Identifying temporal pathways using biomarkers in the presence of latent non-Gaussian components.

Time-series data collected from a network of random variables are useful for identifying temporal pathways among the network nodes. Observed measurements may contain multiple sources of signals and noises, including Gaussian signals of interest and non-Gaussian noises, including artifacts, structured noise, and other unobserved factors (eg, genetic risk factors, disease susceptibility). Existing methods, including vector autoregression (VAR) and dynamic causal modeling do not account for unobserved non-Gaussian components. Furthermore, existing methods cannot effectively distinguish contemporaneous relationships from temporal relations. In this work, we propose a novel method to identify latent temporal pathways using time-series biomarker data collected from multiple subjects. The model adjusts for the non-Gaussian components and separates the temporal network from the contemporaneous network. Specifically, an independent component analysis (ICA) is used to extract the unobserved non-Gaussian components, and residuals are used to estimate the contemporaneous and temporal networks among the node variables based on method of moments. The algorithm is fast and can easily scale up. We derive the identifiability and the asymptotic properties of the temporal and contemporaneous networks. We demonstrate superior performance of our method by extensive simulations and an application to a study of attention-deficit/hyperactivity disorder (ADHD), where we analyze the temporal relationships between brain regional biomarkers. We find that temporal network edges were across different brain regions, while most contemporaneous network edges were bilateral between the same regions and belong to a subset of the functional connectivity network.

Functional support vector machine.

Linear and generalized linear scalar-on-function modeling have been commonly used to understand the relationship between a scalar response variable (e.g. continuous, binary outcomes) and functional predictors. Such techniques are sensitive to model misspecification when the relationship between the response variable and the functional predictors is complex. On the other hand, support vector machines (SVMs) are among the most robust prediction models but do not take account of the high correlations between repeated measurements and cannot be used for irregular data. In this work, we propose a novel method to integrate functional principal component analysis with SVM techniques for classification and regression to account for the continuous nature of functional data and the nonlinear relationship between the scalar response variable and the functional predictors. We demonstrate the performance of our method through extensive simulation experiments and two real data applications: the classification of alcoholics using electroencephalography signals and the prediction of glucobrassicin concentration using near-infrared reflectance spectroscopy. Our methods especially have more advantages when the measurement errors in functional predictors are relatively large.

[Influencing Factors of Bethesda â ¢ Results in Fine-Needle Aspiration Biopsy of Thyroid Nodules].

Objective To investigate the influencing factors of Bethesda Ⅲ results in fine-needle aspiration biopsy of thyroid nodules.Methods A total of 300 thyroid nodules with cytological diagnosis results were analyzed retrospectively,including 100 Bethesda Ⅲ nodules and 50 nodules of Bethesda Ⅱ,Ⅳ,Ⅴ,and Ⅵ categories,respectively.Univariate analysis and Logistic regression analysis were performed on the clinical data of patients and the ultrasound signs of thyroid nodules to clarify the factors influencing the diagnosis of Bethesda Ⅲ nodules.Results Univariate analysis showed that Bethesda Ⅲ nodules were mostly adjacent to the capsule(P<0.001),with no blood flow in the color Doppler assessment(P=0.011)and lack of blood supply(P=0.033)and maximum diameter ≤0.9 cm(P=0.038)as revealed by the contrast-enhanced ultrasound.Logistic regression showed that the position close to the capsule(OR=5.110,95%CI=2.153-12.130,P<0.001)and color Doppler without blood flow signal(OR=3.015,95%CI=1.094-8.311,P=0.033)were independent risk factors for the diagnosis of Bethesda Ⅲ nodules.Conclusions The puncture difficulty caused by the dangerous position of thyroid nodules close to the capsule and the aspiration difficulty caused by the absence of blood flow signal in color Doppler are the main factors influencing the diagnosis of Bethesda Ⅲ nodules.Therefore,corresponding avoidance measures should be taken during the aspiration process to reduce the diagnosis results of Bethesda Ⅲ nodules.

Evaluating effectiveness of public health intervention strategies for mitigating COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) pandemic is an unprecedented global public health challenge. In the United States (US), state governments have implemented various non-pharmaceutical interventions (NPIs), such as physical distance closure (lockdown), stay-at-home order, mandatory facial mask in public in response to the rapid spread of COVID-19. To evaluate the effectiveness of these NPIs, we propose a nested case-control design with propensity score weighting under the quasi-experiment framework to estimate the average intervention effect on disease transmission across states. We further develop a method to test for factors that moderate intervention effect to assist precision public health intervention. Our method takes account of the underlying dynamics of disease transmission and balance state-level pre-intervention characteristics. We prove that our estimator provides causal intervention effect under assumptions. We apply this method to analyze US COVID-19 incidence cases to estimate the effects of six interventions. We show that lockdown has the largest effect on reducing transmission and reopening bars significantly increase transmission. States with a higher percentage of non-White population are at greater risk of increased R t $$ {R}_t $$ associated with reopening bars.

Conditional Gaussian graphical model for estimating personalized disease symptom networks.

The co-occurrence of symptoms may result from the direct interactions between these symptoms and the symptoms can be treated as a system. In addition, subject-specific risk factors (eg, genetic variants, age) can also exert external influence on the system. In this work, we develop a covariate-dependent conditional Gaussian graphical model to obtain personalized symptom networks. The strengths of network connections are modeled as a function of covariates to capture the heterogeneity among individuals and subgroups of individuals. We assess the performance of our proposed method by simulation studies and an application to a large natural history study of Huntington's disease to investigate the networks of symptoms in multiple clinical domains (motor, cognitive, psychiatric) and identify important brain imaging biomarkers that are associated with the connections. We show that the symptoms in the same clinical domain interact more often with each other than cross domains and the psychiatric subnetwork is the densest network. We validate the findings using the subjects' symptom measurements at follow-up visits.

Multiple domain and multiple kernel outcome-weighted learning for estimating individualized treatment regimes.

Individualized treatment rules (ITRs) recommend treatments that are tailored specifically according to each patient's own characteristics. It can be challenging to estimate optimal ITRs when there are many features, especially when these features have arisen from multiple data domains (e.g., demographics, clinical measurements, neuroimaging modalities). Considering data from complementary domains and using multiple similarity measures to capture the potential complex relationship between features and treatment can potentially improve the accuracy of assigning treatments. Outcome weighted learning (OWL) methods that are based on support vector machines using a predetermined single kernel function have previously been developed to estimate optimal ITRs. In this paper, we propose an approach to estimate optimal ITRs by exploiting multiple kernel functions to describe the similarity of features between subjects both within and across data domains within the OWL framework, as opposed to preselecting a single kernel function to be used for all features for all domains. Our method takes into account the heterogeneity of each data domain and combines multiple data domains optimally. Our learning process estimates optimal ITRs and also identifies the data domains that are most important for determining ITRs. This approach can thus be used to prioritize the collection of data from multiple domains, potentially reducing cost without sacrificing accuracy. The comparative advantage of our method is demonstrated by simulation studies and by an application to a randomized clinical trial for major depressive disorder that collected features from multiple data domains. Supplemental materials for this article are available online.

INTEGRATIVE NETWORK LEARNING FOR MULTI-MODALITY BIOMARKER DATA.

The biomarker networks measured by different modalities of data (e.g., structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI)) may share the same true underlying biological model. In this work, we propose a node-wise biomarker graphical model to leverage the shared mechanism between multi-modality data to provide a more reliable estimation of the target modality network and account for the heterogeneity in networks due to differences between subjects and networks of external modality. Latent variables are introduced to represent the shared unobserved biological network and the information from the external modality is incorporated to model the distribution of the underlying biological network. We propose an efficient approximation to the posterior expectation of the latent variables that reduces computational cost by at least 50%. The performance of the proposed method is demonstrated by extensive simulation studies and an application to construct gray matter brain atrophy network of Huntington's disease by using sMRI data and DTI data. The identified network connections are more consistent with clinical literature and better improve prediction in follow-up clinical outcomes and separate subjects into clinically meaningful subgroups with different prognosis than alternative methods.

Evaluating Effectiveness of Public Health Intervention Strategies for Mitigating COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) pandemic is an unprecedented global public health challenge. In the United States (US), state governments have implemented various non-pharmaceutical interventions (NPIs), such as physical distance closure (lockdown), stay-at-home order, mandatory facial mask in public in response to the rapid spread of COVID-19. To evaluate the effectiveness of these NPIs, we propose a nested case-control design with propensity score weighting under the quasi-experiment framework to estimate the average intervention effect on disease transmission across states. We further develop a method to test for factors that moderate intervention effect to assist precision public health intervention. Our method takes account of the underlying dynamics of disease transmission and balance state-level pre-intervention characteristics. We prove that our estimator provides causal intervention effect under assumptions. We apply this method to analyze US COVID-19 incidence cases to estimate the effects of six interventions. We show that lockdown has the largest effect on reducing transmission and reopening bars significantly increase transmission. States with a higher percentage of non-white population are at greater risk of increased $R_t$ associated with reopening bars.

Predictive testing for neurodegenerative diseases in the age of next-generation sequencing.

The availability and cost of next-generation sequencing (NSG) now allow testing large numbers of genes simultaneously. However, the gold standard for predictive testing has been to test only for a known family mutation or confirmed family disease. The goal of this study was to investigate the psychological impact of predictive testing for autosomal dominant neurodegenerative diseases without a known family mutation using next-generation sequencing panels compared to single-gene testing of a known family mutation. Fourteen individuals from families with a known mutation and 10 individuals with unknown family mutations participated. Participants completed questionnaires on demographics, genetic knowledge, and psychological measures of anxiety, depression, perceived personal control, rumination, and intolerance to uncertainty at baseline and 1 and 6 months after receiving results. Decision regret was measured 1 and 6 months after receiving results. Participants completed a modified Huntington disease genetic testing protocol with genetic counseling and neurological and psychological evaluation. Genetic testing of either the known family mutation or an NGS panel of neurodegenerative disease genes was performed. Semi-structured interviews were performed at 6 months post-results about their experience. Two-sample t tests were performed on data collected at each time point to identify significant between-group differences in demographic variables, baseline psychological scores, and baseline genetic knowledge scores. Within-group change over time was assessed by a mixed-effects model. Results of this study indicate that NGS panels for predictive testing for neurodegenerative disease are safe and beneficial to participants when performed within a modified HD protocol. Though significant differences in psychological outcomes were found, these differences may have been driven by genetic results and baseline psychological differences between individuals within the groups. Participants did not regret their decision to test and were largely pleased with the testing protocol.

Survival-Convolution Models for Predicting COVID-19 Cases and Assessing Effects of Mitigation Strategies.

Countries around the globe have implemented unprecedented measures to mitigate the coronavirus disease 2019 (COVID-19) pandemic. We aim to predict the COVID-19 disease course and compare the effectiveness of mitigation measures across countries to inform policy decision making using a robust and parsimonious survival-convolution model. We account for transmission during a pre-symptomatic incubation period and use a time-varying effective reproduction number (Rt ) to reflect the temporal trend of transmission and change in response to a public health intervention. We estimate the intervention effect on reducing the transmission rate using a natural experiment design and quantify uncertainty by permutation. In China and South Korea, we predicted the entire disease epidemic using only early phase data (2-3 weeks after the outbreak). A fast rate of decline in Rt was observed, and adopting mitigation strategies early in the epidemic was effective in reducing the transmission rate in these two countries. The nationwide lockdown in Italy did not accelerate the speed at which the transmission rate decreases. In the United States, Rt significantly decreased during a 2-week period after the declaration of national emergency, but it declined at a much slower rate afterwards. If the trend continues after May 1, COVID-19 may be controlled by late July. However, a loss of temporal effect (e.g., due to relaxing mitigation measures after May 1) could lead to a long delay in controlling the epidemic (mid-November with fewer than 100 daily cases) and a total of more than 2 million cases.

Survival-Convolution Models for Predicting COVID-19 Cases and Assessing Effects of Mitigation Strategies.

Countries around the globe have implemented unprecedented measures to mitigate the coronavirus disease 2019 (COVID-19) pandemic. We aim to predict COVID-19 disease course and compare effectiveness of mitigation measures across countries to inform policy decision making. We propose a robust and parsimonious survival-convolution model for predicting key statistics of COVID-19 epidemics (daily new cases). We account for transmission during a pre-symptomatic incubation period and use a time-varying effective reproduction number (R t ) to reflect the temporal trend of transmission and change in response to a public health intervention. We estimate the intervention effect on reducing the infection rate and quantify uncertainty by permutation. In China and South Korea, we predicted the entire disease epidemic using only data in the early phase (two to three weeks after the outbreak). A fast rate of decline in R t was observed and adopting mitigation strategies early in the epidemic was effective in reducing the infection rate in these two countries. The lockdown in Italy did not further accelerate the speed at which the infection rate decreases. The effective reproduction number has staggered around R t = 1.0 for more than 2 weeks before decreasing to below 1.0, and the epidemic in Italy is currently under control. In the US, R t significantly decreased during a 2-week period after the declaration of national emergency, but afterwards the rate of decrease is substantially slower. If the trend continues after May 1, the first wave of COVID-19 may be controlled by July 26 (CI: July 9 to August 27). However, a loss of temporal effect on infection rate (e.g., due to relaxing mitigation measures after May 1) could lead to a long delay in controlling the epidemic (November 19 with less than 100 daily cases) and a total of more than 2 million cases.

Identifying disease-associated biomarker network features through conditional graphical model.

Biomarkers are often organized into networks, in which the strengths of network connections vary across subjects depending on subject-specific covariates (eg, genetic variants). Variation of network connections, as subject-specific feature variables, has been found to predict disease clinical outcome. In this work, we develop a two-stage method to estimate biomarker networks that account for heterogeneity among subjects and evaluate network's association with disease clinical outcome. In the first stage, we propose a conditional Gaussian graphical model with mean and precision matrix depending on covariates to obtain covariate-dependent networks with connection strengths varying across subjects while assuming homogeneous network structure. In the second stage, we evaluate clinical utility of network measures (connection strengths) estimated from the first stage. The second-stage analysis provides the relative predictive power of between-region network measures on clinical impairment in the context of regional biomarkers and existing disease risk factors. We assess the performance of proposed method by extensive simulation studies and application to a Huntington's disease (HD) study to investigate the effect of HD causal gene on the rate of change in motor symptom through affecting brain subcortical and cortical gray matter atrophy connections. We show that cortical network connections and subcortical volumes, but not subcortical connections are identified to be predictive of clinical motor function deterioration. We validate these findings in an independent HD study. Lastly, highly similar patterns seen in the gray matter connections and a previous white matter connectivity study suggest a shared biological mechanism for HD and support the hypothesis that white matter loss is a direct result of neuronal loss as opposed to the loss of myelin or dysmyelination.

Learning Subject-Specific Directed Acyclic Graphs With Mixed Effects Structural Equation Models From Observational Data.

The identification of causal relationships between random variables from large-scale observational data using directed acyclic graphs (DAG) is highly challenging. We propose a new mixed-effects structural equation model (mSEM) framework to estimate subject-specific DAGs, where we represent joint distribution of random variables in the DAG as a set of structural causal equations with mixed effects. The directed edges between nodes depend on observed exogenous covariates on each of the individual and unobserved latent variables. The strength of the connection is decomposed into a fixed-effect term representing the average causal effect given the covariates and a random effect term representing the latent causal effect due to unobserved pathways. The advantage of such decomposition is to capture essential asymmetric structural information and heterogeneity between DAGs in order to allow for the identification of causal structure with observational data. In addition, by pooling information across subject-specific DAGs, we can identify causal structure with a high probability and estimate subject-specific networks with a high precision. We propose a penalized likelihood-based approach to handle multi-dimensionality of the DAG model. We propose a fast, iterative computational algorithm, DAG-MM, to estimate parameters in mSEM and achieve desirable sparsity by hard-thresholding the edges. We theoretically prove the identifiability of mSEM. Using simulations and an application to protein signaling data, we show substantially improved performances when compared to existing methods and consistent results with a network estimated from interventional data. Lastly, we identify gray matter atrophy networks in regions of brain from patients with Huntington's disease and corroborate our findings using white matter connectivity data collected from an independent study.

Efficient ℓ0 -norm feature selection based on augmented and penalized minimization.

Advances in high-throughput technologies in genomics and imaging yield unprecedentedly large numbers of prognostic biomarkers. To accommodate the scale of biomarkers and study their association with disease outcomes, penalized regression is often used to identify important biomarkers. The ideal variable selection procedure would search for the best subset of predictors, which is equivalent to imposing an ℓ0 -penalty on the regression coefficients. Since this optimization is a nondeterministic polynomial-time hard (NP-hard) problem that does not scale with number of biomarkers, alternative methods mostly place smooth penalties on the regression parameters, which lead to computationally feasible optimization problems. However, empirical studies and theoretical analyses show that convex approximation of ℓ0 -norm (eg, ℓ1 ) does not outperform their ℓ0 counterpart. The progress for ℓ0 -norm feature selection is relatively slower, where the main methods are greedy algorithms such as stepwise regression or orthogonal matching pursuit. Penalized regression based on regularizing ℓ0 -norm remains much less explored in the literature. In this work, inspired by the recently popular augmenting and data splitting algorithms including alternating direction method of multipliers, we propose a 2-stage procedure for ℓ0 -penalty variable selection, referred to as augmented penalized minimization-L0 (APM-L0 ). The APM-L0 targets ℓ0 -norm as closely as possible while keeping computation tractable, efficient, and simple, which is achieved by iterating between a convex regularized regression and a simple hard-thresholding estimation. The procedure can be viewed as arising from regularized optimization with truncated ℓ1 norm. Thus, we propose to treat regularization parameter and thresholding parameter as tuning parameters and select based on cross-validation. A 1-step coordinate descent algorithm is used in the first stage to significantly improve computational efficiency. Through extensive simulation studies and real data application, we demonstrate superior performance of the proposed method in terms of selection accuracy and computational speed as compared to existing methods. The proposed APM-L0 procedure is implemented in the R-package APML0.

Meta-analysis of mismatch negativity to simple versus complex deviants in schizophrenia.

Mismatch negativity (MMN) deficits in schizophrenia (SCZ) have been studied extensively since the early 1990s, with the vast majority of studies using simple auditory oddball task deviants that vary in a single acoustic dimension such as pitch or duration. There has been a growing interest in using more complex deviants that violate more abstract rules to probe higher order cognitive deficits. It is still unclear how sensory processing deficits compare to and contribute to higher order cognitive dysfunction, which can be investigated with later attention-dependent auditory event-related potential (ERP) components such as a subcomponent of P300, P3b. In this meta-analysis, we compared MMN deficits in SCZ using simple deviants to more complex deviants. We also pooled studies that measured MMN and P3b in the same study sample and examined the relationship between MMN and P3b deficits within study samples. Our analysis reveals that, to date, studies using simple deviants demonstrate larger deficits than those using complex deviants, with effect sizes in the range of moderate to large. The difference in effect sizes between deviant types was reduced significantly when accounting for magnitude of MMN measured in healthy controls. P3b deficits, while large, were only modestly greater than MMN deficits (d=0.21). Taken together, our findings suggest that MMN to simple deviants may still be optimal as a biomarker for SCZ and that sensory processing dysfunction contributes significantly to MMN deficit and disease pathophysiology.