Bayesian Phase I/II Biomarker-Based Dose Finding for Precision Medicine With Molecularly Targeted Agents

<p>The optimal dose for treating patients with a molecularly targeted agent may differ according to the patient's individual characteristics, such as biomarker status. In this article, we propose a Bayesian phase I/II dose-finding design to find the optimal dose that is personalized for each patient according to his/her biomarker status. To overcome the curse of dimensionality caused by the relatively large number of biomarkers and their interactions with the dose, we employ canonical partial least squares (CPLS) to extract a small number of components from the covariate matrix containing the dose, biomarkers, and dose-by-biomarker interactions. Using these components as the covariates, we model the ordinal toxicity and efficacy using the latent-variable approach. Our model accounts for important features of molecularly targeted agents. We quantify the desirability of the dose using a utility function and propose a two-stage dose-finding algorithm to find the personalized optimal dose according to each patient's individual biomarker profile. Simulation studies show that our proposed design has good operating characteristics, with a high probability of identifying the personalized optimal dose. Supplementary materials for this article are available online.</p

755122_supp_mat – Supplemental material for A Bayesian basket trial design using a calibrated Bayesian hierarchical model

<p>Supplemental material, 755122_supp_mat for A Bayesian basket trial design using a calibrated Bayesian hierarchical model by Yiyi Chu and Ying Yuan in Clinical Trials</p

Treatment Comparisons in Adaptive Platform Trials Adjusting for Temporal Drift

An adaptive platform trial (APT) is a multi-arm trial in the context of a single disease where treatment arms are allowed to enter or leave the trial based on some decision rule. If a treatment enters the trial later than the control arm, there exist nonconcurrent controls who were not randomized between the two arms under comparison. As APTs typically take long periods of time to conduct, temporal drift may occur, which requires the treatment comparisons to be adjusted for this temporal change. Under the causal inference framework, we propose two approaches for treatment comparisons in APTs that account for temporal drift, both based on propensity score weighting. In particular, to address unmeasured confounders, one approach is doubly robust in the sense that it remains valid so long as either the propensity score model is correctly specified or the time effect model is correctly specified. Simulation study shows that our proposed approaches have desirable operating characteristics with well controlled Type I error rates and high power with or without unmeasured confounders.</p

A Bayesian Phase I/II Trial Design for Immunotherapy

<p>Immunotherapy is an innovative treatment approach that stimulates a patient’s immune system to fight cancer. It demonstrates characteristics distinct from conventional chemotherapy and stands to revolutionize cancer treatment. We propose a Bayesian phase I/II dose-finding design that incorporates the unique features of immunotherapy by simultaneously considering three outcomes: immune response, toxicity, and efficacy. The objective is to identify the biologically optimal dose, defined as the dose with the highest desirability in the risk–benefit tradeoff. An Emax model is utilized to describe the marginal distribution of the immune response. Conditional on the immune response, we jointly model toxicity and efficacy using a latent variable approach. Using the accumulating data, we adaptively randomize patients to experimental doses based on the continuously updated model estimates. A simulation study shows that our proposed design has good operating characteristics in terms of selecting the target dose and allocating patients to the target dose. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.</p

Arg72Pro Polymorphism of <i>TP53</i> Gene and the Risk of Skin Cancer: a Meta-Analysis

<div><p>Background</p><p><i>TP53</i> gene is one of the most important tumor suppressor genes. We undertook this meta-analysis to explore the association between <i>TP53</i> Arg72Pro polymorphism and the risk of skin cancer mainly in Caucasians.</p> <p>Methods</p><p>We searched PubMed for case-control studies published up to March 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.</p> <p>Results</p><p>A total of 5276 skin cancer cases and 5315 controls from 20 studies were included. Overall, no significant association between <i>TP53</i> Arg72Pro polymorphism and skin cancer was observed in all genetic contrast models (Pro/Pro versus Arg/Arg, Pro/Arg versus Arg/Arg, Pro/Pro + Pro/Arg versus Arg/Arg, Pro/Pro versus Arg/Arg + Pro/Arg, Pro allele versus Arg allele). Similar results were obtained in the stratified analysis by ethnicity and histological types of skin cancer, such as melanoma, squamous cell carcinoma and basal cell carcinoma. Power calculations indicated that some studies were underpowered. No publication bias was found by using the funnel plot and Egger's test.</p> <p>Conclusions</p><p>This meta-analysis indicated that <i>TP53</i> Arg72Pro polymorphism probably had little association with skin cancer susceptibility mainly in Caucasians. However, larger sample-size studies are required to verify the conclusion as low statistical powers.</p> </div

Additional file 1: Table S1. of Identification of recurrent focal copy number variations and their putative targeted driver genes in ovarian cancer

Sample information of 587 ovarian patients and normal tissue samples with Copy number variation and mRNA data on different platforms. Table S2. Distributions of focal gains/losses in primary tumors and adjacent normal tissue separately on each of the three microarray platforms. Table S3. List of genes encoded in the recurrent focal event regions. Table S4. Prognostic results of ovarian cancer progression using fCNV on three platforms. (XLSX 20403 kb

Additional file 1: of Sample size determination for mediation analysis of longitudinal data

Estimated numbers of required subjects with ICC = 0.3, 0.5, 0.7 and 0.8. (DOCX 27 kb

Additional file 2: of Identification of recurrent focal copy number variations and their putative targeted driver genes in ovarian cancer

The additional file contains all the details of additional/supplementary figures (Figure S1–S6) and tables (Table S1–S4). (DOCX 1574 kb

Effect of transcranial direct current stimulation on swallowing apraxia and cortical excitability in stroke patients

<p><b>Background:</b> Swallowing apraxia is characterized by impaired volitional swallowing but relatively preserved reflexive swallowing. Few studies are available on the effectiveness of behavioral therapy and management of the condition.</p> <p><b>Objective:</b> This study aimed to investigate the effect of transcranial direct current stimulation (tDCS) on swallowing apraxia and cortical activation in stroke patients.</p> <p><b>Methods:</b> The study included three inpatients (age 48–70 years; 1 male, 2 females; duration of stroke, 35–55 d) with post-stroke swallowing apraxia and six age-matched healthy subjects (age 45–65 years; 3 males, 3 females). Treatments were divided into two phases: Phase A and Phase B. During Phase A, the inpatients received three weeks of sham tDCS and conventional treatments. During Phase B, these patients received three weeks of anodal tDCS over the bilateral primary sensorimotor cortex (S₁M₁) of swallowing and conventional treatments. Swallowing apraxia assessments were measured in three inpatients before Phase A, before Phase B, and after Phase B. The electroencephalography (EEG) nonlinear index of approximate entropy (ApEn) was calculated for three patients and six healthy subjects.</p> <p><b>Results:</b> After tDCS, scores of swallowing apraxia assessments increased, and ApEn indices increased in both stimulated and non-stimulated areas.</p> <p><b>Conclusions:</b> Anodal tDCS might provide a useful means for recovering swallowing apraxia, and the recovery could be related to increased excitability of the swallowing cortex. Further investigations should explore the relationship between lesion size and/or lesion site and the prognosis of swallowing apraxia.</p> <p><b>Clinical trial registry:</b><a href="http://www.chictr.org" target="_blank">http://www.chictr.org</a> Registration Number: ChiCTR-TRC-14004955</p

Forest plot of Pro/Pro+ Pro/Arg versus Arg/Arg for all studies.

<p>Forest plot of Pro/Pro+ Pro/Arg versus Arg/Arg for all studies.</p