Evaluation of 18F-nifene binding to α4β2 nicotinic receptors in the rat brain using microPET imaging

MicroPET imaging studies using 18F-nifene, a new positron emission tomography (PET) radiotracer for nicotinic acetylcholinergic receptors (nAChR) α4β2 receptors in rats, have been carried out. Rats were imaged for 90 min after intravenous injection of 18F-nifene (0.8 to 1 mCi), and binding potential (BPND) was measured. 18F-Nifene binding to thalamic and extrathalamic brain regions was consistent with the α4β2 nAChR distribution in the rat brain. Using the cerebellum as a reference, the values for the thalamus varied less than 5% (BPND = 1.30, n = 3), confirming reproducibility of 18F-nifene binding. 18F-Nifene microPET imaging was also used to evaluate effects of nicotine in a group of Sprague-Dawley rats under isoflurane anesthesia. Nicotine challenge postadministration of 18F-nifene demonstrated reversibility of 18F-nifene binding in vivo. For α4β2 nAChR receptor occupancy (nAChROCC), various doses of nicotine (0, 0.02, 0.1, 0.25, and 0.50 mg/kg nicotine free base) 15 min prior to 18F-nifene were administered. Low-dose nicotine (0.02 mg) reached > 80% nAChROCC while at higher doses (0.25 mg) > 90% nAChROCC was measured. The small amount of 18F-nifene binding with reference to the cerebellum affects an accurate evaluation of nAChROCC. Efforts are underway to identify alternate reference regions for 18F-nifene microPET studies in rodents

Organizational Governance of Emerging Technologies: AI Adoption in Healthcare

Private and public sector structures and norms refine how emerging technology is used in practice. In healthcare, despite a proliferation of AI adoption, the organizational governance surrounding its use and integration is often poorly understood. What the Health AI Partnership (HAIP) aims to do in this research is to better define the requirements for adequate organizational governance of AI systems in healthcare settings and support health system leaders to make more informed decisions around AI adoption. To work towards this understanding, we first identify how the standards for the AI adoption in healthcare may be designed to be used easily and efficiently. Then, we map out the precise decision points involved in the practical institutional adoption of AI technology within specific health systems. Practically, we achieve this through a multi-organizational collaboration with leaders from major health systems across the United States and key informants from related fields. Working with the consultancy IDEO.org, we were able to conduct usability-testing sessions with healthcare and AI ethics professionals. Usability analysis revealed a prototype structured around mock key decision points that align with how organizational leaders approach technology adoption. Concurrently, we conducted semi-structured interviews with 89 professionals in healthcare and other relevant fields. Using a modified grounded theory approach, we were able to identify 8 key decision points and comprehensive procedures throughout the AI adoption lifecycle. This is one of the most detailed qualitative analyses to date of the current governance structures and processes involved in AI adoption by health systems in the United States. We hope these findings can inform future efforts to build capabilities to promote the safe, effective, and responsible adoption of emerging technologies in healthcare

Development and Validation of ML-DQA -- a Machine Learning Data Quality Assurance Framework for Healthcare

The approaches by which the machine learning and clinical research communities utilize real world data (RWD), including data captured in the electronic health record (EHR), vary dramatically. While clinical researchers cautiously use RWD for clinical investigations, ML for healthcare teams consume public datasets with minimal scrutiny to develop new algorithms. This study bridges this gap by developing and validating ML-DQA, a data quality assurance framework grounded in RWD best practices. The ML-DQA framework is applied to five ML projects across two geographies, different medical conditions, and different cohorts. A total of 2,999 quality checks and 24 quality reports were generated on RWD gathered on 247,536 patients across the five projects. Five generalizable practices emerge: all projects used a similar method to group redundant data element representations; all projects used automated utilities to build diagnosis and medication data elements; all projects used a common library of rules-based transformations; all projects used a unified approach to assign data quality checks to data elements; and all projects used a similar approach to clinical adjudication. An average of 5.8 individuals, including clinicians, data scientists, and trainees, were involved in implementing ML-DQA for each project and an average of 23.4 data elements per project were either transformed or removed in response to ML-DQA. This study demonstrates the importance role of ML-DQA in healthcare projects and provides teams a framework to conduct these essential activities.Comment: Presented at 2022 Machine Learning in Health Care Conferenc

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

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

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

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