Publications by authors named "Daniel Ho"

148 Publications

How medical AI devices are evaluated: limitations and recommendations from an analysis of FDA approvals.

Nat Med 2021 Apr 5. Epub 2021 Apr 5.

Department of Electrical Engineering, Stanford University, Stanford, CA, USA.

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http://dx.doi.org/10.1038/s41591-021-01312-xDOI Listing
April 2021

Distributed LMMSE Estimation for Large-Scale Systems Based on Local Information.

IEEE Trans Cybern 2021 Mar 24;PP. Epub 2021 Mar 24.

This article studies the distributed linear minimum mean square error (LMMSE) estimation problem for large-scale systems with local information (LSLI). Large-scale systems are composed of numerous subsystems. Each subsystem only transmits information to its neighbors. Thus, only the local information is available to each subsystem. This implies that the information available to different subsystems is different. Using local information to design an LMMSE estimator, the gains of the estimator must satisfy the sparse structure constraint, which makes the estimator design challenging and complicates the boundedness analysis of the estimation error covariance (EEC). In this article, a framework of the distributed LMMSE estimation for LSLI is established. The gains of the LMMSE estimator are effectively constructed by solving linear matrix equations. A gradient descent algorithm is exploited to design the gains of the LMMSE estimator numerically. Sufficient conditions are derived to ensure the boundedness of the EEC. Also, a gradient-based search algorithm is developed to verify whether the sufficient conditions hold or not. Finally, an example is used to illustrate the effectiveness of the proposed results.
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http://dx.doi.org/10.1109/TCYB.2021.3057769DOI Listing
March 2021

How US law will evaluate artificial intelligence for covid-19.

BMJ 2021 03 15;372:n234. Epub 2021 Mar 15.

Stanford Law School, Stanford University, Stanford, CA, USA

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http://dx.doi.org/10.1136/bmj.n234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958498PMC
March 2021

Interactive influences of food, contexts and neurocognitive systems on addictive eating.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Feb 28;110:110295. Epub 2021 Feb 28.

Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, Australia. Electronic address:

Compulsive eating is a common symptom of different conditions, including obesity, binge eating disorder and bulimia. One hypothesis is that contemporary food products promote compulsive eating via addiction-like mechanisms. However, what is the addictive substance in food, and what is the phenotypic overlap between obesity / eating disorders and addictions are questions that remain unresolved. In this review, we applied a multilevel framework of addiction, which encompasses the 'drug' (certain foods), the person's mindset, and the context, to improve understanding of compulsive eating. Specifically, we reviewed evidence on the addictive properties of specific foods, the neurocognitive systems that control dietary choices, and their interaction with physical, emotional and social contexts. We focused on different target groups to illustrate distinct aspects of the proposed framework: the impact of food and contextual factors were examined across a continuum, with most studies conducted on healthy participants and subclinical populations, whereas the review of neurocognitive aspects focused on clinical groups in which the alterations linked to addictive and compulsive eating are particularly visible. The reviewed evidence suggest that macronutrient composition and level of processing are associated with the addictive properties of food; there are overlapping neuroadaptations in reward and decision-making circuits across compulsive eating conditions; and there are physical and social contexts that fuel compulsive eating by exploiting reward mechanisms and their interaction with emotions. We conclude that a biopsychosocial model that integrates food, neurobiology and context can provide a better understanding of compulsive eating manifestations in a transdiagnostic framework.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110295DOI Listing
February 2021

Cellular heterogeneity and plasticity in liver cancer.

Semin Cancer Biol 2021 Feb 26. Epub 2021 Feb 26.

Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong. Electronic address:

Hepatocarcinogenesis involves complex genetic and cellular dysregulations which drive the formation of hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, with extensive heterogeneity. In contrast to the broad spectrum of molecularly driven therapies available for defined patient groups in certain cancer types, unfortunately the treatment options for HCC are highly limited. The lack of representative molecular and cellular signatures in the heterogeneous HCC tumors that can effectively guide the choice of the most appropriate treatment among the patients unavoidably limits the treatment outcome. Advancement and wide availability of the next-generation sequencing technologies have empowered us to examine and capture not only the detailed genetic alterations of the HCC cells but also the precise composition of different cell types within the tumor microenvironment and their interactions with the HCC cells at an unprecedented level. The information generated has provided new insight and better defined the inter-patient intertumoral heterogeneity, intra-patient intratumoral heterogeneity as well as the plasticity of HCC cells. These collectively provide a robust scientific basis in guiding the development and use of targeted therapy and immunotherapy. To complement, liquid biopsy coupled with high-sensitivity sequencing could potentially be adopted as a more practical and safer approach to detect and reflect the tumor heterogeneity in HCC patients in guiding the choice of treatment and monitoring disease progression.
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http://dx.doi.org/10.1016/j.semcancer.2021.02.015DOI Listing
February 2021

Combining Observation and Physical Practice: Benefits of an Interleaved Schedule for Visuomotor Adaptation and Motor Memory Consolidation.

Front Hum Neurosci 2021 4;15:614452. Epub 2021 Feb 4.

Motor Skills Lab, School of Kinesiology, University of British Columbia, Vancouver, BC, Canada.

Visuomotor adaptation to novel environments can occur via non-physical means, such as observation. Observation does not appear to activate the same implicit learning processes as physical practice, rather it appears to be more strategic in nature. However, there is evidence that interspersing observational practice with physical practice can benefit performance and memory consolidation either through the combined benefits of separate processes or through a change in processes activated during observation trials. To test these ideas, we asked people to practice aiming to targets with visually rotated cursor feedback or engage in a combined practice schedule comprising physical practice and observation of projected videos showing successful aiming. Ninety-three participants were randomly assigned to one of five groups: massed physical practice (Act), distributed physical practice (Act+Rest), or one of 3 types of combined practice: alternating blocks (Obs_During), or all observation before (Obs_Pre) or after (Obs_Post) blocked physical practice. Participants received 100 practice trials (all or half were physical practice). All groups improved in adaptation trials and showed savings across the 24-h retention interval relative to initial practice. There was some forgetting for all groups, but the magnitudes were larger for physical practice groups. The Act and Obs_During groups were most accurate in retention and did not differ, suggesting that observation can serve as a replacement for physical practice if supplied intermittently and offers advantages above just resting. However, after-effects associated with combined practice were smaller than those for physical practice control groups, suggesting that beneficial learning effects as a result of observation were not due to activation of implicit learning processes. Reaction time, variable error, and post-test rotation drawings supported this conclusion that adaptation for observation groups was promoted by explicit/strategic processes.
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http://dx.doi.org/10.3389/fnhum.2021.614452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890187PMC
February 2021

The use of radiolucent (carbon fibre-reinforced polymer) pedicle screw fixation for serial monitoring of clear cell meningioma: a case report.

J Surg Case Rep 2020 Dec 18;2020(12):rjaa510. Epub 2020 Dec 18.

Faculty of Medicine, University of New South Wales Medicine, Sydney, NSW, Australia.

Clear cell meningioma is an uncommon variant of meningioma associated with high rates of local recurrence and metastasis. However, monitoring for local recurrence may be complicated by metal-related artefacts generated by spinal instrumentation. We present a patient with recurrent lumbar atypical clear cell meningioma, which had been resected multiple times throughout her adolescence. Due to extensive bone and ligament resection, posterior stabilization of the lumbar spine with pedicle screws was required. To ensure clear postoperative visualization of the spinal cord for local recurrence, a carbon fibre/polyetheretherketone (CF/PEEK) pedicle screw and rod construct was used. CF/PEEK has non-inferior biomechanical and biocompatible properties to titanium, with a clear advantage of radiolucency to assist in detecting the local recurrence early and facilitating accurate radiotherapy planning.
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http://dx.doi.org/10.1093/jscr/rjaa510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748253PMC
December 2020

Multiplayer Stackelberg-Nash Game for Nonlinear System via Value Iteration-Based Integral Reinforcement Learning.

IEEE Trans Neural Netw Learn Syst 2020 Dec 22;PP. Epub 2020 Dec 22.

In this article, we study a multiplayer Stackelberg-Nash game (SNG) pertaining to a nonlinear dynamical system, including one leader and multiple followers. At the higher level, the leader makes its decision preferentially with consideration of the reaction functions of all followers, while, at the lower level, each of the followers reacts optimally to the leader's strategy simultaneously by playing a Nash game. First, the optimal strategies for the leader and the followers are derived from down to the top, and these strategies are further shown to constitute the Stackelberg-Nash equilibrium points. Subsequently, to overcome the difficulty in calculating the equilibrium points analytically, we develop a novel two-level value iteration-based integral reinforcement learning (VI-IRL) algorithm that relies only upon partial information of system dynamics. We establish that the proposed method converges asymptotically to the equilibrium strategies under the weak coupling conditions. Moreover, we introduce effective termination criteria to guarantee the admissibility of the policy (strategy) profile obtained from a finite number of iterations of the proposed algorithm. In the implementation of our scheme, we employ neural networks (NNs) to approximate the value functions and invoke the least-squares methods to update the involved weights. Finally, the effectiveness of the developed algorithm is verified by two simulation examples.
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http://dx.doi.org/10.1109/TNNLS.2020.3042331DOI Listing
December 2020

A cohort study of 30 day mortality after NON-EMERGENCY surgery in a COVID-19 cold site.

Int J Surg 2020 Dec 24;84:57-65. Epub 2020 Oct 24.

Department of Urology, University College London Hospital NHS Foundation Trust, London, UK; Division of Surgery and Interventional Science, University College London, London, UK.

Background: Two million non-emergency surgeries are being cancelled globally every week due to the COVID-19 pandemic, which will have a major impact on patients and healthcare systems.

Methods: During the peak of the pandemic in the United Kingdom, we set up a multicentre cancer network amongst 14 National Health Service institutions, performing urological, thoracic, gynaecological and general surgical urgent and cancer operations at a central COVID-19 cold site. This is a cohort study of 500 consecutive patients undergoing surgery in this network. The primary outcome was 30-day mortality from COVID-19. Secondary outcomes included all-cause mortality and post-operative complications at 30-days.

Results: 500 patients underwent surgery with median age 62.5 (IQR 51-71). 65% were male, 60% had a known diagnosis of cancer and 61% of surgeries were considered complex or major. No patient died from COVID-19 at 30-days. 30-day all-cause mortality was 3/500 (1%). 10 (2%) patients were diagnosed with COVID-19, 4 (1%) with confirmed laboratory diagnosis and 6 (1%) with probable COVID-19. 33/500 (7%) of patients developed Clavien-Dindo grade 3 or higher complications, with 1/33 (3%) occurring in a patient with COVID-19.

Conclusion: It is safe to continue cancer and urgent surgery during the COVID-19 pandemic with appropriate service reconfiguration.
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http://dx.doi.org/10.1016/j.ijsu.2020.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584883PMC
December 2020

The Association Between Electronic Device Use During Family Time and Family Well-Being: Population-Based Cross-Sectional Study.

J Med Internet Res 2020 10 14;22(10):e20529. Epub 2020 Oct 14.

School of Public Health, University of Hong Kong, Hong Kong, China (Hong Kong).

Background: Electronic devices (eDevices) may have positive or negative influences on family communication and well-being depending on how they are used.

Objective: We examined eDevice use during family time and its association with the quality of family communication and well-being in Hong Kong Chinese adults.

Methods: In 2017, a probability-based 2-stage random sampling landline telephone survey collected data on eDevice use in daily life and during family time (eg, family dinner) and the presence of rules banning eDevice use during family dinner. Family communication quality was rated from 0 to 10 with higher scores being favorable. Family well-being was calculated as a composite mean score of 3 items each using the same scale from 0 to 10. The associations of family communication quality and well-being with eDevice use in daily life and during family time were estimated using beta-coefficient (β) adjusting for sociodemographics. The mediating role of family communication quality in the association between eDevice use and family well-being was analyzed.

Results: Of the 2064 respondents (mean age 56.4 [SD 19.2] years, 1269/2064 [61.48%] female), 1579/2059 (76.69%) used an eDevice daily for a mean of 3.6 hours (SD 0.1) and 257/686 (37.5%) used it for 30+ minutes before sleep. As much as 794/2046 (38.81%) often or sometimes used an eDevice during family time including dinner (311/2017, 15.42%); 713/2012 (35.44%) reported use of an eDevice by family members during dinner. Lower family communication quality was associated with hours of eDevice use before sleep (adjusted β=-.25; 95% CI -0.44 to -0.05), and often use (vs never use) of eDevice during family dinner by oneself (adjusted β=-.51; 95% CI -0.91 to -0.10) and family members (adjusted β=-.54; 95% CI -0.79 to -0.29). Similarly, lower family well-being was associated with eDevice use before sleep (adjusted β=-.26; 95% CI -0.42 to -0.09), and often use during family dinner by oneself (adjusted β=-.48; 95% CI -0.83 to -0.12) and family members (adjusted β=-.50; 95% CI -0.72 to -0.28). Total ban of eDevice use during family dinner was negatively associated with often use by oneself (adjusted odds ratio 0.49; 95% CI 0.29 to 0.85) and family members (adjusted odds ratio 0.41; 95% CI 0.28, 0.60) but not with family communication and well-being. Lower family communication quality substantially mediated the total effect of the association of eDevice use time before sleep (61.2%) and often use at family dinner by oneself (87.0%) and by family members (67.8%) with family well-being.

Conclusions: eDevice use before sleep and during family dinner was associated with lower family well-being, and the association was substantially mediated by family communication quality. Our results suggest that interventions on smart use of eDevice may improve family communication and well-being.
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http://dx.doi.org/10.2196/20529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593857PMC
October 2020

Model-Based Event-Triggered Sliding-Mode Control for Multi-Input Systems: Performance Analysis and Optimization.

IEEE Trans Cybern 2020 Sep 23;PP. Epub 2020 Sep 23.

This article is concerned with the model-based event-triggered sliding-mode control (SMC) issue for multi-input systems, which is motivated by some existing results in a single-input case. A model-based event-triggered SMC scheme is first designed. In particular, a triggered condition is co-designed with SMC to achieve the reachability condition of a specified sliding surface. Thus, it can effectively mitigate the burden of data communication, and also eliminate the effect of the matched external disturbance and the model uncertainties in both system and input. For ensuring the stability of the model dynamics and the resulting sliding-mode dynamics simultaneously, an auxiliary disturbance input is introduced to the nominal model by compensating the switching term of the designed SMC law. Furthermore, the positive lower bound for the minimum interevent time is analyzed to ensure the feasibility of the proposed approach. To illustrate the proposed model-based event-triggered SMC approach from a practical viewpoint, two design problems to maximize the system robustness and performance are proposed, respectively. The nontrivial optimization problems are then solved by a genetic algorithm (GA). Finally, jet transport aircraft is utilized to demonstrate the effectiveness of the proposed results and algorithm.
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http://dx.doi.org/10.1109/TCYB.2020.3020253DOI Listing
September 2020

RSK2-inactivating mutations potentiate MAPK signaling and support cholesterol metabolism in hepatocellular carcinoma.

J Hepatol 2021 Feb 9;74(2):360-371. Epub 2020 Sep 9.

Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong. Electronic address:

Background & Aims: Mutational profiling of patient tumors has suggested that hepatocellular carcinoma (HCC) development is mainly driven by loss-of-function mutations in tumor suppressor genes. p90 ribosomal S6 kinase 2 (RSK2) functions as a direct downstream kinase of ERK1/2 and elevated RSK2 expression has been reported to support oncogenic functions in some cancers. We investigated if RSK2 was also dysregulated by inactivating mutations in cancers including HCC.

Methods: We performed exome sequencing and targeted DNA sequencing on HBV-associated HCCs to examine recurrent RSK2 mutations. The functional significance and mechanistic consequences of RSK2 mutations were examined in natural RSK2-null HCC cells, and RSK2-knockout HCC cells. The potential downstream pathways underlying RSK2 mutations were investigated by RNA sequencing, qRT-PCR and mass spectrometry.

Results: We detected recurrent somatic RSK2 mutations at a rate of 6.3% in our HCC cohorts and revealed that, among many cancer types, HCC was the cancer most commonly harboring RSK2 mutations. The RSK2 mutations were inactivating and associated with a more aggressive tumor phenotype. We found that, functionally, restoring RSK2 expression in natural RSK2-null HBV-positive Hep3B cells suppressed proliferation and migration in vitro and tumorigenicity in vivo. Mechanistically, RSK2-inactivating mutations attenuated a SOS1/2-dependent negative feedback loop, leading to the activation of MAPK signaling. Of note, this RSK2 mutation-mediated MAPK upregulation rendered HCC cells more sensitive to sorafenib, a first-line multi-kinase inhibitor for advanced HCC. Furthermore, such activation of MAPK signaling enhanced cholesterol biosynthesis-related gene expression in HCC cells.

Conclusions: Our findings reveal the mechanistic and functional significance of RSK2-inactivating mutations in HCC. These inactivating mutations may serve as an alternative route to activate MAPK signaling and cholesterol metabolism in HCC.

Lay Summary: In this study, we identified and functionally characterized RSK2-inactivating mutations in human hepatocellular carcinoma and demonstrated their association with aggressive tumor behavior. Mutations in RSK2 drive signaling pathways with known oncogenic potential, leading to enhanced cholesterol biosynthesis and potentially sensitizing tumors to sorafenib treatment.
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http://dx.doi.org/10.1016/j.jhep.2020.08.036DOI Listing
February 2021

Stochastic Strongly Convex Optimization via Distributed Epoch Stochastic Gradient Algorithm.

IEEE Trans Neural Netw Learn Syst 2020 Jul 2;PP. Epub 2020 Jul 2.

This article considers the problem of stochastic strongly convex optimization over a network of multiple interacting nodes. The optimization is under a global inequality constraint and the restriction that nodes have only access to the stochastic gradients of their objective functions. We propose an efficient distributed non-primal-dual algorithm, by incorporating the inequality constraint into the objective via a smoothing technique. We show that the proposed algorithm achieves an optimal O(1/T) (T is the total number of iterations) convergence rate in the mean square distance from the optimal solution. In particular, we establish a high probability bound for the proposed algorithm, by showing that with a probability at least 1-δ, the proposed algorithm converges at a rate of O(ln (ln (T)/δ)/ T ). Finally, we provide numerical experiments to demonstrate the efficacy of the proposed algorithm.
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http://dx.doi.org/10.1109/TNNLS.2020.3004723DOI Listing
July 2020

Feasible Policy Evaluation by Design: A Randomized Synthetic Stepped-Wedge Trial of Mandated Disclosure in King County.

Eval Rev 2020 02 12;44(1):3-50. Epub 2020 Jun 12.

Food Protection Program, Environmental Health Services, Public Health-Seattle & King County, Seattle, WA, USA.

Evidence-based policy is limited by the perception that randomized controlled trials (RCTs) are expensive and infeasible. We argue that carefully tailored research design can overcome these challenges and enable more widespread randomized evaluations of policy implementation. We demonstrate how a stepped-wedge (randomized rollout) design that adapts synthetic control methods overcame substantial practical, administrative, political, and statistical constraints to evaluating King County's new food safety rating system. The core RCT component of the evaluation came at little financial cost to the government, allowed the entire county to be treated, and resulted in no functional implementation delay. The case of restaurant sanitation grading has played a critical role in the scholarship on information disclosure, and our study provides the first evidence from a randomized trial of the causal effects of grading on health outcomes. We find that the grading system had no appreciable effects on foodborne illness, hospitalization, or food handling practices but that the system may have marginally increased public engagement by encouraging higher reporting.
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http://dx.doi.org/10.1177/0193841X20930852DOI Listing
February 2020

Menu labeling, calories, and nutrient density: Evidence from chain restaurants.

PLoS One 2020 7;15(5):e0232656. Epub 2020 May 7.

J.D., Stanford Law School, Stanford, CA, United States of America.

The Food and Drug Administration's menu labeling rule requires chain restaurants to prominently display calories, while leaving other nutritional information (e.g., fat, sodium, sugar) to the request of consumers. We use rich micronutrient data from 257 large chain brands and 24,076 menu items to examine whether calories are correlated with widely used "nutrient profile" scores that measure healthfulness based on nutrient density. We show that calories are indeed statistically significant predictors of nutrient density. However, as a substantive matter, the correlation is highly attenuated (partial R2 < 0.01). Our findings (a) suggest that the promise of calorie labeling to improve nutrient intake quality at restaurants is limited and (b) clarify the basis for transparency of nutrient composition beyond calories to promote healthy menu choices.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232656PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205205PMC
September 2020

Hepatitis B Virus-Telomerase Reverse Transcriptase Promoter Integration Harnesses Host ELF4, Resulting in Telomerase Reverse Transcriptase Gene Transcription in Hepatocellular Carcinoma.

Hepatology 2021 Jan 26;73(1):23-40. Epub 2020 Nov 26.

Department of Pathology, The University of Hong Kong, Hong Kong, China.

Background And Aims: Hepatitis B virus (HBV) integrations are common in hepatocellular carcinoma (HCC). In particular, alterations of the telomerase reverse transcriptase (TERT) gene by HBV integrations are frequent; however, the molecular mechanism and functional consequence underlying TERT HBV integration are unclear.

Approach And Results: We adopted a targeted sequencing strategy to survey HBV integrations in human HBV-associated HCCs (n = 95). HBV integration at the TERT promoter was frequent (35.8%, n = 34/95) in HCC tumors and was associated with increased TERT mRNA expression and more aggressive tumor behavior. To investigate the functional importance of various integrated HBV components, we employed different luciferase reporter constructs and found that HBV enhancer I (EnhI) was the key viral component leading to TERT activation on integration at the TERT promoter. In addition, the orientation of the HBV integration at the TERT promoter further modulated the degree of TERT transcription activation in HCC cell lines and patients' HCCs. Furthermore, we performed array-based small interfering RNA library functional screening to interrogate the potential major transcription factors that physically interacted with HBV and investigated the cis-activation of host TERT gene transcription on viral integration. We identified a molecular mechanism of TERT activation through the E74 like ETS transcription factor 4 (ELF4), which normally could drive HBV gene transcription. ELF4 bound to the chimeric HBV EnhI at the TERT promoter, resulting in telomerase activation. Stable knockdown of ELF4 significantly reduced the TERT expression and sphere-forming ability in HCC cells.

Conclusions: Our results reveal a cis-activating mechanism harnessing host ELF4 and HBV integrated at the TERT promoter and uncover how TERT HBV-integrated HCCs may achieve TERT activation in hepatocarcinogenesis.
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http://dx.doi.org/10.1002/hep.31231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898544PMC
January 2021

OpenArm 2.0: Automated Segmentation of 3D Tissue Structures for Multi-Subject Study of Muscle Deformation Dynamics.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:982-988

We present a novel neural-network-based pipeline for segmentation of 3D muscle and bone structures from localized 2D ultrasound data of the human arm. Building from the U-Net [1] neural network framework, we examine various data augmentation techniques and training data sets to both optimize the network's performance on our data set and hypothesize strategies to better select training data, minimizing manual annotation time while maximizing performance. We then employ this pipeline to generate the OpenArm 2.0 data set, the first factorial set of multi-subject, multi-angle, multi-force scans of the arm with full volumetric annotation of the biceps and humerus. This data set has been made available on SimTK (https://simtk.org/projects/openarm) to enable future exploration of muscle force modeling, improved musculoskeletal graphics, and assistive device control.
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http://dx.doi.org/10.1109/EMBC.2019.8857669DOI Listing
July 2019

A Six Week Therapeutic Ballet Intervention Improved Gait and Inhibitory Control in Children With Cerebral Palsy-A Pilot Study.

Front Public Health 2019 25;7:137. Epub 2019 Jun 25.

Pediatric Exercise and Genomics Research Center, School of Medicine, University of California, Irvine, Irvine, CA, United States.

Children with cerebral palsy (CP) have motor impairments that make it challenging for them to participate in standard physical activity (PA) interventions. There is a need to evaluate adapted PA interventions for this population. Dance can promote coordination, posture, muscle strength, motor learning, and executive functioning. This pilot study evaluated the feasibility and the effects of a new therapeutic ballet intervention specifically designed for children with CP. Eight children with CP (9-14 y/o; 75% female) participated in a 6-week therapeutic ballet intervention. Outcomes were measured in multiple domains, including body composition (DXA), muscle strength (hand-grip dynamometer), habitual physical activity, gait and selective motor control functions, and executive functioning. Follow-up assessments of habitual physical activity, gait, and executive functioning were completed 4 to 5 weeks post-intervention. Five of the eight participants were overfat or obese based on DXA percentage of body fat. All participants were below the 50th percentile for their age and gender for bone density. Four participants showed a trend to improve hand-grip strength in one hand only, while one improved in both hands. There were significant improvements in gait across time points (pre, post, and follow-up), specifically in time of ambulation ( = 4.36, = 4.22, = 3.72, = 0.056, = 0.02), and in step length (cm) on the right: = 48.29, = 50.77, = 52.11, = 0.22, = 0.027, and left stride: = 96.29, = 102.20, = 104.20, = 0.30, = 0.027, indicating gait changes in bilateral lower extremities. There was improvement in inhibitory control ( = 0.78; 95% Confidence Limit = ±0.71, < 0.05) with large individual responses primarily among those above the mean at baseline. Therapeutic ballet may prove to be a useful intervention to promote physiological and cognitive functions in children with CP. Results demonstrated feasibility of the physical, physiological, and cognitive assessments and suggested improvements in participants' gait and inhibitory control with large individual responses. Modifications to personalize the intervention may be needed to optimize positive outcomes. www.ClinicalTrials.gov, identifier: NCT03681171.
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http://dx.doi.org/10.3389/fpubh.2019.00137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603155PMC
June 2019

RNA-Seq in 296 phased trios provides a high-resolution map of genomic imprinting.

BMC Biol 2019 06 24;17(1):50. Epub 2019 Jun 24.

Department of Biomedical Data Sciences, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands.

Background: Identification of imprinted genes, demonstrating a consistent preference towards the paternal or maternal allelic expression, is important for the understanding of gene expression regulation during embryonic development and of the molecular basis of developmental disorders with a parent-of-origin effect. Combining allelic analysis of RNA-Seq data with phased genotypes in family trios provides a powerful method to detect parent-of-origin biases in gene expression.

Results: We report findings in 296 family trios from two large studies: 165 lymphoblastoid cell lines from the 1000 Genomes Project and 131 blood samples from the Genome of the Netherlands (GoNL) participants. Based on parental haplotypes, we identified > 2.8 million transcribed heterozygous SNVs phased for parental origin and developed a robust statistical framework for measuring allelic expression. We identified a total of 45 imprinted genes and one imprinted unannotated transcript, including multiple imprinted transcripts showing incomplete parental expression bias that was located adjacent to strongly imprinted genes. For example, PXDC1, a gene which lies adjacent to the paternally expressed gene FAM50B, shows a 2:1 paternal expression bias. Other imprinted genes had promoter regions that coincide with sites of parentally biased DNA methylation identified in the blood from uniparental disomy (UPD) samples, thus providing independent validation of our results. Using the stranded nature of the RNA-Seq data in lymphoblastoid cell lines, we identified multiple loci with overlapping sense/antisense transcripts, of which one is expressed paternally and the other maternally. Using a sliding window approach, we searched for imprinted expression across the entire genome, identifying a novel imprinted putative lncRNA in 13q21.2. Overall, we identified 7 transcripts showing parental bias in gene expression which were not reported in 4 other recent RNA-Seq studies of imprinting.

Conclusions: Our methods and data provide a robust and high-resolution map of imprinted gene expression in the human genome.
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http://dx.doi.org/10.1186/s12915-019-0674-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589892PMC
June 2019

Robust Partial-Nodes-Based State Estimation for Complex Networks Under Deception Attacks.

IEEE Trans Cybern 2020 Jun 14;50(6):2793-2802. Epub 2019 Jun 14.

In this paper, the partial-nodes-based state estimators (PNBSEs) are designed for a class of uncertain complex networks subject to finite-distributed delays, stochastic disturbances, as well as randomly occurring deception attacks (RODAs). In consideration of the likely unavailability of the output signals in harsh environments from certain network nodes, only partial measurements are utilized to accomplish the state estimation task for the addressed complex network with norm-bounded uncertainties in both the network parameters and the inner couplings. The RODAs are taken into account to reflect the compromised data transmissions in cyber security. We aim to derive the gain parameters of the estimators such that the overall estimation error dynamics satisfies the specified security constraint in the simultaneous presence of stochastic disturbances and deception signals. Through intensive stochastic analysis, sufficient conditions are obtained to guarantee the desired security performance for the PNBSEs, based on which the estimator gains are acquired by solving certain matrix inequalities with nonlinear constraints. A simulation study is carried out to testify the security performance of the presented state estimation method.
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http://dx.doi.org/10.1109/TCYB.2019.2918760DOI Listing
June 2020

Single-cell transcriptomics reveals the landscape of intra-tumoral heterogeneity and stemness-related subpopulations in liver cancer.

Cancer Lett 2019 09 10;459:176-185. Epub 2019 Jun 10.

Department of Pathology, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong. Electronic address:

Hepatocellular carcinoma (HCC) is heterogeneous, rendering its current curative treatments ineffective. The emergence of single-cell genomics represents a powerful strategy in delineating the complex molecular landscapes of cancers. In this study, we demonstrated the feasibility and merit of using single-cell RNA sequencing to dissect the intra-tumoral heterogeneity and analyze the single-cell transcriptomic landscape to detect rare cell subpopulations of significance. Exploration of the inter-relationship among liver cancer stem cell markers showed two distinct major cell populations according to EPCAM expression, and the EPCAM cells had upregulated expression of multiple oncogenes. We also identified a CD24/CD44-enriched cell subpopulation within the EPCAM cells which had specific signature genes and might indicate a novel stemness-related cell subclone in HCC. Notably, knockdown of signature gene CTSE for CD24/CD44 cells significantly reduced self-renewal ability on HCC cells in vitro and the stemness-related role of CTSE was further confirmed by in vivo tumorigenicity assays in nude mice. In summary, single-cell genomics is a useful tool to delineate HCC intratumoral heterogeneity at better resolution. It can identify rare but important cell subpopulations, and may guide better precision medicine in the long run.
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http://dx.doi.org/10.1016/j.canlet.2019.06.002DOI Listing
September 2019

Multilayered Sampled-Data Iterative Learning Tracking for Discrete Systems With Cooperative-Antagonistic Interactions.

IEEE Trans Cybern 2020 Oct 29;50(10):4420-4429. Epub 2019 May 29.

The tracking for discrete systems is discussed by designing two kinds of multilayered iterative learning schemes with cooperative-antagonistic interactions in this paper. The definition of the signed graph is presented and iterative learning schemes are then designed to be multilayered and have cooperative-antagonistic interactions. Moreover, considering the limited bandwidth of information storage, the state information of these controllers is updated in light of previous learning iterations but not just dependent on the last iteration. Two simple criteria are addressed to discuss the tracking of discrete systems with multilayered and cooperative-antagonistic iterative schemes. The simulation results are shown to demonstrate the validity of the given criteria.
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http://dx.doi.org/10.1109/TCYB.2019.2915664DOI Listing
October 2020

Machine Learning SNP Based Prediction for Precision Medicine.

Front Genet 2019 27;10:267. Epub 2019 Mar 27.

Liggins Institute, University of Auckland, Auckland, New Zealand.

In the past decade, precision genomics based medicine has emerged to provide tailored and effective healthcare for patients depending upon their genetic features. Genome Wide Association Studies have also identified population based risk genetic variants for common and complex diseases. In order to meet the full promise of precision medicine, research is attempting to leverage our increasing genomic understanding and further develop personalized medical healthcare through ever more accurate disease risk prediction models. Polygenic risk scoring and machine learning are two primary approaches for disease risk prediction. Despite recent improvements, the results of polygenic risk scoring remain limited due to the approaches that are currently used. By contrast, machine learning algorithms have increased predictive abilities for complex disease risk. This increase in predictive abilities results from the ability of machine learning algorithms to handle multi-dimensional data. Here, we provide an overview of polygenic risk scoring and machine learning in complex disease risk prediction. We highlight recent machine learning application developments and describe how machine learning approaches can lead to improved complex disease prediction, which will help to incorporate genetic features into future personalized healthcare. Finally, we discuss how the future application of machine learning prediction models might help manage complex disease by providing tissue-specific targets for customized, preventive interventions.
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http://dx.doi.org/10.3389/fgene.2019.00267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445847PMC
March 2019

Genome-Scale CRISPR Screens Identify Human Pluripotency-Specific Genes.

Cell Rep 2019 04;27(2):616-630.e6

Department of Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA; Insitro, South San Francisco, CA 94080, USA. Electronic address:

Human pluripotent stem cells (hPSCs) generate a variety of disease-relevant cells that can be used to improve the translation of preclinical research. Despite the potential of hPSCs, their use for genetic screening has been limited by technical challenges. We developed a scalable and renewable Cas9 and sgRNA-hPSC library in which loss-of-function mutations can be induced at will. Our inducible mutant hPSC library can be used for multiple genome-wide CRISPR screens in a variety of hPSC-induced cell types. As proof of concept, we performed three screens for regulators of properties fundamental to hPSCs: their ability to self-renew and/or survive (fitness), their inability to survive as single-cell clones, and their capacity to differentiate. We identified the majority of known genes and pathways involved in these processes, as well as a plethora of genes with unidentified roles. This resource will increase the understanding of human development and genetics. This approach will be a powerful tool to identify disease-modifying genes and pathways.
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http://dx.doi.org/10.1016/j.celrep.2019.03.043DOI Listing
April 2019

Deregulated GATA6 modulates stem cell-like properties and metabolic phenotype in hepatocellular carcinoma.

Int J Cancer 2019 10 28;145(7):1860-1873. Epub 2019 Mar 28.

Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong.

Accumulating evidence illustrates the significance of cell plasticity in the molecular biology of liver cancer. Reprogramming of mature parenchymal cells to a less differentiated state by key molecular targets contributes to the pathogenesis of hepatocellular carcinoma (HCC). Hereby, we investigated the role of GATA6, a transcription factor implicated in hepatocyte lineage specification, in HCC. Our results demonstrated a lower expression of GATA6 in HCC tissues compared to the corresponding nontumoral liver tissues. Moreover, GATA6 underexpression, as observed in about 50% cases in our clinical cohort, was associated with a poorer degree of tumor cell differentiation and worse disease-free survival outcome. In vitro, silencing of GATA6 in HCC cells augmented cell migration and invasion abilities of HCC cells by activating epithelial-mesenchymal transition. Self-renewal was also enhanced in vitro. Consistently, in vivo tumorigenicity and self-renewal was promoted upon GATA6 knockdown. Notably, suppression of GATA6 converts HCC cells to a metabolic phenotype recapitulating stem-cell state. Expression of glycolytic markers was elevated in GATA6-knockdown clones accompanied by increased glucose uptake; while overexpression of GATA6 resulted in opposite effects. Further to this, we identified that GATA6 bound to the promoter region of PKM gene and regulated PKM2 transcription. Taken together, downregulation of GATA6 directs HCC cells to glycolytic metabolism and fosters tumorigenicity, self-renewal and metastasis. GATA6 is a transcriptional regulator and a genetic switch that converts the phenotypic reprogramming of HCC cells. It is a potential prognostic biomarker and therapeutic target for liver cancer.
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http://dx.doi.org/10.1002/ijc.32248DOI Listing
October 2019

Development and feasibility of a brief Zero-time Exercise intervention to reduce sedentary behaviour and enhance physical activity: A pilot trial.

Health Soc Care Community 2019 07 1;27(4):e233-e245. Epub 2019 Mar 1.

School of Public Health, The University of Hong Kong, Hong Kong, SAR, China.

A brief intervention using Zero-time Exercise (ZTEx), a foot-in-the-door approach, was developed to reduce sedentary behaviour and increase physical activity. ZTEx refers to the integration of simple strength- and stamina-enhancing physical activity into daily life, which can be done anytime, anywhere and by anyone. This paper presents the development, feasibility, and preliminary evidence for the effectiveness of this intervention under the Hong Kong Jockey Club FAMILY Project. Needs assessments were conducted with social workers from the Christian Family Services Center(CFSC) and the Social Welfare Department (SWD). This single group prospective ZTEx intervention trial, guided by the Health Action Process Approach, included a 3-hr core session at baseline and a 1-hr booster session at 1-month follow-up. Fifty-six participants (social and service-related workers) from CFSC (n = 28) and SWD (n = 28) received the intervention and completed the self-administered questionnaires at baseline. Forty-nine and 43 participants completed the 1-month and 3-month self-administered questionnaires, respectively. Fifteen participants attended the focus group interviews to share their feedback on ZTEx intervention after implementing their community-based ZTEx activities. Intention-to-treat analysis was conducted with missing data replaced by baseline values. Participants reported significant decreases in sitting time by 27 (2, 52) minutes (mean [95% confidence interval]) and 36 (0.2, 71) minutes on a weekday, increases in physical activity while seated by 0.7 (0.2, 1.4) days and 1.1 (0.6, 1.7) days in a week, and improvements in perceived knowledge, outcome expectancies and plan on doing ZTEx at the 1-month and 3-month follow-up, respectively. Balance and muscle strength significantly improved at the 1-month follow-up. The effect ranged from small to large (Cohen's d: 0.27-1.05, all p < 0.05). The qualitative feedbacks support the quantitative findings. Our findings show early evidence that ZTEx effectively reduced sedentary behaviour and enhanced physical activity and fitness. Further trials on this simple and low-cost intervention as the first step to promote higher intensity exercise are warranted.
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http://dx.doi.org/10.1111/hsc.12728DOI Listing
July 2019

Distributed Secure Cooperative Control Under Denial-of-Service Attacks From Multiple Adversaries.

IEEE Trans Cybern 2020 Aug 15;50(8):3458-3467. Epub 2019 Feb 15.

This paper develops a fully distributed framework to investigate the cooperative behavior of multiagent systems in the presence of distributed denial-of-service (DoS) attacks launched by multiple adversaries. In such an insecure network environment, two kinds of communication schemes, that is, sample-data and event-triggered communication schemes, are discussed. Then, a fully distributed control protocol with strong robustness and high scalability is well designed. This protocol guarantees asymptotic consensus against distributed DoS attacks. In this paper, "fully" emphasizes that the eigenvalue information of the Laplacian matrix is not required in the design of both the control protocol and event conditions. For the event-triggered case, two effective dynamical event-triggered schemes are proposed, which are independent of any global information. Such event-triggered schemes do not exhibit Zeno behavior even in the insecure environment. Finally, a simulation example is provided to verify the effectiveness of theoretical analysis.
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http://dx.doi.org/10.1109/TCYB.2019.2896160DOI Listing
August 2020

Impulsive Control of Nonlinear Systems With Time-Varying Delay and Applications.

IEEE Trans Cybern 2020 Jun 13;50(6):2661-2673. Epub 2019 Feb 13.

Impulsive control of nonlinear delay systems is studied in this paper, where the time delays addressed may be the constant delay, bounded time-varying delay, or unbounded time-varying delay. Based on the impulsive control theory and some analysis techniques, a new theoretical result for global exponential stability is derived from the impulsive control point of view. The significance of the presented result is that the stability can be achieved via the impulsive control at certain impulse points despite the existence of impulsive perturbations which causes negative effect to the control. That is, the impulsive control provides a super performance to allow the existence of impulsive perturbations. In addition, we apply the theoretical result to the problem of impulsive control of delayed neural networks. Some results for global exponential stability and synchronization control of neural networks with time delays are derived via impulsive control. Three illustrated examples are given to show the effectiveness and distinctiveness of the proposed impulsive control schemes.
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http://dx.doi.org/10.1109/TCYB.2019.2896340DOI Listing
June 2020

Event/Self-Triggered Control for Leader-Following Consensus Over Unreliable Network With DoS Attacks.

IEEE Trans Neural Netw Learn Syst 2019 Oct 23;30(10):3137-3149. Epub 2019 Jan 23.

This paper investigates the leader-following consensus issue with event/self-triggered schemes under an unreliable network environment. First, we characterize network communication and control protocol update in the presence of denial-of-service (DoS) attacks. In this situation, an event-triggered communication scheme is first proposed to effectively schedule information transmission over the network possibly subject to malicious attacks. In this communication framework, synchronous and asynchronous updated strategies of control protocols are constructed to achieve leader-following consensus in the presence of DoS attacks. Moreover, to further reduce the cost induced by event detection, a self-triggered communication scheme is proposed in which the next triggering instant can be determined by computing with the most updated information. Finally, a numerical example is provided to verify the effectiveness of the proposed communication schemes and updated strategies in the unreliable network environment.
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http://dx.doi.org/10.1109/TNNLS.2018.2890119DOI Listing
October 2019