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Microbial trend analysis for common dynamic trend, group comparison, and classification in longitudinal microbiome study

Wang, Chan; Hu, Jiyuan; Blaser, Martin J; Li, Huilin
BACKGROUND:The human microbiome is inherently dynamic and its dynamic nature plays a critical role in maintaining health and driving disease. With an increasing number of longitudinal microbiome studies, scientists are eager to learn the comprehensive characterization of microbial dynamics and their implications to the health and disease-related phenotypes. However, due to the challenging structure of longitudinal microbiome data, few analytic methods are available to characterize the microbial dynamics over time. RESULTS:We propose a microbial trend analysis (MTA) framework for the high-dimensional and phylogenetically-based longitudinal microbiome data. In particular, MTA can perform three tasks: 1) capture the common microbial dynamic trends for a group of subjects at the community level and identify the dominant taxa; 2) examine whether or not the microbial overall dynamic trends are significantly different between groups; 3) classify an individual subject based on its longitudinal microbial profiling. Our extensive simulations demonstrate that the proposed MTA framework is robust and powerful in hypothesis testing, taxon identification, and subject classification. Our real data analyses further illustrate the utility of MTA through a longitudinal study in mice. CONCLUSIONS:The proposed MTA framework is an attractive and effective tool in investigating dynamic microbial pattern from longitudinal microbiome studies.
PMID: 34525957
ISSN: 1471-2164
CID: 5012392

AGE/RAGE/DIAPH1 axis is associated with immunometabolic markers and risk of insulin resistance in subcutaneous but not omental adipose tissue in human obesity

Ruiz, Henry H; Nguyen, Anh; Wang, Chan; He, Linchen; Li, Huilin; Hallowell, Peter; McNamara, Coleen; Schmidt, Ann Marie
BACKGROUND/OBJECTIVES/OBJECTIVE:The incidence of obesity continues to increase worldwide and while the underlying pathogenesis remains largely unknown, nutrient excess, manifested by "Westernization" of the diet and reduced physical activity have been proposed as key contributing factors. Western-style diets, in addition to higher caloric load, are characterized by excess of advanced glycation end products (AGEs), which have been linked to the pathophysiology of obesity and related cardiometabolic disorders. AGEs can be "trapped" in adipose tissue, even in the absence of diabetes, in part due to higher expression of the receptor for AGEs (RAGE) and/or decreased detoxification by the endogenous glyoxalase (GLO) system, where they may promote insulin resistance. It is unknown whether the expression levels of genes linked to the RAGE axis, including AGER (the gene encoding RAGE), Diaphanous 1 (DIAPH1), the cytoplasmic domain binding partner of RAGE that contributes to RAGE signaling, and GLO1 are differentially regulated by the degree of obesity and/or how these relate to inflammatory and adipocyte markers and their metabolic consequences. SUBJECTS/METHODS/METHODS:We sought to answer this question by analyzing gene expression patterns of markers of the AGE/RAGE/DIAPH1 signaling axis in abdominal subcutaneous (SAT) and omental (OAT) adipose tissue from obese and morbidly obese subjects. RESULTS:In SAT, but not OAT, expression of AGER was significantly correlated with that of DIAPH1 (n = 16; [Formula: see text], [0.260, 1.177]; q = 0.008) and GLO1 (n = 16; [Formula: see text], [0.364, 1.182]; q = 0.004). Furthermore, in SAT, but not OAT, regression analyses revealed that the expression pattern of genes in the AGE/RAGE/DIAPH1 axis is strongly and positively associated with that of inflammatory and adipogenic markers. Remarkably, particularly in SAT, not OAT, the expression of AGER positively and significantly correlated with HOMA-IR (n = 14; [Formula: see text], [0.338, 1.249]; q = 0.018). CONCLUSIONS:These observations suggest associations of the AGE/RAGE/DIAPH1 axis in the immunometabolic pathophysiology of obesity and insulin resistance, driven, at least in part, through expression and activity of this axis in SAT.
PMID: 34103691
ISSN: 1476-5497
CID: 4903152

Clinical Trial Protocol for a Randomized Trial of Community Health Worker-led Decision Coaching to Promote Shared Decision-making on Prostate Cancer Screening Among Black Male Patients and Their Providers

Makarov, Danil V; Ciprut, Shannon; Martinez-Lopez, Natalia; Fagerlin, Angela; Thomas, Jerry; Shedlin, Michele; Gold, Heather T; Li, Huilin; Bhat, Sandeep; Warren, Rueben; Ubel, Peter; Ravenell, Joseph E
We propose a randomized controlled trial to evaluate the effectiveness of a community health worker-led decision-coaching program to facilitate shared decision-making for prostate cancer screening decisions by Black men at a primary care federally qualified health center.
PMID: 34426097
ISSN: 2405-4569
CID: 5061072

Effect of antibiotic treatment on Oxalobacter formigenes colonization of the gut microbiome and urinary oxalate excretion

Nazzal, Lama; Francois, Fritz; Henderson, Nora; Liu, Menghan; Li, Huilin; Koh, Hyunwook; Wang, Chan; Gao, Zhan; Perez, Guillermo Perez; Asplin, John R; Goldfarb, David S; Blaser, Martin J
The incidence of kidney stones is increasing in the US population. Oxalate, a major factor for stone formation, is degraded by gut bacteria reducing its intestinal absorption. Intestinal O. formigenes colonization has been associated with a lower risk for recurrent kidney stones in humans. In the current study, we used a clinical trial of the eradication of Helicobacter pylori to assess the effects of an antibiotic course on O. formigenes colonization, urine electrolytes, and the composition of the intestinal microbiome. Of 69 healthy adult subjects recruited, 19 received antibiotics for H. pylori eradication, while 46 were followed as controls. Serial fecal samples were examined for O. formigenes presence and microbiota characteristics. Urine, collected serially fasting and following a standard meal, was tested for oxalate and electrolyte concentrations. O. formigenes prevalence was 50%. Colonization was significantly and persistently suppressed in antibiotic-exposed subjects but remained stable in controls. Urinary pH increased after antibiotics, but urinary oxalate did not differ between the control and treatment groups. In subjects not on antibiotics, the O. formigenes-positive samples had higher alpha-diversity and significantly differed in Beta-diversity from the O. formigenes-negative samples. Specific taxa varied in abundance in relation to urinary oxalate levels. These studies identified significant antibiotic effects on O. formigenes colonization and urinary electrolytes and showed that overall microbiome structure differed in subjects according to O. formigenes presence. Identifying a consortium of bacterial taxa associated with urinary oxalate may provide clues for the primary prevention of kidney stones in healthy adults.
PMID: 34385560
ISSN: 2045-2322
CID: 5004452

Maternal cecal microbiota transfer rescues early-life antibiotic-induced enhancement of type 1 diabetes in mice

Zhang, Xue-Song; Yin, Yue Sandra; Wang, Jincheng; Battaglia, Thomas; Krautkramer, Kimberly; Li, Wei Vivian; Li, Jackie; Brown, Mark; Zhang, Meifan; Badri, Michelle H; Armstrong, Abigail J S; Strauch, Christopher M; Wang, Zeneng; Nemet, Ina; Altomare, Nicole; Devlin, Joseph C; He, Linchen; Morton, Jamie T; Chalk, John Alex; Needles, Kelly; Liao, Viviane; Mount, Julia; Li, Huilin; Ruggles, Kelly V; Bonneau, Richard A; Dominguez-Bello, Maria Gloria; Bäckhed, Fredrik; Hazen, Stanley L; Blaser, Martin J
Early-life antibiotic exposure perturbs the intestinal microbiota and accelerates type 1 diabetes (T1D) development in the NOD mouse model. Here, we found that maternal cecal microbiota transfer (CMT) to NOD mice after early-life antibiotic perturbation largely rescued the induced T1D enhancement. Restoration of the intestinal microbiome was significant and persistent, remediating the antibiotic-depleted diversity, relative abundance of particular taxa, and metabolic pathways. CMT also protected against perturbed metabolites and normalized innate and adaptive immune effectors. CMT restored major patterns of ileal microRNA and histone regulation of gene expression. Further experiments suggest a gut-microbiota-regulated T1D protection mechanism centered on Reg3γ, in an innate intestinal immune network involving CD44, TLR2, and Reg3γ. This regulation affects downstream immunological tone, which may lead to protection against tissue-specific T1D injury.
PMID: 34289377
ISSN: 1934-6069
CID: 4948332

Two-dimensional multiplexed assay for rapid and deep SARS-CoV-2 serology profiling and for machine learning prediction of neutralization capacity

Koide, Akiko; Panchenko, Tatyana; Wang, Chan; Thannickal, Sara A; Romero, Larizbeth A; Teng, Kai Wen; Li, Francesca-Zhoufan; Akkappedi, Padma; Corrado, Alexis D; Caro, Jessica; Diefenbach, Catherine; Samanovic, Marie I; Mulligan, Mark J; Hattori, Takamitsu; Stapleford, Kenneth A; Li, Huilin; Koide, Shohei
Antibody responses serve as the primary protection against SARS-CoV-2 infection through neutralization of viral entry into cells. We have developed a two-dimensional multiplex bead binding assay (2D-MBBA) that quantifies multiple antibody isotypes against multiple antigens from a single measurement. Here, we applied our assay to profile IgG, IgM and IgA levels against the spike antigen, its receptor-binding domain and natural and designed mutants. Machine learning algorithms trained on the 2D-MBBA data substantially improve the prediction of neutralization capacity against the authentic SARS-CoV-2 virus of serum samples of convalescent patients. The algorithms also helped identify a set of antibody isotypeâ€"antigen datasets that contributed to the prediction, which included those targeting regions outside the receptor-binding interface of the spike protein. We applied the assay to profile samples from vaccinated, immune-compromised patients, which revealed differences in the antibody profiles between convalescent and vaccinated samples. Our approach can rapidly provide deep antibody profiles and neutralization prediction from essentially a drop of blood without the need of BSL-3 access and provides insights into the nature of neutralizing antibodies. It may be further developed for evaluating neutralizing capacity for new variants and future pathogens.
PMID: 34373852
ISSN: n/a
CID: 5080802

Joint modeling of zero-inflated longitudinal proportions and time-to-event data with application to a gut microbiome study

Hu, Jiyuan; Wang, Chan; Blaser, Martin J; Li, Huilin
Recent studies have suggested that the temporal dynamics of the human microbiome may have associations with human health and disease. An increasing number of longitudinal microbiome studies, which record time to disease onset, aim to identify candidate microbes as biomarkers for prognosis. Owing to the ultra-skewness and sparsity of microbiome proportion (relative abundance) data, directly applying traditional statistical methods may result in substantial power loss or spurious inferences. We propose a novel joint modeling framework [JointMM], which is comprised of two sub-models: a longitudinal sub-model called zero-inflated scaled-Beta generalized linear mixed-effects regression to depict the temporal structure of microbial proportions among subjects; and a survival sub-model to characterize the occurrence of an event and its relationship with the longitudinal microbiome proportions. JointMM is specifically designed to handle the zero-inflated and highly skewed longitudinal microbial proportion data and examine whether the temporal pattern of microbial presence and/or the non-zero microbial proportions are associated with differences in the time to an event. The longitudinal sub-model of JointMM also provides the capacity to investigate how the (time-varying) covariates are related to the temporal microbial presence/absence patterns and/or the changing trend in non-zero proportions. Comprehensive simulations and real data analyses are used to assess the statistical efficiency and interpretability of JointMM. This article is protected by copyright. All rights reserved.
PMID: 34213763
ISSN: 1541-0420
CID: 4950332

Tobacco smoking and the fecal microbiome in a large, multi-ethnic cohort

Prakash, Ajay; Peters, Brandilyn A; Cobbs, Emilia; Beggs, Dia; Choi, Heesun; Li, Huilin; Hayes, Richard B; Ahn, Jiyoung
BACKGROUND:Increasing evidence suggests that tobacco smoking, a well-known driver of carcinogenesis, influences the gut microbiome; however, these relationships remain understudied in diverse populations. Thus, we performed an analysis of smoking and the gut microbiome in a subset of 803 adults from the multi-ethnic NYU FAMiLI study. METHODS:We assessed fecal microbiota using 16S rRNA gene sequencing, and clustered samples into Amplicon Sequence Variants using QIIME2. We evaluated inferred microbial pathway abundance using PICRUSt. We compared population beta diversity, and relative taxonomic and functional pathway abundance, between never smokers, former smokers, and current smokers. RESULTS:We found that the overall composition of the fecal microbiome in former and current smokers differs significantly from that of never smokers. The taxa Prevotella and Veillonellaceae were enriched in current and former smokers, while the taxa Lachnospira and Tenericutes were depleted, relative to never smokers. These shifts were consistent across racial and ethnic subgroups. Relative to never smokers, the abundance of taxa enriched in current smokers were positively correlated with the imputed abundance of pathways involving smoking-associated toxin breakdown and response to reactive oxygen species (ROS). CONCLUSIONS:Our findings suggest common mechanisms of smoking associated microbial change across racial subgroups, regardless of initial microbiome composition. The correlation of these differentials with ROS exposure pathways may suggest a role for these taxa in the known association between smoking, ROS and carcinogenesis. IMPACT/CONCLUSIONS:Smoking shifts in the microbiome may be independent of initial composition, stimulating further studies on the microbiome in carcinogenesis and cancer prevention.
PMID: 34020999
ISSN: 1538-7755
CID: 4888752

Feasibility and Acceptability of mHealth Interventions for Managing Hyperphosphatemia in Patients Undergoing Hemodialysis

St-Jules, David E; Woolf, Kathleen; Goldfarb, David S; Pompeii, Mary Lou; Li, Huilin; Wang, Chan; Mattoo, Aditya; Marcum, Zachary A; Sevick, Mary Ann
OBJECTIVE:The objective of the study was to evaluate the feasibility and acceptability of mobile health (mHealth) phosphorus management programs in hemodialysis (HD) patients. METHODS:Patients receiving thrice-weekly HD who had 3-month average serum phosphorus of >5.5 mg/dL were randomized to one of the three self-directed phosphorus management programs delivered using tablet PCs: (1) educational videos and handouts (Education), (2) education intervention plus mobile self-monitoring with email feedback (Monitoring), or (3) education and monitoring interventions plus social cognitive theory-based behavioral videos (Combined). Feasibility and acceptability were assessed based on enrollment and retention and training needs (feasibility) and adherence to self-monitoring and reported satisfaction (acceptability). RESULTS:Of 312 patients, 56 expressed interest, and 40 were enrolled. The majority of participants (80%) completed the 6-month study; none withdrew for intervention-related reasons. The Monitoring and Combined groups received 44 ± 15 minutes of technology training, which was considered adequate by most (75%). Self-monitoring rates were initially high, with 78% and 71% of the participants recording at least one meal and phosphate binder in week 1, respectively, but decreased over time to 15% and 9% in the final week. Most participants reported that self-monitoring helped them stay motivated (64%), track nutrients (80%), and understand how to change diet (76%), and nearly two-thirds of participants (64%) stated that they would like to continue using the tablet PC to manage their health. However, few participants (16%) indicated that self-monitoring was worth the effort. The Monitoring and Combined groups did not differ from the Education group in study outcomes. CONCLUSION/CONCLUSIONS:Although the mHealth programs were generally well received, self-monitoring rates decreased substantially over time and were unaffected by social cognitive theory-based videos. Self-directed mHealth programs may be a useful adjunct to standard care but should be compared to more resource intensive programs (e.g., involving more "live" contact with a dietitian) to determine overall cost-effectiveness and role in HD care.
PMID: 33160812
ISSN: 1532-8503
CID: 4664642

Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1G93A murine model of amyotrophic lateral sclerosis in a sex-dependent manner

MacLean, Michael; Juranek, Judyta; Cuddapah, Swetha; López-Díez, Raquel; Ruiz, Henry H; Hu, Jiyuan; Frye, Laura; Li, Huilin; Gugger, Paul F; Schmidt, Ann Marie
BACKGROUND:Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology. METHODS:mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord. RESULTS:mice. CONCLUSIONS:murine pathology in male mice and may be relevant in human disease.
PMID: 34130712
ISSN: 1742-2094
CID: 4903542