• Clustering of co-occurring conditions in autism spectrum disorder during early childhood: A retrospective analysis of medical claims data

      Vargason, Troy; Frye, Richard E; McGuinness, Deborah L; Hahn, Juergen; Univ Arizona, Coll Med (WILEY, 2019-05-31)
      Individuals with autism spectrum disorder (ASD) are frequently affected by co‐occurring medical conditions (COCs), which vary in severity, age of onset, and pathophysiological characteristics. The presence of COCs contributes to significant heterogeneity in the clinical presentation of ASD between individuals and a better understanding of COCs may offer greater insight into the etiology of ASD in specific subgroups while also providing guidance for diagnostic and treatment protocols. This study retrospectively analyzed medical claims data from a private United States health plan between years 2000 and 2015 to investigate patterns of COC diagnoses in a cohort of 3,278 children with ASD throughout their first 5 years of enrollment compared to 279,693 children from the general population without ASD diagnoses (POP cohort). Three subgroups of children with ASD were identified by k‐means clustering using these COC patterns. The first cluster was characterized by generally high rates of COC diagnosis and comprised 23.7% (n = 776) of the cohort. Diagnoses of developmental delays were dominant in the second cluster containing 26.5% (n = 870) of the cohort. Children in the third cluster, making up 49.8% (n = 1,632) of the cohort, had the lowest rates of COC diagnosis, which were slightly higher than rates observed in the POP cohort. A secondary analysis using these data found that gastrointestinal and immune disorders showed similar longitudinal patterns of prevalence, as did seizure and sleep disorders. These findings may help to better inform the development of diagnostic workup and treatment protocols for COCs in children with ASD. Autism Res 2019, 12: 1272–1285. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.
    • kMEn: Analyzing noisy and bidirectional transcriptional pathway responses in single subjects

      Li, Qike; Schissler, A. Grant; Gardeux, Vincent; Berghout, Joanne; Achour, Ikbel; Kenost, Colleen; Li, Haiquan; Zhang, Hao Helen; Lussier, Yves A.; Univ Arizona, Ctr Biomed Informat & Biostat; et al. (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2017-01-01)
      Motivation: Understanding dynamic, patient-level transcriptomic response to therapy is an important step forward for precision medicine. However, conventional transcriptome analysis aims to discover cohort-level change, lacking the capacity to unveil patient-specific response to therapy. To address this gap, we previously developed two N-of-l-pathways methods, Wilcoxon and Mahalanobis distance, to detect unidirectionally responsive transcripts within a pathway using a pair of samples from a single subject. Yet, these methods cannot recognize bidirectionally (up and down) responsive pathways. Further, our previous approaches have not been assessed in presence of background noise and are not designed to identify differentially expressed mRNAs between two samples of a patient taken in different contexts (e.g. cancer vs non cancer), which we termed responsive transcripts (RTs). Methods: We propose a new N-of-l-pathways method, k-Means Enrichment (kMEn), that detects bidirectionally responsive pathways, despite background noise, using a pair of transcriptomes from a single patient. kMEn identifies transcripts responsive to the stimulus through k-means clustering and then tests for an over-representation of the responsive genes within each pathway. The pathways identified by kMEn are mechanistically interpretable pathways significantly responding to a stimulus. Results: In similar to 9000 simulations varying six parameters, superior performance of kMEn over previous single-subject methods is evident by: (i) improved precision-recall at various levels of bidirectional response and (ii) lower rates of false positives (1-specificity) when more than 10% of genes in the genome are differentially expressed (background noise). In a clinical proof-of-concept, personal treatment specific pathways identified by kMEn correlate with therapeutic response (p-value < 0.01). Conclusion: Through improved single-subject transcriptome dynamics of bidirectionally-regulated signals, kMEn provides a novel approach to identify mechanism-level biomarkers. (C) 2016 Published by Elsevier Inc.