Functional-mixed effects models for candidate genetic mapping in imaging genetic studies.

The aim of this paper is to develop a functional-mixed effects modeling (FMEM) framework for the joint analysis of high-dimensional imaging data in a large number of locations (called voxels) of a three-dimensional volume with a set of genetic markers and clinical covariates. Our FMEM is extremely useful for efficiently carrying out the candidate gene approaches in imaging genetic studies. FMEM consists of two novel components including a mixed effects model for modeling nonlinear genetic effects on imaging phenotypes by introducing the genetic random effects at each voxel and a jumping surface model for modeling the variance components of the genetic random effects and fixed effects as piecewise smooth functions of the voxels. Moreover, FMEM naturally accommodates the correlation structure of the genetic markers at each voxel, while the jumping surface model explicitly incorporates the intrinsically spatial smoothness of the imaging data. We propose a novel two-stage adaptive smoothing procedure to spatially estimate the piecewise smooth functions, particularly the irregular functional genetic variance components, while preserving their edges among different piecewise-smooth regions. We develop weighted likelihood ratio tests and derive their exact approximations to test the effect of the genetic markers across voxels. Simulation studies show that FMEM significantly outperforms voxel-wise approaches in terms of higher sensitivity and specificity to identify regions of interest for carrying out candidate genetic mapping in imaging genetic studies. Finally, FMEM is used to identify brain regions affected by three candidate genes including CR1, CD2AP, and PICALM, thereby hoping to shed light on the pathological interactions between these candidate genes and brain structure and function.

Reinventing clinical trials: a review of innovative biomarker trial designs in cancer therapies.

INTRODUCTION: Recently, new clinical trial designs involving biomarkers have been studied and proposed in cancer clinical research, in the hope of incorporating the rapid growing basic research into clinical practices. SOURCES OF DATA: Journal articles related to various biomarkers and their role in cancer clinical trial, articles and books about statistical issues in trial design, and regulatory website, documents, and guidance for submission of targeted cancer therapies. AREAS OF AGREEMENT: The drug development process involves four phases. The confirmatory Phase III is essential in regulatory approval of a special treatment. AREAS OF CONTROVERSY: Regulatory agency has restrictions on confirmatory trials 'using adaptive designs'. No rule of thumb to pick the most appropriate design for biomarker-related trials. GROWING POINTS: Statistical issues to solve in new designs. Regulatory acceptance of the 'newly proposed trial designs'. AREAS TIMELY FOR DEVELOPING RESEARCH: Biomarker-related trial designs that can resolve the statistical issues and satisfy the regulatory requirement.

Cantharidin for the treatment of molluscum contagiosum: a prospective, double-blinded, placebo-controlled trial.

Our aim was to study the effects and safety of cantharidin in the treatment of molluscum contagiosum (MC), we conducted a prospective, double-blinded, placebo-controlled, randomized clinical trial to evaluate the safety and efficacy of topical cantharidin for treatment of pediatric MC in an academic ambulatory care center. Twenty-nine children aged 5-10 with a diagnosis of MC were enrolled to receive treatment with cantharidin or placebo. The main outcome measure was complete clearance of all molluscum lesions. In contrast to previous retrospective observational studies, the performance of cantharidin treatment over 2 months was not substantially better than the performance of placebo. The scope of follow-up was limited to five visits over 2 months of treatment. A longer follow-up period might have captured a greater effect of cantharidin. Over a 2 month period, the magnitude of the cantharidin treatment effects in the target population are, at best, not large. This study provided objective unbiased estimates of the magnitude of cantharidin treatment effects and provided important prospective safety data. Our subjects experienced minimal side effects when treated with cantharidin.

Projection regression models for multivariate imaging phenotype.

This paper presents a projection regression model (PRM) to assess the relationship between a multivariate phenotype and a set of covariates, such as a genetic marker, age, and gender. In the existing literature, a standard statistical approach to this problem is to fit a multivariate linear model to the multivariate phenotype and then use Hotelling's T(2) to test hypotheses of interest. An alternative approach is to fit a simple linear model and test hypotheses for each individual phenotype and then correct for multiplicity. However, even when the dimension of the multivariate phenotype is relatively small, say 5, such standard approaches can suffer from the issue of low statistical power in detecting the association between the multivariate phenotype and the covariates. The PRM generalizes a statistical method based on the principal component of heritability for association analysis in genetic studies of complex multivariate phenotypes. The key components of the PRM include an estimation procedure for extracting several principal directions of multivariate phenotypes relating to covariates and a test procedure based on wild-bootstrap method for testing the association between the weighted multivariate phenotype and explanatory variables. Simulation studies and an imaging genetic dataset are used to examine the finite sample performance of the PRM.

Sex differences in grey matter atrophy patterns among AD and aMCI patients: results from ADNI.

We used longitudinal magnetic resonance imaging (MRI) data to determine whether there are any gender differences in grey matter atrophy patterns over time in 197 individuals with probable Alzheimer's disease (AD) and 266 with amnestic mild cognitive impairment (aMCI), compared with 224 healthy controls participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). While previous research has differentiated probable AD and aMCI groups from controls in brain atrophy, it is unclear whether and how sex plays a role in patterns of change over time. Using regional volumetric maps, we fit longitudinal models to the grey matter data collected at repeated occasions, seeking differences in patterns of volume change over time by sex and diagnostic group in a voxel-wise analysis. Additionally, using a region-of-interest approach, we fit longitudinal models to the global volumetric data of predetermined brain regions to determine whether this more conventional approach is sufficient for determining sex and group differences in atrophy. Our longitudinal analyses revealed that, of the various grey matter regions investigated, males and females in the AD group and the aMCI group showed different patterns of decline over time compared to controls in the bilateral precuneus, bilateral caudate nucleus, right entorhinal gyrus, bilateral thalamus, bilateral middle temporal gyrus, left insula, and right amygdala. As one of the first investigation to model more than two time points of structural MRI data over time, our findings add insight into how AD and aMCI males and females differ from controls and from each other over time.

Assessing readability and comprehension of informed consent materials for medical device research: A survey of informed consents from FDA's Center for Devices and Radiological Health.

Legally effective informed consent has been a long-standing requirement for FDA-regulated clinical studies. However, informed consent forms (ICFs) are often thought to be too long, too complex, and too difficult for participants to understand. In this article, investigators from the FDAs Center for Devices and Radiological Health (CDRH) surveyed 399 ICFs from approved investigational device exemption (IDE) applications for fiscal years 2015 and 2016 to evaluate the readability of ICFs. The investigators collected data from the ICFs, using variables related to structure, readability, and comprehension. The investigators found that the mean grade-reading levels of the ICFs ranged from 10th grade to college level (Table 2), higher than the recommended 6th to 8th grade level, when measured by major readability evaluation tools (the SMOG readability grade level formula, the Flesch-Kincaid Index Grade Level Readability Formula, the Flesch Reading Ease test, and the Dale-Chall readability formula). Overall, the ICFs and informed consent (IC) processes, as described in the IDE application, lacked components that enhanced participants' comprehension, such as short sentences (e.g., no more than 8 to 10 to words) and the use of pictures, tables, and diagrams. CDRH investigators believe that information about ICFs' readability, comprehension, and structure will help support current and future efforts to improve the IC process. The intent of the article is to demonstrate that improvements are needed in the IC process and to encourage clinical trial stakeholders to consider implementing those approaches that optimize patient comprehension in the development of their IC processes.

Application of Benchmark Concentration (BMC) Analysis on Zebrafish Data: A New Perspective for Quantifying Toxicity in Alternative Animal Models.

Over the past decade, the zebrafish is increasingly being used as a model to screen for chemical-mediated toxicities including developmental toxicity (DT) and neurotoxicity (NT). One of the major challenges is lack of harmonization in data analysis approaches, thereby posing difficulty in comparing findings across laboratories. To address this, we sought to establish a unified data analysis strategy for both DT and NT data, by adopting the benchmark concentration (BMC) analysis. There are two critical aspects in the BMC analysis: having a toxicity endpoint amenable for BMC and selecting a proper benchmark response (BMR) for the endpoint. For the former, in addition to the typical endpoints in NT assay (eg, hyper/hypo- response quantified by distance moved), we also used endpoints that assess the differences in movement patterns between chemical-treated embryos and control embryos. For the latter, we standardized the selection of BMR, which is analogous to minimum activity threshold, based on intrinsic response variations in the endpoint. When comparing our BMC results with a traditionally used LOAEL method (lowest-observed-adverse-effect level), we found high active compound concordance (100% for DT vs 74% for NT); generally, the BMC was more sensitive than LOAEL (no. of BMC more sensitive/no. of concordant active compounds, 43/50 for DT vs 16/26 for NT). Using the BMC with standardized toxicity endpoints and an appropriate BMR, we may now have a unified data-analysis approach to comparing results across different zebrafish datasets, for a better understanding of strengths and challenges when using the zebrafish as a screening tool.

Sex-Specific Outcomes After Transcatheter Aortic Valve Replacement: FDA Patient-Level Meta-Analysis of Premarket Clinical Trials.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a less invasive alternative approach to surgery. Individual randomized clinical trials evaluating the safety and efficacy of TAVR were mostly underpowered for conducting separate analyses for women and men. We pooled data from premarket TAVR clinical trials comparing short (30 days)- and long-term (∼2 years) outcomes by sex. METHODS: Patient-level data from the TAVR arms of six clinical trials were pooled (2515 patients). Random-effects models for time-to-event outcomes (odds ratios [ORs] for 30-day outcomes and hazard ratios [HRs] for complete follow-up for mortality, ischemic stroke, kidney injury, major bleeding, myocardial infarction, and device migration) and dichotomous outcomes (ORs for reintervention, rehospitalization, and pacemaker implantation) were then fit to directly compare outcomes between women and men. RESULTS: Overall, the pattern of individual comorbidities was more severe in men. There was no difference in mortality risk at 30 days (female-to-male OR = 1.00 [0.69-1.46]); however, at follow-up completion (∼2 years post-TAVR), women had a 24% lower mortality risk than men (HR = 0.76 [95% CI: 0.65-0.89]). Women also had a 30% lower risk of kidney injury at 30 days (OR = 0.70 [0.49-0.98]), which increased to 33% over the complete follow-up period (HR = 0.67 [0.51-0.87]). Major bleeding was more common in women compared to men at both 30 days (OR = 1.44 [1.19-1.76]) and long-term follow-up (HR = 1.22 [1.04-1.43]). For dichotomous outcomes, women had a 68% lower risk for reinterventions (OR = 0.32 [0.18-0.58]). We did not observe any difference in the risk of ischemic stroke, myocardial infarction, device migration, rehospitalizations, or pacemaker implantations between sexes. CONCLUSIONS: This patient-level data meta-analysis of six premarket clinical trials found that women who received TAVR had fewer comorbidities at baseline. Acute outcomes (30 day) with respect to mortality were similar. Women were observed to have a lower risk of kidney injury, but higher risk of major bleeding compared to men receiving TAVR at 30 days. At complete follow-up, statistically significant advantages for women emerged in improved survival and lower reintervention risk. No differences in ischemic stroke, pacemaker implantation, or rehospitalization were observed. That women are healthier at baseline and develop fewer postprocedural complications than men may explain their higher survival.

Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development.

Liver damage and fibrosis are precursors of hepatocellular carcinoma (HCC). In HCC patients, sorafenib-a multikinase inhibitor drug-has been reported to exert anti-fibrotic activity. However, incomplete inhibition of RAF activity by sorafenib may also induce paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in malignant cells. The consequence of this effect in non-malignant disease (hepatic fibrosis) remains unknown. This study aimed to examine the effects of sorafenib on activated hepatic stellate cells (HSCs), and develop effective therapeutic approaches to treat liver fibrosis and prevent cancer development. Methods: We first examined the effects of sorafenib in combination with MEK inhibitors on fibrosis pathogenesis in vitro and in vivo. To improve the bioavailability and absorption by activated HSCs, we developed CXCR4-targeted nanoparticles (NPs) to co-deliver sorafenib and a MEK inhibitor to mice with liver damage. Results: We found that sorafenib induced MAPK activation in HSCs, and promoted their myofibroblast differentiation. Combining sorafenib with a MEK inhibitor suppressed both paradoxical MAPK activation and HSC activation in vitro, and alleviated liver fibrosis in a CCl4-induced murine model of liver damage. Furthermore, treatment with sorafenib/MEK inhibitor-loaded CXCR4-targeted NPs significantly suppressed hepatic fibrosis progression and further prevented fibrosis-associated HCC development and liver metastasis. Conclusions: Our results show that combined delivery of sorafenib and a MEK inhibitor via CXCR4-targeted NPs can prevent activation of ERK in activated HSCs and has anti-fibrotic effects in the CCl4-induced murine model. Targeting HSCs represents a promising strategy to prevent the development and progression of fibrosis-associated HCC.

Real-time cell toxicity profiling of Tox21 10K compounds reveals cytotoxicity dependent toxicity pathway linkage.

Cytotoxicity is a commonly used in vitro endpoint for evaluating chemical toxicity. In support of the U.S. Tox21 screening program, the cytotoxicity of ~10K chemicals was interrogated at 0, 8, 16, 24, 32, & 40 hours of exposure in a concentration dependent fashion in two cell lines (HEK293, HepG2) using two multiplexed, real-time assay technologies. One technology measures the metabolic activity of cells (i.e., cell viability, glo) while the other evaluates cell membrane integrity (i.e., cell death, flor). Using glo technology, more actives and greater temporal variations were seen in HEK293 cells, while results for the flor technology were more similar across the two cell types. Chemicals were grouped into classes based on their cytotoxicity kinetics profiles and these classes were evaluated for their associations with activity in the Tox21 nuclear receptor and stress response pathway assays. Some pathways, such as the activation of H2AX, were associated with the fast-responding cytotoxicity classes, while others, such as activation of TP53, were associated with the slow-responding cytotoxicity classes. By clustering pathways based on their degree of association to the different cytotoxicity kinetics labels, we identified clusters of pathways where active chemicals presented similar kinetics of cytotoxicity. Such linkages could be due to shared underlying biological processes between pathways, for example, activation of H2AX and heat shock factor. Others involving nuclear receptor activity are likely due to shared chemical structures rather than pathway level interactions. Based on the linkage between androgen receptor antagonism and Nrf2 activity, we surmise that a subclass of androgen receptor antagonists cause cytotoxicity via oxidative stress that is associated with Nrf2 activation. In summary, the real-time cytotoxicity screen provides informative chemical cytotoxicity kinetics data related to their cytotoxicity mechanisms, and with our analysis, it is possible to formulate mechanism-based hypotheses on the cytotoxic properties of the tested chemicals.

Correction: Real-time cell toxicity profiling of Tox21 10K compounds reveals cytotoxicity dependent toxicity pathway linkage.

[This corrects the article DOI: 10.1371/journal.pone.0177902.].