Search

In genetic association studies, it is typically thought that genetic variants and environmental variables jointly will explain more of the inheritance of a phenotype than either of these two components separately. Traditional methods to identify gene-environment interactions typically consider only one measured environmental variable at a time. However, in practice, multiple environmental factors may each be imprecise surrogates for the underlying physiological process that actually interacts with the genetic factors. In this paper, we develop a variant of L2 boosting that is specifically designed to identify combinations of environmental variables that jointly modify the effect of a gene on a phenotype. Because the effect modifiers might have a small signal compared with the main effects, working in a space that is orthogonal to the main predictors allows us to focus on the interaction space. In a simulation study that investigates some plausible underlying model assumptions, our method outperforms the least absolute shrinkage and selection and Akaike Information Criterion and Bayesian Information Criterion model selection procedures as having the lowest test error. In an example for the Women's Health Initiative-Population Architecture using Genomics and Epidemiology study, the dedicated boosting method was able to pick out two single-nucleotide polymorphisms for which effect modification appears present. The performance was evaluated on an independent test set, and the results are promising. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines., Patients and Methods: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed., Results: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest., Conclusion: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing., (© The Author(s) 2024. Published by Oxford University Press.)

When considering low-dimensional gene-treatment or gene-environment interactions we might suspect groups of genes to interact with treatment or environment in a similar way. For example, genes associated with related biological processes might interact with an environmental factor or a clinical treatment in its effect on a phenotype correspondingly. We use the idea of a structured interaction model together with penalized regression to limit the model complexity in a model in which we believe the interactions might behave in a similar way. We propose the directed lasso, a regression modeling strategy using a pairwise fused lasso penalty to encourage interaction model simplicity through fusion of effect size. We compare the performance of the directed lasso to the lasso and other methods in a simulation study and on data sampled from a breast cancer clinical trial.

Study Design: Secondary analysis of data from a double-blind randomized controlled trial., Objective: To identify mediators of the effect of lumbar epidural injections of corticosteroid plus lidocaine on patient satisfaction at 6 weeks postinjection in patients with lumbar spinal stenosis. We hypothesized that short-term (≤3 wk) change in leg pain would be a significant mediator of satisfaction., Summary of Background Data: No prior studies have identified mediators of effects of epidural injections on patient satisfaction with treatment of lumbar spinal stenosis., Methods: We used mediation analysis methods to examine selected intermediate variables (adverse events and change in leg pain, back pain, disability, depression, and fatigue at 3 wk) as potential mediators of the effect of lumbar epidural injections of corticosteroid plus lidocaine on patient satisfaction with treatment. We used the overall satisfaction item from the Swiss Spinal Stenosis Questionnaire as our primary outcome to measure patient satisfaction with the injection procedure at 6 weeks., Results: Among 400 patients randomized to receive epidural injections with corticosteroid plus lidocaine or with lidocaine alone, 369 had complete data for the satisfaction outcome and potential mediators and served as the analysis sample. Contrary to our expectations, 3-week change in leg pain intensity did not have significant mediation effects on patient satisfaction. Three-week change in disability as measured by the Roland-Morris Disability Questionnaire was a significant mediator of the effects of lumbar epidural corticosteroid injections on patient satisfaction at 6 weeks, explaining 48% to 60% of the treatment effect on satisfaction. Changes in pain intensity in the leg and back together explained very little of the treatment effect on satisfaction beyond the information contributed by disability change alone. We did not find other intermediate variables to be mediators of patient satisfaction., Conclusion: These findings support the current approach of examining disability as a primary patient-reported outcome in comparative effectiveness studies of lumbar spinal stenosis., Level of Evidence: 2.

Objectives: To estimate the prevalence of tooth wear and to investigate factors associated with tooth wear in patients from general practices in the Northwest United States., Methods: Data on the diagnosis and treatment of oral diseases during the previous year were collected in a survey with a systematic random sample of patients (n= 1530) visiting general dentists from the Northwest Practice-based REsearch Collaborative in Evidence-based DENTistry (PRECEDENT) (n=80). Prevalence ratios (PRs) of moderate to severe occlusal and incisal tooth wear by patient characteristics were estimated using cluster-adjusted multiple binomial regression for adults (18+ years) and children/adolescents (3-17 years)., Results: For adults, the mean number of teeth with wear facets was 5.4 [95% confidence interval (CI) =4.6-6.2] and 51% of the adults had four or more teeth with wear. Participants 45-64 and 65+ years old were 1.3 (95% CI=1.1-1.6) and 1.4 (95% CI=1.1-1.8) times as likely to have 4+ teeth with moderate to severe wear facets as participants 18-44 years old. Adult males had a 20% (PR=1.2; 95% CI=1.1-1.4) higher prevalence of wear than adult females. Adults who were using, or had ever used occlusal splints had higher prevalence of tooth wear compared to those who never used such appliances (PR=1.3; 95% CI=1.0-1.5). Adults with any periodontal bone loss also had a 20% higher prevalence of wear than adults without periodontal disease (PR=1.2; 95% CI=1.0-1.4). For children/adolescents, the mean number of teeth with moderate to severe wear facets was 1.6 (95% CI=0.9-2.6) and 31% of the children had one or more teeth with wear facets. The adjusted prevalence ratio of tooth wear (1+ teeth with wear facets) for boys was 1.6 times as high (95% CI=1.1-2.4) as compared with girls. The prevalence of wear for children 12+ years old was 50% (PR=0.5; 95% CI=0.3-0.8) lower than that of children <12 years old. Angle's class II was associated with higher tooth wear prevalence (PR= 1.8; 95% CI=1.3-2.6) than class I. Children with posterior or anterior open bite had lower prevalence of wear than their counterparts (PR=0.6; 95% CI=0.3-1.0). No associations were observed between tooth wear and orthodontic treatment, missing teeth, and race/ethnicity., Conclusion: Tooth wear is a prevalent condition in this population. Among adults, higher prevalences of tooth wear were observed among those who were older, males, had used occlusal splints and had periodontal disease. Among children, higher prevalences were associated with younger age, male gender, class II malocclusion and the absence of open bite. Submitted on behalf of the Northwest PRECEDENT network, with support from NIDCR grants DE016750 and DE016752., (© 2010 John Wiley & Sons A/S.)