Abstract Motivation Testing for differences in within-group dispersion is a fundamental problem in multivariate data analysis, with direct implications for interpreting group structure and validating statistical assumptions of other analysis such as ANOVA. Existing methods typically construct test statistics either based on the distance of each observation from the group center or on the mean of pairwise dissimilarities among observations within a group. Both approaches can fail when the mean within-group distance is similar across groups but the distributions of the within-group distances differ. This issue is particularly relevant in high-dimensional microbiome data, where outliers and overdispersion can distort the performance of mean-dissimilarity-based tests. Results We introduce the non-parametric Distance-based Test for Homogeneity (DTH), which measures dispersion of a group by computing within-group dissimilarity. Difference in dispersion across groups is tested by comparing the distributions of the within-group dissimilarity across different groups. A combination of Kolmogorov-Smirnov and Wasserstein distances are used to construct the difference between the distributions. For more than two groups, pairwise group tests are combined using a permutation-based p-value. Through simulations, we show that our method has higher power than existing tests for homogeneity in certain situations and comparable power in others. For continuous covariates, we offer an heuristic extension of DTH that showed good performance in simulations. Availability and implementation The DTH package, along with the code for reproducing all simulations, analyses, and an accompanying vignette, is available at https://github.com/asmita112358/DTH.

MOTIVATION: T cell receptors (TCRs) constitute a major component of our adaptive immune system, governing the recognition and response to internal and external antigens. Studying the TCR diversity via sequencing technology is critical for a deeper understanding of immune dynamics. However, library sizes differ substantially across samples, hindering the accurate estimation/comparisons of alpha diversities. To address this, researchers frequently use an overall rarefying approach in which all samples are sub-sampled to an even depth. Despite its pervasive application, its efficacy has never been rigorously assessed. RESULTS: In this paper, we develop an innovative "multi-bin" rarefying approach that partitions samples into multiple bins according to their library sizes, conducts rarefying within each bin for alpha diversity calculations, and performs meta-analysis across bins. Extensive simulations using real-world data highlight the inadequacy of the overall rarefying approach in controlling the confounding effect of library size. Our method proves robust in addressing library size confounding, outperforming competing normalization strategies by achieving better-controlled type-I error rates and enhanced statistical power in association tests. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/mli171/MultibinAlpha. The datasets are freely available at https://doi.org/10.21417/B7001Z and https://doi.org/10.21417/AR2019NC.

Since its launch, ChatGPT has achieved remarkable success as a versatile conversational AI platform, drawing millions of users worldwide and garnering widespread recognition across academic, industrial, and general communities. This paper aims to point a portrait of early GPT users and understand how they evolved. Specific questions include their topics of interest and their potential careers; and how this changes over time. We conduct a detailed analysis of real-world ChatGPT datasets with multi-turn conversations between users and ChatGPT. Through a multi-pronged approach, we quantify conversation dynamics by examining the number of turns, then gauge sentiment to understand user sentiment variations, and finally employ Latent Dirichlet Allocation (LDA) to discern overarching topics within the conversation. By understanding shifts in user demographics and interests, we aim to shed light on the changing nature of human-AI interaction and anticipate future trends in user engagement with language models.

BACKGROUND: Microbial communities are known to be closely related to many diseases, such as obesity and HIV, and it is of interest to identify differentially abundant microbial species between two or more environments. Since the abundances or counts of microbial species usually have different scales and suffer from zero-inflation or over-dispersion, normalization is a critical step before conducting differential abundance analysis. Several normalization approaches have been proposed, but it is difficult to optimize the characterization of the true relationship between taxa and interesting outcomes. RESULTS: To avoid the challenge of picking an optimal normalization and accommodate the advantages of several normalization strategies, we propose an omnibus approach. Our approach is based on a Cauchy combination test, which is flexible and powerful by aggregating individual p values. We also consider a truncated test statistic to prevent substantial power loss. We experiment with a basic linear regression model as well as recently proposed powerful association tests for microbiome data and compare the performance of the omnibus approach with individual normalization approaches. Experimental results show that, regardless of simulation settings, the new approach exhibits power that is close to the best normalization strategy, while controling the type I error well. CONCLUSIONS: The proposed omnibus test releases researchers from choosing among various normalization methods and it is an aggregated method that provides the powerful result to the underlying optimal normalization, which requires tedious trial and error. While the power may not exceed the best normalization, it is always much better than using a poor choice of normalization.

Adding cuffless blood pressure (BP) measurement function to wearable devices is of great value in the fight against hypertension. The widely used arterial pulse transit time (PTT)-based method for BP monitoring relies primarily on vascular status-determined BP models and typically exhibits degraded performance over time and is sensitive to measurement procedures. Developing alternative methods with improved accuracy and adaptability to various application scenarios is highly desired for cuffless BP measurement. In this work, we proposed a pattern-fusion (PF) method that incorporates cardiovascular coupling effects in the vascular model by combining three calculation modules - cardiac parameter extraction module, cardiac parameter-to-BP mapping module, and BP regulation module. Specifically, the first module combines feedforward, feedback, and propagation modes to model different modulation functions of a cardiovascular system and is responsible for extracting BP-related features from electrocardiography (ECG) and photoplethysmography (PPG) signals; the cardiac parameter-to-BP mapping module is used to map cardiac parameters into mean blood pressure (MBP) by fusing different features; finally, the BP regulation module recovers accurate systolic BP (SBP) and diastolic BP (DBP) from given MBP. With the concerted use of these three modules, the pattern fusion method consistently demonstrates excellent BP prediction accuracy in a variety of measurement scenarios and durations, exhibiting SBP/DBP mean absolute error (MAE) of 3.65/4.56 mmHg for the short-term (<10 mins) continuous measurement dataset, SBP/DBP MAE of 6.84/3.81 mmHg for the medium-term (avg. > 20 hours) continuous measurement dataset, and SBP/DBP MAE of 6.24/3.65 mmHg for the long-term (>1 month) intermittent measurement dataset.

SUMMARY: Distance-based tests of microbiome beta diversity are an integral part of many microbiome analyses. MiRKAT enables distance-based association testing with a wide variety of outcome types, including continuous, binary, censored time-to-event, multivariate, correlated and high-dimensional outcomes. Omnibus tests allow simultaneous consideration of multiple distance and dissimilarity measures, providing higher power across a range of simulation scenarios. Two measures of effect size, a modified R-squared coefficient and a kernel RV coefficient, are incorporated to allow comparison of effect sizes across multiple kernels. AVAILABILITY AND IMPLEMENTATION: MiRKAT is available on CRAN as an R package. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The prevalence of hypertension has made blood pressure (BP) measurement one of the most wanted functions in wearable devices for convenient and frequent self-assessment of health conditions. The widely adopted principle for cuffless BP monitoring is based on arterial pulse transit time (PTT), which is measured with electrocardiography and photoplethysmography (PPG). To achieve cuffless BP monitoring with more compact wearable electronics, we have previously conceived a multi-wavelength PPG (MWPPG) strategy to perform BP estimation from arteriolar PTT, requiring only a single sensing node. However, challenges remain in decoding the compounded MWPPG signals consisting of both heterogeneous physiological information and motion artifact (MA). In this work, we proposed an improved MWPPG algorithm based on principal component analysis (PCA) which matches the statistical decomposition results with the arterial pulse and capillary pulse. The arteriolar PTT is calculated accordingly as the phase shift based on the entire waveforms, instead of local peak lag time, to enhance the feature robustness. Meanwhile, the PCA-derived MA component is employed to identify and exclude the MA-contaminated segments. To evaluate the new algorithm, we performed a comparative experiment (N = 22) with a cuffless MWPPG measurement device and used double-tube auscultatory BP measurement as a reference. The results demonstrate the accuracy improvement enabled by the PCA-based operations on MWPPG signals, yielding errors of 1.44 ± 6.89 mmHg for systolic blood pressure and -1.00 ± 6.71 mm Hg for diastolic blood pressure. In conclusion, the proposed PCA-based method can improve the performance of MWPPG in wearable medical devices for cuffless BP measurement.

Capillary blood pressure (CBP) is the primary driving force for fluid exchange across microvessels. Subclinical systemic venous congestion prior to overt peripheral edema can directly result in elevated peripheral CBP. Therefore, CBP measurements can enable timely edema control in a variety of clinical cases including venous insufficiency, heart failure and so on. However, currently CBP measurements can be only done invasively and with a complicated experimental setup. In this work, we proposed an opto-mechanical system to achieve non-invasive and automatic CBP measurements through modifying the widely implemented oscillometric technique in home-use arterial blood pressure monitors. The proposed CBP system is featured with a blue light photoplethysmography sensor embedded in finger/toe cuffs to probe skin capillary pulsations. The experimental results demonstrated the proposed CBP system can track local CBP changes induced by different levels of venous congestion. Leveraging the decision tree technique, we demonstrate the use of a multi-site CBP measurement at fingertips and toes to classify four categories of subjects (total N = 40) including patients with peripheral arterial disease, varicose veins and heart failure. Our work demonstrates the promising non-invasive CBP measurement as well as its great potential in realizing point-of-care systems for the management of cardiovascular diseases.

MOTIVATION: It is of substantial interest to discover novel genetic markers that influence drug response in order to develop personalized treatment strategies that maximize therapeutic efficacy and safety. To help enable such discoveries, we focus on testing the association between the cumulative effect of multiple single nucleotide polymorphisms (SNPs) in a particular genomic region and a drug response of interest. However, the currently existing methods are either computational inefficient or not able to control type I error and provide decent power for whole exome or genome analysis in Pharmacogenetics (PGx) studies with small sample sizes. RESULTS: In this article, we propose the Composite Kernel Association Test (CKAT), a flexible and robust kernel machine-based approach to jointly test the genetic main effect and SNP-treatment interaction effect for SNP-sets in Pharmacogenetics (PGx) assessments embedded within randomized clinical trials. An analytic procedure is developed to accurately calculate the P-value so that computationally extensive procedures (e.g. permutation or perturbation) can be avoided. We evaluate CKAT through extensive simulation studies and application to the gene-level association test of the reduction in Clostridium difficile infection recurrence in patients treated with bezlotoxumab. The results demonstrate that the proposed CKAT controls type I error well for PGx studies, is efficient for whole exome/genome association analysis and provides better power performance than existing methods across multiple scenarios. AVAILABILITY AND IMPLEMENTATION: The R package CKAT is publicly available on CRAN https://cran.r-project.org/web/packages/CKAT/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The most commonly used oscillometric upper-arm (UA) blood pressure (BP) monitors are not convenient enough for ambulatory BP monitoring, given the large size of the arm cuff and the compression of UA during the measurement. Finger-worn oscillometric BP devices featuring miniaturized finger cuff have been developed and researched as an alternative solution to the UA-based measurement, yet the reliability of the finger-based measurement is still questioned. To investigate the feasibility of oscillometric BP measurements at the finger position, we performed model-based analysis and experimental validation to explore the underlying issues associated with extending the cuff-based oscillometric approach from UA to other alternative sites. The simulation results revealed that a larger bone-to-tissue volume ratio produced a lower pressure transmission efficiency, which can account for the inter-site measurement discrepancies of mean blood pressure (MBP). We also experimentally compared the oscillometric MBP measurements at UA, middle forearm, wrist, finger proximal phalanx, and finger distal phalanx (FD) of 20 young adults, and each position was matched with a cuff of appropriate size and kept at the same height with the heart. The experimental results demonstrated that FD could be a superior alternative position for oscillometric BP measurement, as it requires the smallest cuff size while providing the most consistent MBP with the UA. Our analysis also suggested that further study is demanded to identify the appropriate oscillometric algorithm for reliable systolic blood pressure and diastolic blood pressure measurements at FD.

For many cerebrovascular diseases both blood pressure (BP) and hemodynamic changes are important clinical variables. In this paper, we describe the development of a novel approach to noninvasively and simultaneously monitor cerebral hemodynamics, BP, and other important parameters at high temporal resolution (250 Hz sampling rate). In this approach, cerebral hemodynamics are acquired using near infrared spectroscopy based sensors and algorithms, whereas continuous BP is acquired by superficial temporal artery tonometry with pulse transit time based drift correction. The sensors, monitoring system, and data analysis algorithms used in the prototype for this approach are reported in detail in this paper. Preliminary performance tests demonstrated that we were able to simultaneously and noninvasively record and reveal cerebral hemodynamics and BP during people's daily activity. As examples, we report dynamic cerebral hemodynamic and BP fluctuations during postural changes and micturition. These preliminary results demonstrate the feasibility of our approach, and its unique power in catching hemodynamics and BP fluctuations during transient symptoms (such as syncope) and revealing the dynamic features of related events.

MOTIVATION: Copy number variants (CNVs) have been implicated in a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability and schizophrenia. Recent advances in high-throughput genomic technologies have enabled rapid discovery of many genetic variants including CNVs. As a result, there is increasing interest in studying the role of CNVs in the etiology of many complex diseases. Despite the availability of an unprecedented wealth of CNV data, methods for testing association between CNVs and disease-related traits are still under-developed due to the low prevalence and complicated multi-scale features of CNVs. RESULTS: We propose a novel CNV kernel association test (CKAT) in this paper. To address the low prevalence, CNVs are first grouped into CNV regions (CNVR). Then, taking into account the multi-scale features of CNVs, we first design a single-CNV kernel which summarizes the similarity between two CNVs, and next aggregate the single-CNV kernel to a CNVR kernel which summarizes the similarity between two CNVRs. Finally, association between CNVR and disease-related traits is assessed by comparing the kernel-based similarity with the similarity in the trait using a score test for variance components in a random effect model. We illustrate the proposed CKAT using simulations and show that CKAT is more powerful than existing methods, while always being able to control the type I error. We also apply CKAT to a real dataset examining the association between CNV and autism spectrum disorders, which demonstrates the potential usefulness of the proposed method. AVAILABILITY AND IMPLEMENTATION: A R package to implement the proposed CKAT method is available at http://works.bepress.com/debashis_ghosh/ CONTACTS: [email protected] or [email protected] information: Supplementary data are available at Bioinformatics online.

The year 2016 marks the 200th birth anniversary of Carl Friedrich Wilhelm Ludwig (1816-1895). As one of the most remarkable scientists, Ludwig invented the kymograph, which for the first time enabled the recording of continuous blood pressure (BP), opening the door to the modern study of physiology. Almost a century later, intraarterial BP monitoring through an arterial line has been used clinically. Subsequently, arterial tonometry and volume clamp method were developed and applied in continuous BP measurement in a noninvasive way. In the last two decades, additional efforts have been made to transform the method of unobtrusive continuous BP monitoring without the use of a cuff. This review summarizes the key milestones in continuous BP measurement; that is, kymograph, intraarterial BP monitoring, arterial tonometry, volume clamp method, and cuffless BP technologies. Our emphasis is on recent studies of unobtrusive BP measurements as well as on challenges and future directions.

Recent advances in unobtrusive sensing technology, especially those in flexible, stretchable, and printable sensing, have given rise to various novel signal acquisition modalities, such as stretchable epidermal electrocardiography (ECG), organic photoplethysmography (PPG), and flexible tonoarteriography (TAG) which is the cuffless and continuous recording of arterial blood pressure (BP). With the fast development of wearable computing and wireless communication technologies, all these modalities can be integrated into a body sensor network (BSN) for remote physiological multi-parameter monitoring. In this paper, we propose a TAG-based BSN for unobtrusive BP measurement with possible automatic cuffless BP calibration, and our efforts focus on the effect of posture change on the various pulse transit time (PTT) calculated from different BSN nodes consisting of TAG, ECG, and PPG sensors. Specifically, correlations of different PTTs with reference continuous BP at different postures are examined. The results of this study demonstrate that the PTT from ECG and TAG sensors has higher correlation with the reference BP as compared to that from ECG and PPG sensors, which suggests that flexible TAG sensor may potentially be utilized not only for cuffless calibration, but also as an alternative node in the BSN for continuous, cuffless BP measurement with better accuracy.

Flexible and stretchable sensors have recently emerged as an active area of research for designing wearable, implantable and ingestible systems that allow pervasive and unobtrusive health monitoring in mobile health (m-Health) applications. Nevertheless, there lacks systematical study that compares the performances of these new types of sensors with their conventional counterparts. In this study, we reported the fabrication of serpentine-shape, flexible and stretchable electrodes that can be conformally attached to the skin via a printing-transfer process, and we introduced Area Density (AD) as a key parameter to guide the future design of these sensors. Sensors of AD 10, 20 and 40 percentages were designed and fabricated. The performances of these sensors for capturing one type of electrophysiological signals, i.e. electrocardiogram (ECG), were compared against ECG obtained by conventional gold and stainless steel metal clips. The results of this study found that flexible sensors designed with larger AD resulted in ECG of higher signal-to-noise ratio (SNR). In particular, ECG with SNR comparable to those measured by conventional metal clips (SNR>25dB) can be achieved when this new type of flexible sensors were designed with AD=40%. The results of this study shed light on the design of novel wearable and flexible electrodes, which can be used not only for on-body sensing but also in-body measurement inside the gastrointestinal tract.

In this correspondence, we point out some lethal errors in the proof of the theorems given in the aforementioned paper.