Existing methods for estimating the mean outcome under a given sequential treatment rule often rely on intention‐to‐treat analyses, which estimate the effect of following a certain treatment rule ...regardless of compliance behavior of patients. There are two major concerns with intention‐to‐treat analyses: (1) the estimated effects are often biased toward the null effect; (2) the results are not generalizable and reproducible due to the potentially differential compliance behavior. These are particularly problematic in settings with a high level of non‐compliance, such as substance use disorder studies. Our work is motivated by the Adaptive Treatment for Alcohol and Cocaine Dependence study (ENGAGE), which is a multi‐stage trial that aimed to construct optimal treatment strategies to engage patients in therapy. Due to the relatively low level of compliance in this trial, intention‐to‐treat analyses essentially estimate the effect of being randomized to a certain treatment, instead of the actual effect of the treatment. We obviate this challenge by defining the target parameter as the mean outcome under a dynamic treatment regime conditional on a potential compliance stratum. We propose a flexible non‐parametric Bayesian approach based on principal stratification, which consists of a Gaussian copula model for the joint distribution of the potential compliances, and a Dirichlet process mixture model for the treatment sequence specific outcomes. We conduct extensive simulation studies which highlight the utility of our approach in the context of multi‐stage randomized trials. We show robustness of our estimator to non‐linear and non‐Gaussian settings as well.
Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic ...alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.
Although populations referred for coronary angiography are increasingly diverse, there is limited information on coronary artery disease (CAD) prevalence and in-hospital mortality other than for ...predominately white male patients.
We examined gender and ethnic differences in CAD prevalence and in-hospital mortality in a prospective cohort of patients referred for angiographic evaluation of stable angina (n=375,886) or acute coronary syndromes (ACS; unstable angina or myocardial infarction, n=450,329) at 388 US hospitals participating in the American College of Cardiology-National Cardiovascular Data Registry, an angiographic registry. Univariable and multivariable (with covariates that included risk factors, symptoms, and comorbidities) logistic regression models were used to estimate significant CAD, defined as > or = 70% stenosis, and in-hospital mortality. Within stable angina and ACS cohorts, 7% of patients were black, 2% were Hispanic, 0.3% were Native American, 1% were Asian, and 90% were white, respectively. In stable angina, the risk-adjusted OR for significant CAD was 0.34 for women compared with men (P<0.0001), with black women having the lowest risk-adjusted odds (P<0.0001) compared with other females. Among ACS patients, the risk-adjusted OR of significant CAD was 0.47 for women compared with men (P<0.0001); similarly, black women had the lowest risk-adjusted odds (P<0.0001) compared with other females. Higher in-hospital mortality was reported for white women presenting with stable angina (P<0.00001). White women had a 1.34-fold (95% CI 1.21 to 1.48) higher risk-adjusted odds ratio for mortality than white men with stable angina (P<0.0001), with higher rates noted for white women who were older or had significant CAD (both P<0.0001). Lower utilization of elective coronary revascularization, aspirin, and glycoprotein IIb/IIIa inhibitors (all P<0.0001) may have contributed to higher in-hospital mortality for white women. In ACS, higher in-hospital mortality was reported for Hispanic (P=0.015) and white (P<0.0001) women; however, neither white (P=0.51) or Hispanic (P=0.13) women had higher in-hospital risk-adjusted mortality.
The likelihood for significant CAD at coronary angiography and for in-hospital mortality varied significantly by ethnicity and gender. Future clinical practice guidelines should be tailored to gender subsets of the population, in particular for black women, to improve the efficient use of angiographic laboratories and to target at-risk populations of women and men.
The aim of this clinical investigation was to obtain preliminary treatment outcome data concerning the Mentor Alpha-1, the first 3-piece inflatable penile prosthesis with pre-connected tubing between ...the pump and the penile cylinders. The study was designed to be the first multi-institutional treatment outcome report for any clinically available penile prosthesis with data analysis to be independent of the participating surgeons. A total of 12 board-certified urologists of mixed surgical training backgrounds and practices implanted the Alpha-1 device in 112 consecutive patients. With a mean of 27 +/- 5 months of followup the surgical complication rate included a 4% mechanical malfunction, 2% infection rate and 9% reoperation rate. Patient experience with the implanted device was computed from information on 96 of the 112 patients who returned a questionnaire. Of the patients 82% stated that the device fulfilled expectations as a treatment for impotence and 83% had improved sexual intercourse by 8 weeks after implantation. Patient satisfaction was computed on a scale of 12 equally weighted interrelated variables. Of the patients 77% recorded 9 or more cumulative satisfaction points. Patient and physician questionnaire data were analyzed for their relation to the cumulative prosthesis satisfaction score. A significant difference in cumulative scores was found for physician reported long-term postoperative problems (mean satisfaction score 8.1 for patients with problems versus 10.2 for patients without problems, p = 0.018). The Alpha-1, with its feature of pre-connected tubing, is a reliable 3-piece inflatable penile prosthesis associated with a high level of patient satisfaction.
Sequential, multiple assignment, randomized trials (SMARTs) compare sequences of treatment decision rules called dynamic treatment regimes (DTRs). In particular, the Adaptive Treatment for Alcohol ...and Cocaine Dependence (ENGAGE) SMART aimed to determine the best DTRs for patients with a substance use disorder. While many authors have focused on a single pairwise comparison, addressing the main goal involves comparisons of >2 DTRs. For complex comparisons, there is a paucity of methods for binary outcomes. We fill this gap by extending the multiple comparisons with the best (MCB) methodology to the Bayesian binary outcome setting. The set of best is constructed based on simultaneous credible intervals. A substantial challenge for power analysis is the correlation between outcome estimators for distinct DTRs embedded in SMARTs due to overlapping subjects. We address this using Robins' G‐computation formula to take a weighted average of parameter draws obtained via simulation from the parameter posteriors. We use non‐informative priors and work with the exact distribution of parameters avoiding unnecessary normality assumptions and specification of the correlation matrix of DTR outcome summary statistics. We conduct simulation studies for both the construction of a set of optimal DTRs using the Bayesian MCB procedure and the sample size calculation for two common SMART designs. We illustrate our method on the ENGAGE SMART. The R package SMARTbayesR for power calculations is freely available on the Comprehensive R Archive Network (CRAN) repository. An RShiny app is available at
https://wilart.shinyapps.io/shinysmartbayesr/.
Long-term cyclic treatment with 17beta-estradiol reverses age-related impairment in ovariectomized rhesus monkeys on a test of cognitive function mediated by the prefrontal cortex (PFC). Here, we ...examined potential neurobiological substrates of this effect using intracellular loading and morphometric analyses to test the possibility that the cognitive benefits of hormone treatment are associated with structural plasticity in layer III pyramidal cells in PFC area 46. 17beta-Estradiol did not affect several parameters such as total dendritic length and branching. In contrast, 17beta-estradiol administration increased apical and basal dendritic spine density, and induced a shift toward smaller spines, a response linked to increased spine motility, NMDA receptor-mediated activity, and learning. These results document that, although the aged primate PFC is vulnerable in the absence of factors such as circulating estrogens, it remains responsive to long-term cyclic 17beta-estradiol treatment, and that increased dendritic spine density and altered spine morphology may contribute to the cognitive benefits of such treatment.
Abstract
Background
Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the ...inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts.
Methods
We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided.
Results
A novel risk locus in the USP7 gene (rs74010351, odds ratio OR = 1.44, 95% confidence interval CI = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias.
Conclusions
These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).
Elucidation of the transcriptome and proteome of the normal retina will be difficult since it is comprised of at least 55 different cell types. However the characteristic layered cellular anatomy of ...the retina makes it amenable to planar sectioning, enabling the generation of enriched retinal cell populations. The aim of this study was to validate a reproducible method for preparing enriched retinal layers from porcine retina.
The thicknesses of the retinal photoreceptor, inner nuclear and ganglion cell, and fiber layers were determined by routine histology of cross sections of fresh whole retina mounted on polyvinylidene difluoride (PVDF) membrane. Dissected retina (5 mm2) was placed on PVDF membrane and a series of planar cryosections corresponding to the photoreceptor and inner nuclear layer were removed leaving the ganglion cell and fiber layer which was subsequently detached from the membrane. The retinal specimens were stored at -80 degrees C. Representative planar tissue sections were sonicated in ice-chilled 40 mM ammonium bicarbonate pH 7.9 and aliquots removed for RNA extraction. Quantitative RT-PCR was used to analyze the mRNA expression of genes indicative of specific retinal layers. Ammonium bicarbonate protein extracts were centrifuged, lyophilized and prepared for direct liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using a Waters Q-Tof Ultima.
Histological analysis established the parameters for planar cryosectioning: photoreceptor layer (69+/-1.8 microm), outer plexiform (11+/-0.6 microm), inner nuclear layer (28+/-0.5 microm), inner plexiform, ganglion cell and fiber layer (100+/-5.3 microm). Gene expression profiling provided an independent method for validating the respective retinal preparations. For example, glial fibrillary acidic protein (GFAP) was expressed up to 21 fold higher in the inner retinal "ganglion cell enriched" fraction than in the outer retinal "photoreceptor enriched" fraction. The pattern was reversed for blue cone opsin, which was expressed up to 24 fold higher in the "photoreceptor enriched" fraction. Endogenous protein fragments indicative of each layer were identified by mass spectrometry and de novo sequence data obtained.
Combined histological and mRNA expression profiling has confirmed the development of a reproducible method for generating validated porcine retinal layers enriched for specific cell types. Direct proteome analysis detected endogenous peptide fragments of characteristic retinal proteins. Further analysis of these enriched retinal cell preparations will facilitate a more selective investigation of the retinal transcriptome and proteome than studies of the intact retina.
Weather and climate variations on subseasonal to decadal time scales can have enormous social, economic, and environmental impacts, making skillful predictions on these time scales a valuable tool ...for decision-makers. As such, there is a growing interest in the scientific, operational, and applications communities in developing forecasts to improve our foreknowledge of extreme events. On subseasonal to seasonal (S2S) time scales, these include high-impact meteorological events such as tropical cyclones, extratropical storms, floods, droughts, and heat and cold waves. On seasonal to decadal (S2D) time scales, while the focus broadly remains similar (e.g., on precipitation, surface and upper-ocean temperatures, and their effects on the probabilities of high-impact meteorological events), understanding the roles of internal variability and externally forced variability such as anthropogenic warming in forecasts also becomes important. The S2S and S2D communities share common scientific and technical challenges. These include forecast initialization and ensemble generation; initialization shock and drift; understanding the onset of model systematic errors; bias correction, calibration, and forecast quality assessment; model resolution; atmosphere–ocean coupling; sources and expectations for predictability; and linking research, operational forecasting, and end-user needs. In September 2018 a coordinated pair of international conferences, framed by the above challenges, was organized jointly by the World Climate Research Programme (WCRP) and the World Weather Research Programme (WWRP). These conferences surveyed the state of S2S and S2D prediction, ongoing research, and future needs, providing an ideal basis for synthesizing current and emerging developments in these areas that promise to enhance future operational services. This article provides such a synthesis.
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