Simultaneous variable selection for joint models of longitudinal and survival outcomes

Joint models of longitudinal and survival outcomes have been used with increasing frequency in clinical investigations. Correct specification of fixed and random effects is essential for practical data analysis. Simultaneous selection of variables in both longitudinal and survival components functions as a necessary safeguard against model misspecification. However, variable selection in such models has not been studied. No existing computational tools, to the best of our knowledge, have been made available to practitioners. In this article, we describe a penalized likelihood method with adaptive least absolute shrinkage and selection operator (ALASSO) penalty functions for simultaneous selection of fixed and random effects in joint models. To perform selection in variance components of random effects, we reparameterize the variance components using a Cholesky decomposition; in doing so, a penalty function of group shrinkage is introduced. To reduce the estimation bias resulted from penalization, we propose a two-stage selection procedure in which the magnitude of the bias is ameliorated in the second stage. The penalized likelihood is approximated by Gaussian quadrature and optimized by an EM algorithm. Simulation study showed excellent selection results in the first stage and small estimation biases in the second stage. To illustrate, we analyzed a longitudinally observed clinical marker and patient survival in a cohort of patients with heart failure

Adiposity has unique influence on the renin-aldosterone axis and blood pressure in black children

OBJECTIVE: To comparatively examine the effects of adiposity on the levels of plasma renin activity (PRA), plasma aldosterone concentration (PAC), and aldosterone-renin ratio (ARR) in young black and white children. STUDY DESIGN: We prospectively assessed 248 black and 345 white children and adolescents. A novel analytical technique was used to assess the concurrent influences of age and body mass index (BMI) on PRA, PAC, and ARR. The estimated effects were depicted by colored contour plots. RESULTS: In contrast to whites, blacks had lower PRA (2.76 vs 3.36 ng/mL/h; P < .001) and lower PAC (9.01 vs 14.59 ng/dL; P < .001). In blacks, BMI was negatively associated with PRA (P = .001), consistent with an association with a more expanded plasma volume; there was no association with PAC. In whites, BMI was positively associated with PAC (P = .005); we did not detect a BMI-PRA association. The effects of BMI on ARR were directionally similar in the two race groups but more pronounced in blacks. Mean systolic blood pressure was greater in blacks with lower PRA (P < .01), higher PAC (P = .015), and higher ARR (P = .49). CONCLUSIONS: An increase in adiposity was associated with a suppressed PRA in blacks and an increase in PAC in whites. The unique relationship between adiposity and renin-aldosterone axis in blacks suggests the possible existence of a population-specific mechanism characterized by volume expansion, which could in turn enhance the influences of adiposity on blood pressure in black children and adolescents

Opioid Use as a Predictor of Health Care Use and Pain Outcomes: Analysis of Clinical Trial Data

Objective . To examine effects of pre-enrollment opioid use on outcomes of a 12-month collaborative pain care management trial. We hypothesized that participants with opioid use would have worse pain at baseline; use more health care services and analgesics; and have worse pain outcomes during the trial. Design . Secondary analysis of randomized controlled trial data. Setting . Veterans Affairs (VA) primary care. Subjects . Patients age 18-65 years with chronic pain of at least moderate severity who were enrolled in a 12-month pragmatic trial of a telephone-based collaborative care intervention for chronic musculoskeletal pain. Methods . Participants were categorized as opioid users (n = 84) or non-users (n = 166) at baseline and trial randomization was stratified by opioid use. We used logistic regression to examine cross-sectional associations with baseline opioid use and mixed-effect models for repeated measures to examine baseline opioid use as a predictor of Brief Pain Inventory (BPI) scores over 12 months. Results . At baseline, 33.6% reported use of prescribed opioids. Baseline opioid users had higher baseline BPI scores and higher health-related disability than non-users. Baseline opioid users also had more outpatient visits (15.0 vs. 10.1; p = 0.001) and received more analgesics (p < 0.001) during the trial. In the final multivariable model examining effects of baseline opioid use on BPI over 12 months, opioid users and nonusers had a non-significant difference of 0.25 points (p = 0.098). In conclusion, although baseline opioid users had worse pain at baseline and used more health care during the study, response to the intervention was not significantly modified by pre-existing opioid therapy

A semiparametric recurrent events model with time-varying coefficients

We consider a recurrent events model with time-varying coefficients motivated by two clinical applications. We use a random effects (Gaussian frailty) model to describe the intensity of recurrent events. The model can accommodate both time-varying and time-constant coefficients. We use the penalized spline method to estimate the time-varying coefficients. We use Laplace approximation to evaluate the penalized likelihood without a closed form. We estimate the smoothing parameters in a similar way to variance components. We conduct simulations to evaluate the performance of the estimates for both time-varying and time-independent coefficients. We apply this method to analyze two data sets: a stroke study and a child wheeze study

Glutathione-S-transferase P1 may predispose children to a decline in pulmonary function after stem cell transplant

RATIONALE: Pulmonary complications after hematopoietic stem cell transplant (SCT) are associated with increased mortality. Genetic markers for those at risk for pulmonary impairment post-SCT have not been widely investigated. METHODS: Forty-nine patients were retrospectively selected from a single institution's biorepository with linked clinical data. All subjects performed pre-SCT PFTs. Genotyping was conducted using the Infinium Exome-24 BeadChip. Four single nucleotide polymorphisms (SNPs) were selected (rs1800871, rs1695, rs1800629, rs12477314) and evaluated for association with PFT parameters as change over time from baseline. Associations between SNPs and PFT parameters were assessed and adjusted for the following confounding variables: age, gender, and race. RESULTS: Using the recessive genetic model, patients with one or two minor alleles for the glutathione S-transferase P1 (GSTP1) SNP rs1695 had a lower decline in FEV1 and FEF25-75 at 1-year post-SCT compared to patients who were homozygous for the ancestral allele (adjusted P-values <0.01 and 0.02, respectively). No other SNPs were significantly associated with other PFT parameters. CONCLUSIONS: Our findings suggest that GSTP1 genotype may be associated with lung function during the first year post-SCT. Identifying and investigating genes that predispose patients to pulmonary complications after SCT may allow for more personalized patient management based on pre-emptive genetic testing. The glutathione S-transferase gene merits further investigation

Does comorbid chronic pain affect posttraumatic stress disorder diagnosis and treatment? Outcomes of posttraumatic stress disorder screening in Department of Veterans Affairs primary care

Because posttraumatic stress disorder (PTSD) is both prevalent and underrecognized, routine primary care-based screening for PTSD has been implemented across the Veterans Health Administration. PTSD is frequently complicated by the presence of comorbid chronic pain, and patients with both conditions have increased symptom severity and poorer prognosis. Our objective was to determine whether the presence of pain affects diagnosis and treatment of PTSD among Department of Veterans Affairs (VA) patients who have a positive PTSD screening test. This retrospective cohort study used clinical and administrative data from six Midwestern VA medical centers. We identified 4,244 VA primary care patients with a positive PTSD screen and compared outcomes for those with and without a coexisting pain diagnosis. Outcomes were three clinically appropriate responses to positive PTSD screening: (1) mental health visit, (2) PTSD diagnosis, and (3) new selective serotonin reuptake inhibitor (SSRI) prescription. We found that patients with coexisting pain had a lower rate of mental health visits than those without pain (hazard ratio: 0.889, 95% confidence interval: 0.821–0.962). There were no significant differences in the rate of PTSD diagnosis or new SSRI prescription between patients with and without coexisting pain

Associations between menarche-related genetic variants and pubertal growth in male and female adolescents

PURPOSE: Previous studies have identified novel genetic variants associated with age at menarche in females of European descent. The pubertal growth effects of these variants have not been carefully evaluated in non-European descent groups. We aimed to examine the effects of 31 newly identified menarche-related single-nucleotide polymorphisms (SNPs) on growth outcomes in African-American (AA) and European-American (EA) children in a prospective cohort. METHODS: We analyzed longitudinal data collected from 263 AAs and 338 EAs enrolled between ages 5 and 17 years; the subjects were followed semiannually for an average of 6 years. The associations between the SNPs and growth-related outcomes, including weight, height, and body mass index (BMI), were examined using mixed-effect models. RESULTS: Longitudinal analyses revealed that 4 (near or in genes VGLL3, PEX2, CA10, and SKOR2) of the 14 menarche-only-related SNPs were associated with changes in weight and BMI in EA and AA (p ≤ .0032), but none of them was associated with changes in height. Of the eight menarche-timing and BMI-related SNPs, none was associated with changes in height, but three (in or near genes NEGR1, ETV5, and FTO) were associated with more rapid increases in weight and/or BMI in EA (p ≤ .0059). Among the nine menarche-timing and height-related SNPs, four (in or near genes ZBTB38, LOC728666, TBX2, and CABLES) were associated with changes in weight or height in EA and AA (p ≤ .0042). CONCLUSIONS: Genetic variants related to age at menarche were found to be associated with various growth parameters in healthy adolescents. The identified associations were often race and sex specific