Sequential tests and estimates after overrunning based on pp-value combination

Often in sequential trials additional data become available after a stopping boundary has been reached. A method of incorporating such information from overrunning is developed, based on the ``adding weighted Zs'' method of combining $p$-values. This yields a combined $p$-value for the primary test and a median-unbiased estimate and confidence bounds for the parameter under test. When the amount of overrunning information is proportional to the amount available upon terminating the sequential test, exact inference methods are provided; otherwise, approximate methods are given and evaluated. The context is that of observing a Brownian motion with drift, with either linear stopping boundaries in continuous time or discrete-time group-sequential boundaries. The method is compared with other available methods and is exemplified with data from two sequential clinical trials.Comment: Published in at http://dx.doi.org/10.1214/074921708000000039 the IMS Collections (http://www.imstat.org/publications/imscollections.htm) by the Institute of Mathematical Statistics (http://www.imstat.org

Evidence for Positive Selection in the C-terminal Domain of the Cholesterol Metabolism Gene PCSK9 Based on Phylogenetic Analysis in 14 Primate Species

Cholesterol homeostasis is maintained through finely tuned mechanisms regulating intestinal absorption, hepatic biosynthesis and secretion as well as plasma clearance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted enzyme of the serine protease family that reduces cellular uptake of plasma low-density lipoprotein (LDL) cholesterol by promoting LDL receptor (LDL-R) degradation. Species-specific positive selection has been noted in the LDLR promoter, leading to differential expression of LDLR among primates. Whether PCSK9 experienced significant selective pressure to maintain a functional relationship with its target protein, LDL-R, is unknown.We compiled the sequences of the coding regions of PCSK9 from 14 primate species in the clade of Hominoids, Old World monkeys and New World monkeys. To detect selective pressure at the protein level, the ratios of nonsynonymous/synonymous substitution rate (d(N)/d(S)) under different evolutionary models were calculated across the phylogeny of PCSK9. Maximum likelihood analyses of d(N)/d(S) ratios for the aligned coding region sequences among 14 primate species indicated that PCSK9 was subject to a strong functional constraint (i.e., purifying selection). However, positive selection was noted in the functional carboxyl-terminal (C-terminal) domain in many branches across the phylogeny, especially in the lineage leading to the orangutan. Furthermore, at least five positively selected amino acids were detected in this lineage using the branch-site model A. In a sliding-window analysis, several d(N)/d(S) peaks in the C-terminal domain in both the human and the orangutan branches were noted.These results suggest that among primates, differential selective pressure has shaped evolutionary patterns in the functional domains of PCSK9, an important regulator of cholesterol homeostasis

htSNPer1.0: software for haplotype block partition and htSNPs selection

BACKGROUND: There is recently great interest in haplotype block structure and haplotype tagging SNPs (htSNPs) in the human genome for its implication on htSNPs-based association mapping strategy for complex disease. Different definitions have been used to characterize the haplotype block structure in the human genome, and several different performance criteria and algorithms have been suggested on htSNPs selection. RESULTS: A heuristic algorithm, generalized branch-and-bound algorithm, is applied to the searching of minimal set of haplotype tagging SNPs (htSNPs) according to different htSNPs performance criteria. We develop a software htSNPer1.0 to implement the algorithm, and integrate three htSNPs performance criteria and four haplotype block definitions for haplotype block partitioning. It is a software with powerful Graphical User Interface (GUI), which can be used to characterize the haplotype block structure and select htSNPs in the candidate gene or interested genomic regions. It can find the global optimization with only a fraction of the computing time consumed by exhaustive searching algorithm. CONCLUSION: htSNPer1.0 allows molecular geneticists to perform haplotype block analysis and htSNPs selection using different definitions and performance criteria. The software is a powerful tool for those focusing on association mapping based on strategy of haplotype block and htSNPs

A survey of electromagnetic influence on uavs from an ehv power converter stations and possible countermeasures

National Natural Science Foundation of China (Grant Nos. 11872148, U1908217, 61801034).It is inevitable that high-intensity, wide-spectrum electromagnetic emissions are generated by the power electronic equipment of the Extra High Voltage (EHV) power converter station. The surveillance flight of Unmanned Aerial Vehicles (UAVs) is thus, situated in a complex electromagnetic environment. The ubiquitous electromagnetic interference demands higher electromagnetic protection requirements from the UAV construction and operation. This article is related to the UAVs patrol inspections of the power line in the vicinity of the EHV converter station. The article analyzes the electromagnetic interference characteristics of the converter station equipment in the surrounding space and the impact of the electromagnetic emission on the communication circuits of the UAV. The anti-electromagnetic interference countermeasures strive to eliminate or reduce the threats of electromagnetic emissions on the UAV’s hardware and its communication network.publishersversionpublishe

A Genome-Wide Association Study of Red Blood Cell Traits Using the Electronic Medical Record

The Electronic Medical Record (EMR) is a potential source for high throughput phenotyping to conduct genome-wide association studies (GWAS), including those of medically relevant quantitative traits. We describe use of the Mayo Clinic EMR to conduct a GWAS of red blood cell (RBC) traits in a cohort of patients with peripheral arterial disease (PAD) and controls without PAD.Results for hemoglobin level, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were extracted from the EMR from January 1994 to September 2009. Out of 35,159 RBC trait values in 3,411 patients, we excluded 12,864 values in 1,165 patients that had been measured during hospitalization or in the setting of hematological disease, malignancy, or use of drugs that affect RBC traits, leaving a final genotyped sample of 3,012, 80% of whom had ≥2 measurements. The median of each RBC trait was used in the genetic analyses, which were conducted using an additive model that adjusted for age, sex, and PAD status. We identified four genomic loci that were associated (P<5 × 10(-8)) with one or more of the RBC traits (HBLS1/MYB on 6q23.3, TMPRSS6 on 22q12.3, HFE on 6p22.1, and SLC17A1 on 6p22.2). Three of these loci (HBLS1/MYB, TMPRSS6, and HFE) had been identified in recent GWAS and the allele frequencies, effect sizes, and the directions of effects of the replicated SNPs were similar to the prior studies.Our results demonstrate feasibility of using the EMR to conduct high throughput genomic studies of medically relevant quantitative traits

Covert Communications in STAR-RIS Assisted NOMA IoT Networks over Nakagami-m Fading Channels

The combination of simultaneously transmitting and reflecting-reconfigurable intelligent surface (STAR-RIS) and non-orthogonal multiple (NOMA) brings the necessary full-space degrees of freedom and spatial multiplexing gains for the Internet of Things (IoT) networks. The inherent network heterogeneity and sharing of wireless channels may however increase the exposure of the information interactions to the third party. To address this issue, we propose a covert communication scheme in STAR-RIS assisted NOMA networks over Nakagami-m fading channels, where both downlink and uplink IoT scenarios are considered. Under the NOMA protocol with imperfect successive interference cancellation (SIC), an IoT access point interacts with two IoT users aided by a STAR-RIS without being detected by two wardens. In this scenario, the two IoT users are located on both sides of the STAR-RIS which adopts coherent phase shifting and operates according to the mode switching protocol. To evaluate the wardens&#x2019; detection performance, the Kullback-Leibler (KL) divergence is used. Furthermore, the cascaded channel gains of IoT users and wardens are respectively characterized as Gamma and complex Gaussian random variables. The closed-form expressions of the expectations of KL divergence and the interruption probabilities for downlink and uplink are derived. To further improve the performance, we formulate the effective covert rate maximization as the joint optimization problems of the transmit power and power allocation coefficient for downlink and uplink, subject to the constraints for covertness, reliability and power budget, which are respectively resolved analytically. Extensive simulation results indicate that the proposed scheme improves covertness compared with the benchmarks

A Clinical Prognostic Index for Patients Treated with Erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21

IntroductionBR.21 demonstrated significant survival benefit for non-small cell lung cancer patients receiving erlotinib compared with placebo. We undertook to characterize, by exploratory subset analysis, patients less likely to benefit from erlotinib.MethodsUsing stratification and potential prognostic factors, Cox regression with stepwise selection with minimum Akaike Information Criteria was used to separate erlotinib patients into risk categories based on 10th, 50th, and 90th percentiles of prognostic index scores. The hypothesis was that characteristics of treated patients in the highest risk group would be predictive of lack of benefit from erlotinib when comparing erlotinib to placebo patients in the same risk group.ResultsTen factors (smoking history, performance status, weight loss, anemia, lactic dehydrogenase, response to prior chemotherapy, time from diagnosis, number of prior regimens, epidermal growth factor receptor copy, and ethnicity) were predictive of overall survival for erlotinib-treated patients and were used in the final model. Four risk groups were derived from the index score of the Prognostic Model: Low Risk (HR = 0.34, p < 0.001), Intermediate Low and Intermediate High Risk (HR 0.76, p = 0.05; HR 0.92; p = 0.51) and High Risk (HR 1.07; p = 0.78). Median survivals for erlotinib (placebo) patients in each group were 20.6 (8.9), 10.4 (7.6), 4.0 (4.1), 1.9 (2.3) months. The trend test showed that higher risk was associated with shorter survival (p < 0.001) and less treatment effect (p = 0.03).ConclusionsBy establishing a prognostic model, we identified a small group of patients who did not seem to benefit from erlotinib in this study. This model requires prospective validation to confirm that it is both prognostic and predictive of outcome