Browsing by Author "Wang, Lu"
- Results Per Page
- Sort Options
Item Open Access Bayesian network-response regression.(Bioinformatics, 2017-01-06) Wang, Lu; Durante, Daniele; Jung, Rex E; Dunson, David BMotivation: There is increasing interest in learning how human brain networks vary as a function of a continuous trait, but flexible and efficient procedures to accomplish this goal are limited. We develop a Bayesian semiparametric model, which combines low-rank factorizations and flexible Gaussian process priors to learn changes in the conditional expectation of a network-valued random variable across the values of a continuous predictor, while including subject-specific random effects. Results: The formulation leads to a general framework for inference on changes in brain network structures across human traits, facilitating borrowing of information and coherently characterizing uncertainty. We provide an efficient Gibbs sampler for posterior computation along with simple procedures for inference, prediction and goodness-of-fit assessments. The model is applied to learn how human brain networks vary across individuals with different intelligence scores. Results provide interesting insights on the association between intelligence and brain connectivity, while demonstrating good predictive performance. Availability and Implementation: Source code implemented in R and data are available at https://github.com/wangronglu/BNRR. Contact: rl.wang@duke.edu. Supplementary information: Supplementary data are available at Bioinformatics online.Item Open Access Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.(Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023-11) Liang, Yaosi; Pan, Christopher; Yin, Tao; Wang, Lu; Gao, Xia; Wang, Ergang; Quang, Holly; Huang, De; Tan, Lianmei; Xiang, Kun; Wang, Yu; Alexander, Peter B; Li, Qi-Jing; Yao, Tso-Pang; Zhang, Zhao; Wang, Xiao-FanThe essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.Item Open Access Hijacking Oogenesis Enables Massive Propagation of LINE and Retroviral Transposons(Cell, 2018-08) Wang, Lu; Dou, Kun; Moon, Sungjin; Tan, Frederick J; Zhang, ZZ ZhaoItem Open Access IPMDS-Sponsored Scale Translation Program: Process, Format, and Clinimetric Testing Plan for the MDS-UPDRS and UDysRS(Movement Disorders Clinical Practice, 2014-06-01) Goetz, Christopher G; Stebbins, Glenn T; Wang, Lu; LaPelle, Nancy R; Luo, Sheng; Tilley, Barbara CWe present the methodology and results of the clinimetric testing program for non-English translations of International Parkinson and Movement Disorder Society (MDS)–sponsored scales. The programs focus on the MDS revision of the UPDRS (MDS-UPDRS) and the Unified Dyskinesia Rating Scale (UDysRS). The original development teams of both the MDS-UPDRS and UDysRS envisioned official non-English translations and instituted a rigorous translation methodology. The formal process includes five core steps: (1) registration and start-up; (2) translation and independent back-translation; (3) cognitive pretesting to establish that the translation is clear and that it is comfortably administered to and completed by native-speaker raters and patients; (4) field testing in the native language using a large sample of Parkinson's disease patients; and (5) full clinimetric testing. To date, the MDS-UPDRS has 21 active language programs. Nine official translations are available, having completed all phases successfully, and the others are in different stages of development. For the UDysRS, 19 programs are active, with three official translations now available and the rest in development at different stages. Very few scales in neurology and none in movement disorders have fully validated translations, and this model may be adopted or modified by other scale programs to allow careful validation of translations. Having validated translations allows for maximal homogeneity of tools utilized in multicenter research or clinical trial programs.Item Open Access Irritable Bowel Syndrome and Quality of Life in Women With Fecal Incontinence.(Female Pelvic Med Reconstr Surg, 2017-08-01) Markland, Alayne D; Jelovsek, J Eric; Rahn, David D; Wang, Lu; Merrin, Leah; Tuteja, Ashok; Richter, Holly E; Meikle, Susan; Pelvic Floor Disorders NetworkOBJECTIVES: The objectives of this work were to determine the prevalence of irritable bowel syndrome (IBS) and IBS subtypes in women presenting for fecal incontinence (FI) treatment and to assess the impact of IBS on FI symptoms and quality of life (QOL). METHODS: In this multicenter prospective cohort study, women reported at least monthly solid, liquid, or mucus FI. Rome III clinical criteria defined IBS. Women also self-reported having an IBS diagnosis. Baseline questionnaires included the following: Modified Manchester Health Questionnaire, Fecal Incontinence Severity Index, Bristol Stool Scale, Pelvic Floor Distress Inventory, and the Pelvic Floor Impact Questionnaire. RESULTS: Of the 133 women enrolled, 119 completed Rome III IBS questionnaires, and 111 reported on whether they had a previous diagnosis of IBS. The prevalence of IBS was 31% (95% confidence interval [CI], 22.9%-40.2%) according to the Rome III IBS criteria. The most common subtypes were IBS-mixed (41%) and IBS-diarrhea (35%). Twenty-four (22%) of 111 patients had a previous diagnosis of IBS. Among women who met Rome III IBS criteria, 23 (66%) of 35 women had never had a diagnosis of IBS. Women with FI and IBS reported significantly worse QOL compared to women without IBS despite similar FI severity and stool consistency. CONCLUSIONS: Irritable bowel syndrome negatively affects QOL and affects one third of women with FI presenting for care in tertiary centers. Our findings suggest that assessment of IBS symptoms and diagnosis may be important for women presenting for FI treatment.Item Open Access Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial.(The Lancet. Infectious diseases, 2023-05) Lyke, Kirsten E; Berry, Andrea A; Mason, Kaitlin; Idris, Azza H; O'Callahan, Mark; Happe, Myra; Strom, Larisa; Berkowitz, Nina M; Guech, Mercy; Hu, Zonghui; Castro, Mike; Basappa, Manjula; Wang, Lu; Low, Kwang; Holman, LaSonji A; Mendoza, Floreliz; Gordon, Ingelise J; Plummer, Sarah H; Trofymenko, Olga; Strauss, Kathleen S; Joshi, Sudhaunshu; Shrestha, Biraj; Adams, Matthew; Chagas, Andrezza Campos; Murphy, Jittawadee R; Stein, Judy; Hickman, Somia; McDougal, Andrew; Lin, Bob; Narpala, Sandeep R; Vazquez, Sandra; Serebryannyy, Leonid; McDermott, Adrian; Gaudinski, Martin R; Capparelli, Edmund V; Coates, Emily E; Wu, Richard L; Ledgerwood, Julie E; Dropulic, Lesia K; Seder, Robert A; VRC 612 Part C Study TeamBackground
Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS.Methods
VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18-50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7-18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332.Findings
Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection.Interpretation
CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases.Funding
National Institute of Allergy and Infectious Diseases, National Institutes of Health.Item Open Access Statistical Modeling of Brain Network Data(2018) Wang, LuThere has been an increasing interest in using brain imaging technologies to better understand the relationship between brain structural connectivity networks -- also known as connectomes -- and human traits, ranging from cognitive abilities to neurological disorders. The brain network for an individual corresponds to a set of interconnections among anatomical regions in the brain. Modern neuroimaging technology allows a very fine segmentation of the brain, producing very large structural brain networks. Therefore, dimensionality reduction and feature extraction for such large complex networks become crucial. We first focus on the problem of studying shared- and individual-specific structure in brain networks or replicated graph data. We proposed Multiple GRAph Factorization (M-GRAF) model to estimate a common structure and low-dimensional individual-specific deviations from replicated graphs, which relies on a logistic regression mapping combined with a hierarchical eigenvalue decomposition. We develop an efficient algorithm for estimation and study basic properties of our approach. Application of our method to human brain connectomics data provides better prediction and goodness-of-fit (in terms of topological properties) to brain networks than some popular dimension-reduction methods.
To relate brain connectivity pattern with human cognitive traits, there is a strong need for accurate and efficient statistical methods on learning a set of small outcome-relevant subgraphs in network-predictor regression, which can greatly improve the interpretation of the association between the network predictor and the response. For example in brain connectomics, the extracted signal subgraphs can lead to discovery of key interconnected brain regions related to the trait and important insights on the mechanism of variation in human cognitive traits. We propose a symmetric bilinear model with $L_1$ penalty to search for small clique subgraphs that contain useful information about the response. A coordinate descent algorithm is developed to estimate the model where we derive analytical solutions for a sequence of conditional convex optimizations. Application of this method on human connectome and language comprehension data shows interesting discovery of relevant interconnections among several small sets of brain regions and better predictive performance than competitors.
Another possible formulation to tackle the problem of interest is by taking the connectivity network as the response and learning how human brain networks vary as a function of a continuous trait. We develop a Bayesian semiparametric model, which combines low-rank factorizations and flexible Gaussian process priors to learn changes in the conditional expectation of a network-valued random variable across the values of a continuous predictor, while including subject-specific random effects. The formulation leads to a general framework for inference on changes in brain network structures across human traits, facilitating borrowing of information and coherently characterizing uncertainty. We provide an efficient Gibbs sampler for posterior computation along with simple procedures for inference, prediction and goodness-of-fit assessments. The model is applied to learn how human brain networks vary across individuals with different intelligence scores. Results provide interesting insights on the association between intelligence and brain connectivity, while demonstrating good predictive performance.