Browsing by Author "Markowitz, James"

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    Analysis of Using the Total White Blood Cell Count to Define Severe New-onset Ulcerative Colitis in Children
    (Wolters Kluwer, 2020-09) Mack, David R.; Saul, Bradley; Boyle, Brendan; Griffiths, Anne; Sauer, Cary; Markowitz, James; LeLeiko, Neal; Keljo, David; Rosh, Joel R.; Baker, Susan S.; Steiner, Steve; Heyman, Melvin B.; Patel, Ashish S.; Baldassano, Robert; Noe, Joshua; Rufo, Paul; Kugathasan, Subra; Walters, Thomas; Marquis, Alison; Thomas, Sonia M.; Denson, Lee; Hyams, Jeffrey; Pediatrics, School of Medicine
    Objectives: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis. Methods: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (<65) and total Mayo score, severe (10-12) versus not severe (<10); mucosal disease by Mayo endoscopic subscore, severe (3) versus not severe (<3); and extensive disease versus not extensive (left-sided and proctosigmoiditis). Results: Mean age was 12.7 years; 49.6% (n = 212) were girls, and 83% (n = 351) were Caucasian. Severe total Mayo score was present in 28% (n = 120), mean PUCAI score was 49.8 ± 20.1, and 33% (n = 142) had severe mucosal disease with extensive involvement in 82% (n = 353). Classification and regression trees identified white blood cell count, erythrocyte sedimentation rate, and platelet count (PLT) as the set of 3 best blood laboratory tests to predict disease extent and severity. For mucosal severity, albumin (Alb) replaced PLT. Classification models for PUCAI and total Mayo provided sensitivity of at least 0.65 using standard clinical cut-points with misclassification rates of approximately 30%. Conclusions: A combination of the white blood cell count, erythrocyte sedimentation rate, and either PLT or albumin is the best predictive subset of standard laboratory tests to identify severe from nonsevere clinical or mucosal disease at diagnosis in relation to objective clinical scores.
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    Association of Baseline Luminal Narrowing With Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease
    (Oxford University Press, 2021) Ta, Allison D.; Ollberding, Nicholas J.; Karns, Rebekah; Haberman, Yael; Alazraki, Adina L.; Hercules, David; Baldassano, Robert; Markowitz, James; Heyman, Melvin B.; Kim, Sandra; Kirschner, Barbara; Shapiro, Jason M.; Noe, Joshua; Oliva-Hemker, Maria; Otley, Anthony; Pfefferkorn, Marian; Kellermayer, Richard; Snapper, Scott; Rabizadeh, Shervin; Xavier, Ramnik; Dubinsky, Marla; Hyams, Jeffrey; Kugathasan, Subra; Jegga, Anil G.; Dillman, Jonathan R.; Denson, Lee A.; Pediatrics, School of Medicine
    Background: Transmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures. Materials and methods: Baseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH. Results: After controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression. Conclusions: Pediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets.
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    Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course
    (Elsevier, 2018-10-10) Schirmer, Melanie; Denson, Lee; Vlamakis, Hera; Franzosa, Eric A.; Thomas, Sonia; Gotman, Nathan M.; Rufo, Paul; Baker, Susan S.; Sauer, Cary; Markowitz, James; Pfefferkorn, Marian; Oliva-Hemker, Maria; Rosh, Joel; Otley, Anthony; Boyle, Brendan; Mack, David; Baldassano, Robert; Keljo, David; LeLeiko, Neal; Heyman, Melvin; Griffiths, Anne; Patel, Ashish S.; Noe, Joshua; Kugathasan, Subra; Walters, Thomas; Huttenhower, Curtis; Hyams, Jeffrey; Xavier, Ramnik J.; Medicine, School of Medicine
    Evaluating progression risk and determining optimal therapy for ulcerative colitis (UC) is challenging as many patients exhibit incomplete responses to treatment. As part of the PROTECT (Predicting Response to Standardized Colitis Therapy) Study, we evaluated the role of the gut microbiome in disease course for 405 pediatric, new-onset, treatment-naive UC patients. Patients were monitored for 1 year upon treatment initiation, and microbial taxonomic composition was analyzed from fecal samples and rectal biopsies. Depletion of core gut microbes and expansion of bacteria typical of the oral cavity were associated with baseline disease severity. Remission and refractory disease were linked to species-specific temporal changes that may be implicative of therapy efficacy, and a pronounced increase in microbiome variability was observed prior to colectomy. Finally, microbial associations with disease-associated serological markers suggest host-microbial interactions in UC. These insights will help improve existing treatments and develop therapeutic approaches guiding optimal medical care
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    Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression
    (Elsevier, 2021) Mo, Angela; Nagpal, Sini; Gettler, Kyle; Haritunians, Talin; Giri, Mamta; Haberman, Yael; Karns, Rebekah; Prince, Jarod; Arafat, Dalia; Hsu, Nai-Yun; Chuang, Ling-Shiang; Argmann, Carmen; Kasarskis, Andrew; Suarez-Farinas, Mayte; Gotman, Nathan; Mengesha, Emebet; Venkateswaran, Suresh; Rufo, Paul A.; Baker, Susan S.; Sauer, Cary G.; Markowitz, James; Pfefferkorn, Marian D.; Rosh, Joel R.; Boyle, Brendan M.; Mack, David R.; Baldassano, Robert N.; Shah, Sapana; LeLeiko, Neal S.; Heyman, Melvin B.; Griffiths, Anne M.; Patel, Ashish S.; Noe, Joshua D.; Davis Thomas, Sonia; Aronow, Bruce J.; Walters, Thomas D.; McGovern, Dermot P.B.; Hyams, Jeffrey S.; Kugathasan, Subra; Cho, Judy H.; Denson, Lee A.; Gibson, Greg; Pediatrics, School of Medicine
    An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
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    Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
    (Springer Nature, 2019-01-03) Haberman, Yael; Karns, Rebekah; Dexheimer, Phillip J.; Schirmer, Melanie; Somekh, Judith; Jurickova, Ingrid; Braun, Tzipi; Novak, Elizabeth; Bauman, Laura; Collins, Margaret H.; Mo, Angela; Rosen, Michael J.; Bonkowski, Erin; Gotman, Nathan; Marquis, Alison; Nistel, Mason; Rufo, Paul A.; Baker, Susan S.; Sauer, Cary G.; Markowitz, James; Pfefferkorn, Marian D.; Rosh, Joel R.; Boyle, Brendan M.; Mack, David R.; Baldassano, Robert N.; Shah, Sapana; Leleiko, Neal S.; Heyman, Melvin B.; Grifiths, Anne M.; Patel, Ashish S.; Noe, Joshua D.; Aronow, Bruce J.; Kugathasan, Subra; Walters, Thomas D.; Gibson, Greg; Thomas, Sonia Davis; Mollen, Kevin; Shen-Orr, Shai; Huttenhower, Curtis; Xavier, Ramnik J.; Hyams, Jeffrey S.; Denson, Lee A.; Pediatrics, School of Medicine
    Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.