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

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.

Comparative cardiovascular safety of glucagon-like peptide-1 receptor agonists versus other antidiabetic drugs in routine care: a cohort study.

Aims: To evaluate the comparative cardiovascular disease (CVD) safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in head-to-head comparisons with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulphonylureas or insulin, when added to metformin, as used in 'real-world' patients with type 2 diabetes mellitus (T2DM).

Methods: Within a large US commercial health plan database linked to laboratory test results, we identified three pairwise 1 : 1 propensity-score-matched cohorts of patients with T2DM aged ≥18 years treated with metformin who initiated a GLP-1 RA or a comparator, i.e.

Circulating N-Linked Glycoprotein Acetyls and Longitudinal Mortality Risk.

Rationale: Circulating glycoprotein N-acetyl glucosamine residues have recently been associated with incident cardiovascular disease and diabetes mellitus.

Objective: Using a plasma glycan biosignature (GlycA) to identify circulating N-acetyl glycan groups, we examined the longitudinal association between GlycA and mortality among initially healthy individuals.

Methods And Results: We quantified GlycA by 400 MHz (1)H nuclear magnetic resonance spectroscopy in 27,524 participants in the Women's Health Study (NCT00000479).

Comparison of high-dimensional confounder summary scores in comparative studies of newly marketed medications.

Objective: To compare confounding adjustment by high-dimensional propensity scores (hdPSs) and historically developed high-dimensional disease risk scores (hdDRSs) in three comparative study examples of newly marketed medications: (1) dabigatran vs. warfarin on major hemorrhage; (2) on death; and (3) cyclooxygenase-2 inhibitors vs. nonselective nonsteroidal anti-inflammatory drugs on gastrointestinal bleeds.

Prenatal stress and newborn telomere length.

Background: The developmental origin of the health and disease hypothesis is based on the premise that many chronic diseases have their roots in fetal development. Specifically, maternal stress during pregnancy is associated with altered fetal development and many adverse long-term health outcomes. Although the mechanisms underlying this effect are currently unclear, at the cellular level 1 possible mediator is the regulation of telomere length.

Minimally Invasive Transsulcal Resection of Intraventricular and Periventricular Lesions Through a Tubular Retractor System: Multicentric Experience and Results.

Background: Conventional approaches to deep-seated cerebral lesions range from biopsy to transcortical or transcallosal resection. Although the former does not reduce tumor burden, the latter are more invasive and associated with greater potential for irreparable injury to normal brain. Disconnection syndrome, hemiparesis, hemianesthesia, or aphasia is not uncommon after such surgery, especially when lesion is large.

Folic Acid, Vitamin B6, and Vitamin B12 in Combination and Age-Related Cataract in a Randomized Trial of Women.

Purpose: To examine the incidence of cataract and cataract extraction in a trial of folic acid and vitamins B6 and B12.

Methods: In a randomized, double-masked, placebo-controlled trial, 5442 female health professionals aged 40 years or older with preexisting cardiovascular disease (CVD) or three or more CVD risk factors were randomly assigned to receive a combination of folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin B12 (1 mg/day), or placebo.

Developing alerting thresholds for prospective drug safety monitoring.

Background: Current methods for prospective drug safety monitoring focus on determining whether and when to generate safety alerts indicating that a new drug may be less safe than a comparator. Approaches are needed to develop safety thresholds that can be used to define whether a new drug is no less than or equally safe as the comparator.

Objectives: Our aim is to develop a framework for determining which safety statements can be made about a new drug and when they can be made during prospective monitoring.

Injection of new psychoactive substance snow blow associated with recently acquired HIV infections among homeless people who inject drugs in Dublin, Ireland, 2015.

In February 2015, an outbreak of recently acquired HIV infections among people who inject drugs (PWID) was identified in Dublin, following similar outbreaks in Greece and Romania in 2011. We compared drug and risk behaviours among 15 HIV cases and 39 controls. Injecting a synthetic cathinone, snow blow, was associated with recent HIV infection (AOR: 49; p=0.

Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial.

Background: Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo.

Methods And Results: In 11 186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522).

Association Between High-Sensitivity C-Reactive Protein and Total Stroke by Hypertensive Status Among Men.

Background: High-sensitivity C-reactive protein (hsCRP), a marker of systemic inflammation, may promote atherosclerosis, particularly among adults with elevated blood pressure; however, data are sparse. We examined the association between hsCRP concentrations and risk of total stroke by hypertension status (normotension, prehypertension, and hypertension) among men in the Physicians' Health Study (PHS).

Methods And Results: Blood samples were collected (1996-1997) and assayed for hsCRP among 10 456 initially healthy men from PHS I and PHS II and followed from 1997 to 2012.

Is grand-parental smoking associated with adolescent obesity? A three-generational study.

Background/objectives: Data from previous studies consistently suggest that maternal smoking is positively associated with obesity later in life. Whether this association persists across generations is unknown. We examined whether grand-parental smoking was positively associated with overweight status in adolescence.

The influence of reporting mode on children's cued personal memories.

The Autobiographical Memory Test (AMT) is widely used in research contexts to measure the extent to which participants (children or adults) report specific or general memories in response to cue words. Recalling fewer specific and more general memories (overgeneral memory) has been shown to be linked to depression in adults, but findings for youth, in particular, are mixed. Different versions of the AMT may be one contributing factor, yet this issue has received little research attention.

Regularized Regression Versus the High-Dimensional Propensity Score for Confounding Adjustment in Secondary Database Analyses.

Selection and measurement of confounders is critical for successful adjustment in nonrandomized studies. Although the principles behind confounder selection are now well established, variable selection for confounder adjustment remains a difficult problem in practice, particularly in secondary analyses of databases. We present a simulation study that compares the high-dimensional propensity score algorithm for variable selection with approaches that utilize direct adjustment for all potential confounders via regularized regression, including ridge regression and lasso regression.

Type 2 Diabetes Research Yield, 1951-2012: Bibliometrics Analysis and Density-Equalizing Mapping.

The objective of this paper is to provide a detailed evaluation of type 2 diabetes mellitus research output from 1951-2012, using large-scale data analysis, bibliometric indicators and density-equalizing mapping. Data were retrieved from the Science Citation Index Expanded database, one of the seven curated databases within Web of Science. Using Boolean operators "OR", "AND" and "NOT", a search strategy was developed to estimate the total number of published items.

Comparative Effectiveness of Oxaliplatin Versus 5-flourouricil in Older Adults: An Instrumental Variable Analysis.

Background: Oxaliplatin was rapidly adopted for treatment of stage III colon cancer after FDA approval in November 2004, thus providing an opportunity to use calendar time as an instrumental variable in nonexperimental comparative effectiveness research. Assuming instrument validity, instrumental variable analyses account for unmeasured confounding and are particularly valuable in sub-populations of unresolved effectiveness, such as older individuals.

Methods: We examined stage III colon cancer patients ages 65+ years initiating chemotherapy between 2003 and 2008 using US population-based cancer registry data linked with Medicare claims (N = 3,660).

Dietary Fat Intake Is Differentially Associated with Risk of Paroxysmal Compared with Sustained Atrial Fibrillation in Women.

Background: Dietary fats have effects on biological pathways that may influence the development and maintenance of atrial fibrillation (AF). However, associations between n-3 (ω-3) polyunsaturated fatty acids and AF are inconsistent, and data on other dietary fats and AF risk are sparse.

Objectives: We examined the association between dietary fatty acid (FA) subclasses and risk of incident AF and explored whether these associations differed for sustained and paroxysmal AF.

High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy.

Background: Cardiac troponin and B-type natriuretic peptide (BNP) concentrations are associated with adverse cardiovascular outcome in primary prevention populations. Whether statin therapy modifies this association is poorly understood.

Methods And Results: We measured high-sensitivity cardiac troponin I (hsTnI) in 12 956 and BNP in 11 076 participants without cardiovascular disease in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial before randomization to rosuvastatin 20 mg/d or placebo.

Effects of gestational age at enrollment in pregnancy exposure registries.

Purpose: This study aims to explore the influence of gestational age at enrollment, and enrollment before or after prenatal screening, on the estimation of drug effects in pregnancy exposure registries.

Methods: We assessed the associations between first trimester antiepileptic drug (AED) exposure and risk of spontaneous abortion and major congenital malformations in the North American AED Registry (1996-2013). We performed logistic regression analyses, conditional or unconditional on gestational age at enrollment, to estimate relative risk (RR) for first trimester AED users compared with non-users.

Model Misspecification When Excluding Instrumental Variables From PS Models in Settings Where Instruments Modify the Effects of Covariates on Treatment.

Theory and simulations show that variables affecting the outcome only through exposure, known as instrumental variables (IVs), should be excluded from propensity score (PS) models. In pharmacoepidemiologic studies based on automated healthcare databases, researchers will sometimes use a single PS model to control for confounding when evaluating the effect of a treatment on multiple outcomes. Because these "full" models are not constructed with a specific outcome in mind, they will usually contain a large number of IVs for any individual study or outcome.

Effects of xanthine oxidase inhibitors on cardiovascular disease in patients with gout: a cohort study.

Background: Hyperuricemia and gout are associated with an increased risk of cardiovascular disease (CVD). It is unknown whether treating hyperuricemia with xanthine oxidase inhibitors (XOIs), including allopurinol and febuxostat, modifies cardiovascular risks.

Methods: We used US insurance claims data to conduct a cohort study among gout patients, comparing XOI initiators with non-users with hyperuricemia defined as serum uric acid level ≥6.

Evaluating possible confounding by prescriber in comparative effectiveness research.

In nonrandomized studies of comparative effectiveness of medications, the prescriber may be the most important determinant of treatment assignment, yet the majority of analyses ignore the prescriber. Via Monte Carlo simulation, we evaluated the bias of 3 approaches that utilize the prescriber in analysis compared against the default approach that ignores the prescriber. Prescriber preference instrumental variable (IV) analyses were unbiased when IV criteria were met, which required no clustering of unmeasured patient characteristics within prescriber.

Prospective study of body size throughout the life-course and the incidence of endometrial cancer among premenopausal and postmenopausal women.

Although adult obesity is known to increase endometrial cancer risk, evidence for childhood obesity is limited. We prospectively examined the association between body fatness throughout life and endometrial cancer risk. 47,289 participants in the Nurses' Health Study (NHS) and 105,386 of the Nurses' Health Study II (NHS II) recalled their body fatness at ages 5, 10 and 20 using a pictogram.

Risk of venous thromboembolism in patients with rheumatoid arthritis: initiating disease-modifying antirheumatic drugs.

Objectives: Recent research suggests that rheumatoid arthritis increases the risk of venous thromboembolism. This study compared the risk of venous thromboembolism in patients with newly diagnosed rheumatoid arthritis initiating a biologic disease-modifying antirheumatic drug (DMARD) with those initiating methotrexate or a nonbiologic DMARD.

Methods: We conducted a population-based cohort study using US insurance claims data (2001-2012).