic regression with adjustment for demographics and comorbidities in a cross-sectional study.Results: When 9715 AH/LLD users were compared with 3725 non-users, AH/LLD users were more likely to be: highly educated (OR 1.2, 95% CI 1.2 to 1.3), non-impoverished (OR 1.3, 95% CI 1.2 to 1.4), current non-smokers (OR 1.2, 95% CI 1.1 to 1.4), physically active (OR 1.1, 95% CI 1.0 to 1.2) and consume more calcium (OR 1.1, 95% CI 1.0 to 1.3) but less likely to have normal body mass index (OR 0.6, 95% CI 0.6 to 0.7) or to meet dietary sodium recommendations (OR 0.8, 95% CI 0.7 to 0.9).Conclusions: We identified several salutary lifestyle factors associated with AH/LLD use in a representative US population. Healthy user effect may be partly explained by better socioeconomic profiles and lifestyles in AH/LLD users compared with non-users.</p

Influence of healthy candidate bias in assessing clinical effectiveness for implantable cardioverter-defibrillators: cohort study of older patients with heart failure

Objective: To assess the potential contribution of unmeasured general health status to patient selection in assessments of the clinical effectiveness of implantable cardioverter-defibrillator (ICD) therapy. Design: Retrospective cohort study. Setting: Linked data from an ICD registry, heart failure registry, and Medicare claims data for ICDs implanted in 2005 through 2009. Participants: 29 426 patients admitted to hospital with heart failure aged 66 years or older and eligible for ICD therapy for primary prevention. Main outcome measures Non-traumatic hip fracture, admission to a skilled nursing facility, and 30 day mortality—outcomes unlikely to be improved by ICD therapy. Results: Compared with 17 853 patients without ICD therapy, 11 573 patients with ICD therapy were younger and had lower ejection fraction and more cardiac admissions to hospital but fewer non-cardiac admissions to hospital and comorbid conditions. Patients with ICD therapy had greater freedom from unrelated events after adjusting for age and sex: hip fracture (hazard ratio 0.77, 95% confidence interval 0.64 to 0.92), skilled nursing facility admission (0.53, 0.50 to 0.55), and 30 day mortality (0.12, 0.10 to 0.15). Conclusions: Lower risks of measured outcomes likely reflect unmeasured differences in comorbidity and frailty. The findings highlight potential pitfalls of observational comparative effectiveness research and support physician consideration of general health status in selecting patients for ICD therapy

Lifestyle Changes in Relation to Initiation of Antihypertensive and Lipid-Lowering Medication: A Cohort Study

Background Lifestyle modification is a key component of cardiovascular disease prevention before and concurrently with pharmacologic interventions. We evaluated whether lifestyle factors change in relation to the initiation of antihypertensive or lipid‐lowering medication (statins).Methods and Results The study population comprised 41 225 participants of the FPS (Finnish Public Sector) study aged ≥40 years who were free of cardiovascular disease at baseline and responded to ≥2 consecutive surveys administered in 4‐year intervals in 2000–2013. Medication use was ascertained through pharmacy‐claims data. Using a series of pre–post data sets, we compared changes in body mass index, physical activity, alcohol consumption, and smoking between 8837 initiators and 46 021 noninitiators of antihypertensive medications or statins. In participants who initiated medication use, body mass index increased more (difference in change 0.19; 95% CI, 0.16–0.22) and physical activity declined (−0.09 metabolic equivalent of task hour/day; 95% CI, −0.16 to −0.02) compared with noninitiators. The likelihood of becoming obese (odds ratio: 1.82; 95% CI, 1.63–2.03) and physically inactive (odds ratio: 1.08; 95% CI, 1.01–1.17) was higher in initiators. However, medication initiation was associated with greater decline in average alcohol consumption (−1.85 g/week; 95% CI, −3.67 to −0.14) and higher odds of quitting smoking (odds ratio for current smoking in the second survey: 0.74; 95% CI, 0.64–0.85).Conclusions These findings suggest that initiation of antihypertensive and statin medication is associated with lifestyle changes, some favorable and others unfavorable. Weight management and physical activity should be encouraged in individuals prescribed these medications.</p