Statistical Methods for Integrated Cancer Genomic Data Using a Joint Latent Variable Model

Inspired by the TCGA (The Cancer Genome Atlas), we explore multimodal genomic datasets with integrative methods using a joint latent variable approach. We use iCluster+, an existing clustering method for integrative data, to identify potential subtypes within TCGA sarcoma and mesothelioma tumors, and across a large cohort of 33 dierent TCGA cancer datasets. For classication, motivated to improve the prediction of platinum resistance in high grade serous ovarian cancer (HGSOC) treatment, we propose novel integrative methods, iClassify to perform classication using a joint latent variable model. iClassify provides eective data integration and classication while handling heterogeneous data types, while providing a natural framework to incorporate covariate risk factors and examine genomic driver by covariate risk factor interaction. Feature selection is performed through a thresholding parameter that combines both latent variable and feature coecients. We demonstrate increased accuracy in classication over methods that assume homogeneous data type, such as linear discriminant analysis and penalized logistic regression, and improved feature selection. We apply iClassify to a TCGA cohort of HGSOC patients with three types of genomic data and platinum response data. This methodology has broad applications beyond predicting treatment outcomes and disease progression in cancer, including predicting prognosis and diagnosis in other diseases with major public health implications

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Can Genetic Pleiotropy Replicate Common Clinical Constellations of Cardiovascular Disease and Risk?

<div><p>The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD) is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions from the NHGRI genome-wide association study (GWAS) catalog, in an attempt to replicate the established notion of shared pathophysiology and risk. We used pathway-based analyses to detect subsets of pleiotropic genes involved in similar biological processes. We identified 107 eligible GWAS studies related to CVD and its established comorbidities and risk factors and assigned genes that correspond to the associated signals based on their position. We found 44 positional genes shared across at least two CVD-related phenotypes that independently recreated the established relationship between the six phenotypes, but only if studies representing non-European populations were included. Seven genes revealed pleiotropy across three or more phenotypes, mostly related to lipid transport and metabolism. Yet, many genes had no relationship to each other or to genes with established functional connection. Whilst we successfully reproduced established relationships between CVD risk factors using GWAS findings, interpretation of biological pathways involved in the observed pleiotropy was limited. Further studies linking genetic variation to gene expression, as well as describing novel biological pathways will be needed to take full advantage of GWAS results.</p> </div

Number of studies, SNPs and genes by phenotype for all eligible studies.

*<p>includes a 4-SNP haplotype.</p

List of genes from all studies that showed three-way and four-way overlaps across CVD-related phenotypes.

<p>BP, blood pressure; CAD, coronary artery disease, T2D, type 2 diabetes.</p

A plot of 38 positional genes that overlapped between at least two CVD-related phenotypes.

<p>Plotted using VIZ-GRAIL <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046419#pone.0046419-Raychaudhuri2" target="_blank">[28]</a>. For each plot, phenotypic overlap is arranged along the outer circle; bold indicates three-way or four-way overlaps. Inner circle represents individual genes. The redness and thickness of lines connecting pairs of genes represent the strength of the connections with the thickness of the lines being inversely proportional to the probability that a literature-based connection would be seen by chance. Pathway-related links between 9 of 38 genes scored <i>P</i><0.05 using GRAIL. To accurately assess the statistical significance of this set of connections, we conducted simulations in which we selected 100 sets of 38 genes and scored them with GRAIL. We determined that the likelihood of observing 9 hits with P<0.05 by chance is about 7%.</p

Similar Incidence of Typhlitis in Patients Receiving Various Doses of Daunorubicin or Idarubicin as Induction for Acute Myeloid Leukemia

BACKGROUND: The current standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) is an anthracycline plus cytarabine. Both anthracyclines and cytarabine have been associated with the development of typhlitis, a serious adverse event characterized by inflammation of the bowel wall in patients with profound neutropenia, diagnosed by abdominal CT imaging and clinical symptoms. Given the paucity of available data, the aim of our study was to determine the incidence of typhlitis among AML patients receiving induction chemotherapy with idarubicin 12 mg/m METHODS: Adult patients with AML or MDS receiving either daunorubicin or idarubicin along with cytarabine as part of their induction regimen between January 1, 2009 and June 30, 2013 were included. A definition of typhlitis required CT confirmation of inflammation of the cecum only, defined as non-tumoral bowel wall thickening with or without pericolonic fat infiltration and fluid, according to CTCAE version 4.03 along with clinical symptoms. The primary endpoint was to determine the incidence of typhlitis among IDA, DNA60, and DNA90. Secondary endpoints included characterizing the variability of doses used in induction therapy and identifying any potential risk factors for the development of typhlitis. RESULTS: The overall incidence of typhlitis was 2.5%. When the definition was broadened to include the colitis, enteritis, or enterocolitis, the incidence increased. The inter-reliability ratings of the 2 radiologists\u27 evaluations for each definition indicated substantial agreement (0.803 cecum, 0.834 ileocecal region only, and 0.752 enterocolitis). Neither the anthracycline chosen, nor the dose had a statistically significant impact on the incidence of typhlitis. In patients that developed typhlitis, all patients had clinical symptoms in addition to documented cecum inflammation on CT scan. All patients were managed conservatively with intravenous broad-spectrum antibiotics. CONCLUSION: To our knowledge, this is the first study to compare the incidence of typhlitis in adult patients receiving idarubicin or daunorubicin for the treatment of AML. The cumulative incidence of typhlitis was similar to the currently published literature, with the incidence being similar irrespective of the anthracycline chosen or dose. All patients were managed conservatively with broad-spectrum antibiotics. A more definitive definition of typhlitis may help clinicians identify affected patients sooner and choose appropriate targeted therapy

Similar incidence of typhlitis in patients receiving various doses of daunorubicin or idarubicin as induction for acute myeloid leukemia

BACKGROUND: The current standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) is an anthracycline plus cytarabine. Both anthracyclines and cytarabine have been associated with the development of typhlitis, a serious adverse event characterized by inflammation of the bowel wall in patients with profound neutropenia, diagnosed by abdominal CT imaging and clinical symptoms. Given the paucity of available data, the aim of our study was to determine the incidence of typhlitis among AML patients receiving induction chemotherapy with idarubicin 12 mg/m METHODS: Adult patients with AML or MDS receiving either daunorubicin or idarubicin along with cytarabine as part of their induction regimen between January 1, 2009 and June 30, 2013 were included. A definition of typhlitis required CT confirmation of inflammation of the cecum only, defined as non-tumoral bowel wall thickening with or without pericolonic fat infiltration and fluid, according to CTCAE version 4.03 along with clinical symptoms. The primary endpoint was to determine the incidence of typhlitis among IDA, DNA60, and DNA90. Secondary endpoints included characterizing the variability of doses used in induction therapy and identifying any potential risk factors for the development of typhlitis. RESULTS: The overall incidence of typhlitis was 2.5%. When the definition was broadened to include the colitis, enteritis, or enterocolitis, the incidence increased. The inter-reliability ratings of the 2 radiologists\u27 evaluations for each definition indicated substantial agreement (0.803 cecum, 0.834 ileocecal region only, and 0.752 enterocolitis). Neither the anthracycline chosen, nor the dose had a statistically significant impact on the incidence of typhlitis. In patients that developed typhlitis, all patients had clinical symptoms in addition to documented cecum inflammation on CT scan. All patients were managed conservatively with intravenous broad-spectrum antibiotics. CONCLUSION: To our knowledge, this is the first study to compare the incidence of typhlitis in adult patients receiving idarubicin or daunorubicin for the treatment of AML. The cumulative incidence of typhlitis was similar to the currently published literature, with the incidence being similar irrespective of the anthracycline chosen or dose. All patients were managed conservatively with broad-spectrum antibiotics. A more definitive definition of typhlitis may help clinicians identify affected patients sooner and choose appropriate targeted therapy