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Gene set correlation enrichment analysis for interpreting and annotating gene expression profiles

Nucleic Acids Research 2024年第3期52卷 E17页

作者： Chang, Lan-Yun Lee, Meng-Zhan Wu, Yujia Lee, Wen-Kai Ma, Chia-Liang Chang, Jun-Mao Chen, Ciao-Wen Huang, Tzu-Chun Lee, Chia-Hwa Lee, Jih-Chin Tseng, Yu-Yao Lin, Chun-Yu Institute of Bioinformatics and Systems Biology National Yang Ming Chiao Tung University Hsinchu 300 Taiwan School of Medical Laboratory Science and Biotechnology College of Medical Science and Technology Taipei Medical University New Taipei City 235 Taiwan Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) National Yang Ming Chiao Tung University Hsinchu 300 Taiwan TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei 110 Taiwan Ph.D. Program in Medical Biotechnology College of Medical Science and Technology Taipei Medical University New Taipei City 235 Taiwan Department of Otolaryngology-Head and Neck Surgery Tri-Service General Hospital National Defense Medical Center Taipei 110 Taiwan Department of Food Science Nutrition and Nutraceutical Biotechnology Shih Chien University Taipei 104 Taiwan Department of Biological Science and Technology National Yang Ming Chiao Tung University Hsinchu 300 Taiwan Cancer and Immunology Research Center National Yang Ming Chiao Tung University Taipei 112 Taiwan Institute of Data Science and Engineering National Yang Ming Chiao Tung University Hsinchu 300 Taiwan School of Dentistry Kaohsiung Medical University Kaohsiung 807 Taiwan

Pathway analysis, including nontopology-based (non-TB) and topology-based (TB) methods, is widely used to interpret the biological phenomena underlying differences in expression data between two phenotypes. By considering dependencies and interactions between genes, TB methods usually perform better than non-TB methods in identifying pathways that include closely relevant or directly causative genes for a given phenotype. However, most TB methods may be limited by incomplete pathway data used as the reference network or by difficulties in selecting appropriate reference networks for different research topics. Here, we propose a gene set correlation enrichment analysis method, Gscore, based on an expression dataset-derived coexpression network to examine whether a differentially expressed gene (DEG) list (or each of its DEGs) is associated with a known gene set. Gscore is better able to identify target pathways in 89 human disease expression datasets than eight other state-of-the-art methods and offers insight into how disease-wide and pathway-wide associations reflect clinical outcomes. When applied to RNA-seq data from COVID-19-related cells and patient samples, Gscore provided a means for studying how DEGs are implicated in COVID-19-related pathways. In summary, Gscore offers a powerful analytical approach for annotating individual DEGs, DEG lists, and genome-wide expression profiles based on existing biological knowledge. © 2024 Oxford University Press. All rights reserved.

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PATHOLOGY RESIDENT EXPERIENCE USING A LOW-COST 3D PRINTED MICROSCOPE FOR PORTABLE DIGITAL PATHOLOGY

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Journal of Pathology Informatics 2022年 13卷 100043-100043页

作者： Williamson, Drew F.K. Chen, Tiffany Y. Mahmood, Faisal Department of Pathology Brigham and Women’s Hospital and Harvard Medical School Boston Massachusetts United States Cancer Program Broad Institute of Harvard and MIT Cambridge Massachusetts United States Department of Biomedical Informatics Harvard Medical School Boston Massachusetts United States Cancer Data Science Program Dana-Farber Cancer Institute Boston Massachusetts United States

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Development and Evaluation of a Process to Link cancer Patients in the SEER Registries to National Medicaid Enrollment data

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Journal of the National cancer Institute - Monographs 2020年第55期2020卷 89-95页

作者： Warren, Joan L. Benner, Suzie Stevens, Jennifer Enewold, Lindsey Huang, Bin Zhao, Lirong Tilahun, Negussie Bradley, Cathy J. Healthcare Assessment Research Branch Healthcare Delivery Research Program Division of Cancer Control and Population Science National Cancer Institute Bethesda MD United States Fu Associates Ltd Arlington VA United States Information Management Services Calverton MD United States Department of Biostatistics College of Public Health Markey Cancer Center University of Kentucky Lexington KY United States Division of Data Research and Analytic Methods Center for Medicare and Medicaid Innovation Centers for Medicare and Medicaid Services Baltimore MD United States Department of Health Systems Management and Policy School of Public Health University of Colorado Aurora CO United States

cancer patients receiving Medicaid have worse prognosis. Patients in 14 Surveillance, Epidemiology, and End Results (SEER) cancer registries were linked to national Medicaid enrollment files, 2006-2013, to determine enrollment status during the year before and after diagnosis. A deterministic algorithm based on Social Security number, Medicare Health Insurance Claim number, sex, and date of birth was utilized. Results were compared with an independent linkage of Kentucky-based SEER and Medicaid data. A total 559 484 cancer cases were linked to national Medicaid enrollment files, representing 15-17% of persons with cancer yearly. About 60% of these cases were a complete match on all variables. There was 99% agreement on enrollment status compared with the Kentucky linked data. SEER data were successfully linked to national Medicaid enrollment data. NCI will make the linked data available to researchers, allowing for more detailed assessments of the impact Medicaid enrollment has on cancer diagnosis and outcomes. © 2020 Published by Oxford University Press. This work is written by US Government employees and is in the public domain in the US.

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Deep learning-based computational pathology predicts origins for cancers of unknown primary

arXiv

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arXiv 2020年

作者： Lu, Ming Y. Zhao, Melissa Shady, Maha Lipkova, Jana Chen, Tiffany Y. Williamson, Drew F.K. Mahmood, Faisal Department of Pathology Brigham and Women’s Hospital Harvard Medical School BostonMA United States Department of Biomedical Informatics Harvard Medical School BostonMA United States Cancer Program Broad Institute of Harvard and MIT CambridgeMA United States Cancer Data Science Program Dana-Farber Cancer Institute BostonMA United States

cancer of unknown primary (CUP) is an enigmatic group of diagnoses where the primary anatomical site of tumor origin cannot be determined1,2. This poses a significant challenge, since modern therapeutics such as chemotherapy regimen and immune checkpoint inhibitors are specific to the primary tumor3. Patients with a CUP diagnosis routinely undergo an extensive diagnostic work-up of pathology, radiology, endoscopy, laboratory tests, and clinical correlation in an attempt to determine the primary origin. Such exploration is not only time and resource consuming, but it might significantly delay administration of the suitable treatment. Despite extensive diagnostic work-ups the primary may never be determined in many cases. Recent work has focused on using genomics and transcriptomics for identification of tumor origins4–6. However, genomic testing is not conducted for every patient and lacks clinical penetration in low resource settings. Herein, to overcome these challenges, we present a deep learning-based computational pathology algorithm-TOAD-that can provide a differential diagnosis for CUP using routinely acquired histology slides. We used 17,486 gigapixel whole slide images with known primaries spread over 18 common origins to train a multi-task deep model to simultaneously identify the tumor as primary or metastatic and predict its site of origin. We tested our model on an internal test set of 4,932 cases with known primaries and achieved a top-1 accuracy of 0.84, a top-3 accuracy of 0.94 while on our external test set of 662 cases from 202 different hospitals, it achieved a top-1 and top-3 accuracy of 0.79 and 0.93 respectively. We further curated a dataset of 717 CUP cases from 151 different medical centers and identified a subset of 290 cases for which a differential diagnosis was assigned. Our model predictions resulted in concordance for 50% of cases (κ=0.4 when adjusted for agreement by chance) and a top-3 agreement of 75%. Our proposed method can be used

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Barriers to Allogeneic Stem Cell Transplant in Patients with Malignant and Non-Malignant Hematologic Conditions

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Transplantation and Cellular Therapy 2025年第2期31卷 S359-S359页

作者： Burkart, Madelyn, MD Jabir, Abdur Rahman, MD Guasch, Sara Alicia, MD Isom, Scott, MS Jennings, Mrs. Rebecca, MSN, RN, BMTCN, OCN Grunwald, Michael Richard, MD Pang, Yifan, MD Howard, Dianna S., MD Wofford, Anne, MD Atrium health Wake Forest Baptist Comprehensive Cancer Center Winston Salem NC Department of Internal Medicine Atrium Health Wake Forest Baptist Medical Center Winston Salem NC Biostatistics and Data Science Atrium Health Wake Forest Baptist Comprehensive Cancer Center Winston Salem NC BMT Quality Atrium Health Wake Forest Baptist Winston Salem NC Department of Hematologic Oncology and Blood Disorders Atrium Health Levine Cancer Institute Charlotte NC Atrium Health Levine Cancer Institute Charlotte NC Stem Cell Transplant and Cellular Therapy Program Atrium Health Wake Forest Baptist Comprehensive Cancer Center Winston Salem NC Atrium Health Wake Forest Baptist Comprehensive Cancer Center Winston Salem NC

BackgroundAllogeneic stem cell transplant (HSCT) is a curative modality for many hematological conditions. Several advances have contributed to significant improvement of transplant accessibility including reduced intensity conditioning regimens and use of alternative donors. However, given the complexity of and need for specialized care there are still numerous barriers to HSCT. We explore these barriers in patients (pts) referred for HSCT at our center and present descriptive data, including disease and social characteristics, on the first 98 pts of our cohort. MethodsThis is a retrospective review of pts (age >/= 18 years) with malignant and non-malignant hematologic conditions referred for HSCT at Atrium Health Wake Forest Baptist Comprehensive cancer Center during 2017- 2022 to query what factors influenced rates of HSCT. Barriers examined include comorbidities, age, psychosocial barriers, caregiver support, donor availability, pt preference, progression of disease (POD), death and other. ResultsTable 1 shows pt characteristics; 40 received HSCT, 55% were male, 78% were non-Hispanic white. Median age was 59.5 years. 65% of pts had a diagnosis of acute leukemia. Most pts were referred in first CR; this did not differ in HSCT and non-HSCT pts (67.5% vs 53.4%). There was no significant difference in sex, race/ethnicity, payer source, marital status or neighborhood deprivation using the national Area Deprivation Index between the two groups. The main barriers to HSCT included comorbidities (22.4%), pt preference (22.4%) and POD (12.1%). Overall, 44 pts died; 34 did not receive an HSCT with 68% of deaths due to relapsed disease. OS was worse in non-HSCT pts compared to HSCT recipients at 1 year (82% vs 97%), 2 years (62% vs 87%) and 3 years (47% vs 75%). DiscussionPt preference and comorbidities were the main barriers to HSCT, with psychosocial barriers, caregiver support and donor availability playing a lesser role. This emphasizes the need for multidisciplinary ap

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AI-BASED FAST AND SCALABLE IMAGE SEARCH FOR RARE DISEASE DIAGNOSIS

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Journal of Pathology Informatics 2022年 13卷 100046-100046页

作者： Chen, Chengkuan Lu, Ming Y. Williamson, Drew F.K. Chen, Tiffany Y. Schaumberg, Andrew J. Mahmood, Faisal Department of Pathology Brigham and Women’s Hospital Harvard Medical School Boston MA USA Cancer Program Broad Institute of Harvard and MIT Cambridge MA USA Cancer Data Science Dana-Farber Cancer Institute Boston MA USA Department of Biomedical Informatics Harvard Medical School Boston MA USA

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Suboptimal Engraftment and Toxicity after Post-Transplant Cyclophosphamide

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Transplantation and Cellular Therapy 2025年第2期31卷 S141-S142页

作者： Scarpetti, Lauren, MD Kim, Haesook T., PhD Ikeda, Daniel Collier, Kerry Chung, Jooho DeFilipp, Zachariah, MD El-Jawahri, Areej R., MD Frigault, Matthew J., MD McAfee, Steven L., MD Newcomb, Richard Andrew, MD Spitzer, Thomas R, MD Westervelt, Peter O'Donnell, Paul Chen, Yi-Bin, MD Hematopoetic Cell Transplant & Cell Therapy Program Massachusetts General Hospital Boston MA Department of Data Science Dana-Farber Cancer Institute Harvard School of Public Health Boston MA Massachusetts General Hospital Boston MA Hematopoietic Cell Transplant & Cell Therapy Program Massachusetts General Hospital Boston MA Hematopoietic Cell Transplant and Cellular Therapy Program Massachusetts General Hospital Boston MA Medicine Division of Hematology & Oncology Massachusetts General Hospital Boston MA Blood and Marrow Transplant Program Massachusetts General Hospital Boston MA Hematopoietic Cell Transplant and Cell Therapy Program Massachusetts General Hospital Boston MA

BackgroundPost-transplant cyclophosphamide (PTCy) after hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) is increasingly considered standard. We conducted a single-center retrospective cohort study to evaluate suboptimal engraftment (SE) and toxicity after PTCy. MethodsPatients receiving PTCy from Feb 2016 to Apr 2023 were included. Exclusion criteria were history of aplasia after chimeric antigen receptor T-cell therapy, prior HCT complicated by graft failure and 2 nd HCT. The primary objective was to define the incidence of specific early events defined as suboptimal engraftment (SE): primary or secondary graft failure, death before neutrophil (NE) or platelet engraftment and NE 3 21 days. The secondary objective was identification of clinical factors associated with SE including early organ toxicity. Results170 patients met eligibility criteria. HCT was most often for acute myeloid leukemia (AML; 38%) and myelodysplastic syndrome (MDS; 12%). Patients received reduced intensity (60%), non-myeloablative (24%), and myeloablative (17%) conditioning. Grafts were haploidentical (49%), mismatched unrelated (30%), matched unrelated (13%) and matched related (8%). Most grafts were peripheral blood progenitor cells (86%). Median follow-up for survivors was 47 months. 35 patients (21%) experienced an SE event. 5 (3%) patients had primary graft failure, and 4 (2%) had secondary graft failure. 6 (4%) died before NE: 3 from infection, 2 from renal failure, and 1 from cirrhosis. Median time to NE was 16 days (12-29). 19 patients achieved NE ≥ 21 days after HCT (11% of all NE). 4 (2%) died before platelet engraftment - 2 also had delayed NE. Median time to platelet engraftment was 25 days (10-194). Univariable analysis showed age ≥ 70 (OR 2.58, p = 0.044) and diagnosis of MDS (OR 3.03, p = 0.044) were significantly associated with SE. Myeloablative conditioning was protective against SE (OR 0.118, p = 0.039). When analysis was restricted to AM

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Tumor-Intrinsic and Immune Predictors of Response to Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

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Blood 2024年 144卷 1928-1928页

作者： Michelle P. Aranha Omar Nadeem Robert A. Redd Michael Timonian Sophie Magidson Elizabeth D. Lightbody Jean-Baptiste Alberge Ting Wu Junko Tsuji Luca Bertamini Ankit K. Dutta Habib El-Khoury Mark Bustoros Jacob Laubach Giada Bianchi Elizabeth K. O'Donnell Kenneth C. Anderson Gad Getz Lorenzo Trippa Paul G. Richardson Irene Ghobrial Broad Institute of MIT and Harvard Cambridge MA Dana-Farber Cancer Institute Boston MA Harvard Medical School Boston MA Center for Early Detection and Interception of Blood Cancers Dana-Farber Cancer Institute Boston MA Department of Data Science Dana-Farber Cancer Institute Boston MA Division of Hematology & Medical Oncology Weill Cornell Medicine/New York Presbyterian Hospital New York NY Amyloidosis Program Division of Hematology Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston MA

Background Early treatment of patients with high-risk smoldering myeloma (HRSMM) has been shown to delay progression to multiple myeloma (MM), but not all patients respond well. Identifying biological predictors of response and resistance to treatment can help optimize treatment selection for patients and improve outcomes. Here, we identify tumor and immune biomarkers of response to ixazomib, lenalidomide, and dexamethasone treatment (I-PRISM study) that can be measured at diagnosis. Methods We performed single-cell RNA sequencing (scRNAseq), coupled with B cell receptor and T cell receptor sequencing, on CD138+ tumor and CD138- immune cells as well as whole genome sequencing (WGS) on tumor cells from the bone marrow of 22 HRSMM patients (14 biochemical progressors, 8 non-progressors) enrolled in the I-PRISM study and 11 healthy donors . Among progressors, 5 patients went on to develop myeloma by the SLiM-CRAB criteria . Results The median time to biochemical progression was 33 months and the median follow-up for non-progressors was 48 months. 35 patients were successfully cytogenetically classified by FISH; in the remaining patients (n=10), we inferred the presence of IgH translocations and copy number variants (CNVs) using scRNAseq and WGS. Translocations and CNVs inferred from scRNAseq showed excellent concordance with WGS data, suggesting that scRNAseq-based cytogenetic classification is reliable. Notably, scRNAseq identified additional CNVs (n=7) that were missed by FISH, highlighting its greater sensitivity. No significant association was observed between cytogenetics and response to treatment. Differential expression analysis of tumor cells identified by BCRseq revealed higher MHC-I gene expression in non-progressors compared to progressors, suggesting a potential link between MHC-I expression and response to therapy. We validated this observation using data from the PADIMAC study, where MM patients were treated with a different proteasome inhibitor (PI; Bort

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A randomized phase 2 study of neratinib with or without fulvestrant for patients with HER2-positive, estrogen receptor-positive metastatic breast cancer

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Clinical Breast cancer 2025年

作者： Stefania Morganti Xiangying Chu Tarah J. Ballinger Nisha Unni Sarah Sinclair Robert Wesolowski Alyssa M. Pereslete Paulina Lange Nabihah Tayob Nancy U. Lin Jose P. Leone Ian E. Krop Sara M. Tolaney Heather A. Parsons Department of Medical Oncology Dana-Farber Cancer Institute Boston MA Breast Oncology Program Dana-Farber Brigham Cancer Center Boston MA Harvard Medical School Boston MA Broad Institute of MIT and Harvard Cambridge MA Data Science Dana-Farber Cancer Institute Boston MA Indiana University School of Medicine Indianapolis IN University of Texas Southwestern Medical Center Dallas TX Northern Light Cancer Care Brewer ME Department of Medicine The Ohio State University College of Medicine Columbus OH Florida International University Herbert Wertheim College of Medicine Miami FL Boston Medical Center Boston MA Yale Cancer Center New Haven CT

Background Most HER2-positive breast cancers co-express estrogen receptor (ER). Given crosstalk between HER2 and ER signaling pathways, dual blockade may be beneficial. Methods In this randomized, open-label, phase 2 clinical trial, patients with ER-positive (ER≥10%), HER2-positive metastatic breast cancer were randomized (1:1) to neratinib (240mg daily) or the same dose of neratinib with fulvestrant. Any number of prior therapies was allowed; prior trastuzumab, pertuzumab and trastuzumab emtansine were required. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate, and duration of response. Exploratory objectives included the identification of predictive biomarkers via circulating tumor DNA (ctDNA). Results Of 21 patients enrolled, 18 were evaluable for outcomes and safety (neratinib-fulvestrant arm, n=8; neratinib-only arm, n=10). The study was closed before completing enrollment due to slow accrual. Median PFS did not differ between treatment arms (2.79 months with neratinib-fulvestrant versus 5.55 months with neratinib only [HR 0.94; 95% CI 0.24-3.64; P=0.98]). Grade 3 adverse events occurred in 1 (12.5%) patient in the neratinib-fulvestrant arm and 6 (60%) patients in the neratinib-only arm, with diarrhea being the most frequent. Median OS did not differ between the two arms (p=0.91). Clearance of ctDNA was associated with PFS and OS. Conclusions The combination of neratinib and fulvestrant is safe and tolerable. Due to early study closure, this study was underpowered to detect the benefit of adding fulvestrant to neratinib. Chemotherapy-free regimens targeting ER and HER2 warrant further investigation, along with prospective studies investigating ctDNA dynamics may guide treatment switch.

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Feasibility of Distress Thermometer Screening for Caregivers of Patients Undergoing Inpatient or Outpatient Hematopoietic Stem Cell Transplantation (HSCT)

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Transplantation and Cellular Therapy 2025年第2期31卷 S493-S494页

作者： Gray, Tamryn Fowler, RN, PhD, MPH Heiling, Hillary, PhD Mazzola, Emanuele, PhD Amonoo, Hermioni Lokko, MD, MPP Sullivan, Lauren, MSN, RN, AGCNS-BC, OCN, BMTCN Kelkar, Amar H., MD, MPH, FACP Pirl, William, MD, MPH Hammer, Marilyn J. Tulsky, James A., MD El-Jawahri, Areej, M.D. Cutler, Corey S., MD MPH Partridge, Ann H., MD, MPH School of Nursing UNC Chapel Hill Chapel Hill NC Data Science Dana-Farber Cancer Institute Boston MA Dana-Farber Cancer Institute Boston MA Harvard Medical School Boston MA Commercial AbbVie North Chicago IL Department of Medical Oncology Dana-Farber Cancer Institute Boston MA Psychosocial Oncology and Palliative Care Dana-Farber Cancer Institute Boston MA Supportive Oncology Dana-Farber Cancer Institute Boston MA Medicine Division of Hematology & Oncology Massachusetts General Hospital Boston MA Department of Medical Oncology Dana-Farber Cancer Institute and Harvard Medical School Boston MA Division of Transplantation and Cellular Therapy Department of Medical Oncology Dana-Farber Cancer Institute Boston MA Stem Cell/Bone Marrow Transplantation Program Dana-Farber Cancer Institute Boston MA Division of Hematological Malignancies Department of Medical Oncology Dana Farber Cancer Institute Boston MA

Topic Significance & Study Purpose/Background/RationaleCaregivers of adults undergoing HSCT face considerable emotional challenges, yet few are screened for distress and limited data exists on whether caregiver distress differs between inpatient or outpatient HSCT. The aim of this study is to assess the feasibility of using the Distress Thermometer (DT) and Problem List to screen for distress in caregivers of HSCT recipients at Day -6 before HSCT and Days +1, +8, +15, and +28 post-HSCT. Methods, Intervention, & AnalysisIn this longitudinal study conducted between 2021-2023, caregivers completed the FamilyStrong caregiver distress thermometer adapted from the NCCN DT and Problem List, including 36 items organized within practical, family, spiritual/religious concerns, and physical problems. Caregivers were asked to rate their distress on a 0-10 numeric scale. Feasibility was defined as enrollment of ≥ 70% of eligible caregivers, and completion of ≥60% of study assessments. Findings & InterpretationAmong 86 eligible, 60 HCT caregivers enrolled (70% female, 35.0% aged 60-69, 96.7% White, 68.3% spouse/partnered, and 60% outpatient caregivers). DT completion rates across five time points were 100.0%, 91.7%, 93.3%, 80.0%, and 86.7, respectively. Within the sample, Day +1 post-HCT had the largest proportion of caregivers reporting high distress (72.7% (n=40/55) followed by Day +8 with 67.9% (n=38/56). Among inpatient caregivers, 63.6% (n=14/22) had high distress on Day +1 and 68.4% (n=13/19) reported high distress on Day +15. Among outpatient caregivers, 78.8% (n=26/33) had high distress on Day +1 and 79.4% (n=27/34) reported high distress on Day +8. The most common concerns at baseline were practical issues (66.7% in both inpatient and outpatient caregivers), information and skill needs (54.2% inpatient, 63.9% outpatient), and emotional challenges (54.2% inpatient, 50% outpatient). Discussion & ImplicationsThe adapted FamilyStrong caregiver DT is feasible to use and demon

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