Featured
-
-
Article
| Open AccessQuantifying the causal impact of biological risk factors on healthcare costs
Understanding the causal impact that risk factors have on healthcare cost is critical to evaluate healthcare interventions. Here, authors show that waist circumference, body mass index, and blood pressure have robust causal impact on healthcare cost.
- Jiwoo Lee
- , Sakari Jukarainen
- & Andrea Ganna
-
Article
| Open AccessDetection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas
Recurrence of meningiomas is unpredictable by current methods based on surgically removed specimens, and identification of patients likely to recur could inform treatment strategy. Here, the authors analysed DNA methylation in liquid biopsy specimens from meningioma patients to help classify recurrence risk noninvasively even before surgery.
- Grayson A. Herrgott
- , James M. Snyder
- & Houtan Noushmehr
-
Article
| Open AccessMulti-trait discovery and fine-mapping of lipid loci in 125,000 individuals of African ancestry
There have been few genome-wide association studies that analyze multiple lipid traits simultaneously, especially in individuals of African ancestry. To address this, the authors performed a multi-trait analysis of GWAS along with fine-mapping to find new genetic loci associated with lipid traits in individuals of African ancestry.
- Abram Bunya Kamiza
- , Sounkou M. Touré
- & Segun Fatumo
-
Article
| Open AccessThe Oncology Biomarker Discovery framework reveals cetuximab and bevacizumab response patterns in metastatic colorectal cancer
Identifying actionable biomarkers remains a challenge. Here, the authors develop a framework Oncology Biomarker Discovery (OncoBird), apply it to a phase III trial and investigate the molecular and biomarker landscape of metastatic colorectal carcinoma patients.
- Alexander J. Ohnmacht
- , Arndt Stahler
- & Michael P. Menden
-
Article
| Open AccessA versatile, fast and unbiased method for estimation of gene-by-environment interaction effects on biobank-scale datasets
Identification of gene-by-environment interactions is crucial to understand the interplay of environmental effects on complex traits. Here, the authors present MonsterLM, a method for estimating the proportion of trait variance explained by gene-by-environment interactions in a fast, unbiased manner on biobank-scale datasets.
- Matteo Di Scipio
- , Mohammad Khan
- & Guillaume Paré
-
Article
| Open AccessGut microbiota and fecal short chain fatty acids differ with adiposity and country of origin: the METS-microbiome study
Here, using amplicon sequencing and metabolomics in a large multi-country cohort, the authors find that adiposity-related microbiota differences differ between low-to-middle-income compared to high-income countries.
- Gertrude Ecklu-Mensah
- , Candice Choo-Kang
- & Lara R. Dugas
-
Article
| Open AccessDiurnal rhythms of wrist temperature are associated with future disease risk in the UK Biobank
Many chronic diseases present with desynchronized sleep-wake cycles, indicative of disrupted biorhythms. Here, the authors propose peripheral thermoregulation as a digital biomarker based on the association between lower temperature rhythms measured from wearable activity trackers with future onset of disease, such as type 2 diabetes, non-alcoholic fatty liver disease, hypertension and pneumonia.
- Thomas G. Brooks
- , Nicholas F. Lahens
- & Carsten Skarke
-
Article
| Open AccessBiology-guided deep learning predicts prognosis and cancer immunotherapy response
The clinical application of data-driven deep learning models remains challenging. Here, a biology-guided deep learning approach allows the simultaneous prediction of the tumour immune and stromal microenvironment status as well as treatment outcomes from medical images in gastric cancer.
- Yuming Jiang
- , Zhicheng Zhang
- & Ruijiang Li
-
Article
| Open AccessAt-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis
“In ALS clinical trials, efficacy is often assessed via subjective patient or clinician reports. The authors introduce a machine-learned severity score based on wearable sensor data from daily activities, which is reliable, sensitive, and could reduce clinical trial sizes.”
- Anoopum S. Gupta
- , Siddharth Patel
- & Fernando Vieira
-
Article
| Open AccessElucidation of the low-expressing erythroid CR1 phenotype by bioinformatic mining of the GATA1-driven blood-group regulome
This study provides a systematic approach to explore how blood group expression is regulated by transcription factors. As proof-of-principle, the genetic basis underlying the very low levels of CR1 on red cells of the Helgeson phenotype is explained.
- Ping Chun Wu
- , Yan Quan Lee
- & Martin L. Olsson
-
Article
| Open AccessAssociation between vmPFC gray matter volume and smoking initiation in adolescents
The relationship between brain development and smoking behaviour is not well understood. Here, the authors show an association between volume of the left ventromedial prefrontal cortex and smoking initiation in adolescents.
- Shitong Xiang
- , Tianye Jia
- & Jianfeng Feng
-
Article
| Open AccessA machine-learning approach to human ex vivo lung perfusion predicts transplantation outcomes and promotes organ utilization
Ex vivo perfusion is a unique platform to study isolated human lungs. Here, authors show that a machine learning model, InsighTx, derived from data generated during ex vivo lung perfusion can accurately predict transplant outcomes and increase organ utilization rates.
- Andrew T. Sage
- , Laura L. Donahoe
- & Shaf Keshavjee
-
Article
| Open AccessMulti-PGS enhances polygenic prediction by combining 937 polygenic scores
Polygenic scores (PGS) have high potential for clinical use but are currently underpowered for many applications. Here, the authors develop an approach that leverages an agnostic library of hundreds of PGS to increase prediction of complex diseases and other traits. This multi-PGS framework is ideal for emerging biobank data.
- Clara Albiñana
- , Zhihong Zhu
- & Bjarni J. Vilhjálmsson
-
Article
| Open AccessMAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas
The MAPK pathway is a key driver of pediatric low-grade gliomas (pLGG); however, response to MAPK inhibitors (MAPKi) in pLGG patients is not consistent. Here, the authors develop MAPKi sensitivity scores (MSS) to predict response to MAPKi and apply them to bulk and single-cell sequencing datasets from pLGG patients and preclinical models.
- Romain Sigaud
- , Thomas K. Albert
- & Till Milde
-
Article
| Open AccessOpportunistic detection of type 2 diabetes using deep learning from frontal chest radiographs
Traditional type 2 diabetes (T2D) screening methods often depend on age, BMI guidelines and glucose measurements. Here, authors use a deep learning model that leverages chest radiographs and electronic health record data to screen for T2D, highlighting potential for early detection and intervention.
- Ayis Pyrros
- , Stephen M. Borstelmann
- & William Galanter
-
Article
| Open AccessOptimal strategies for learning multi-ancestry polygenic scores vary across traits
There are challenges with transferring genetic risk scores from ancestry in which they were generated to another. Here, the authors investigate the use of multi-ancestry versus single-ancestry training sets to construct polygenic scores and find that the optimal strategy varies across traits.
- Brieuc Lehmann
- , Maxine Mackintosh
- & Chris Holmes
-
Article
| Open AccessSUMOylation of Rho-associated protein kinase 2 induces goblet cell metaplasia in allergic airways
Allergic asthma is characterized by goblet cell metaplasia. Here, the authors show protein SUMOylation contributes to goblet cell metaplasia and SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signalling pathway in controlling the airway goblet cell metaplasia.
- Dan Tan
- , Meiping Lu
- & Ximei Wu
-
Article
| Open AccessNivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial
A combination of chemoradiotherapy followed by brachytherapy is recommended for patients with locally-advanced cervical cancer (LACC), however there is still a high risk of disease recurrence. Here the authors report clinical outcomes and immunologic correlates of a clinical trial of the PD-1 inhibitor nivolumab in combination with chemoradiotherapy in LACC patients.
- Manuel Rodrigues
- , Giulia Vanoni
- & Emanuela Romano
-
Article
| Open AccessA dorsomedial prefrontal cortex-based dynamic functional connectivity model of rumination
Rumination, which is the tendency to dwell on negative internal states repetitively, is a well-known cognitive style associated with depression. The authors developed a predictive model of rumination and observed that the dorsomedial prefrontal cortex plays an important role in rumination.
- Jungwoo Kim
- , Jessica R. Andrews-Hanna
- & Choong-Wan Woo
-
Article
| Open AccessElevated plasma complement factor H related 5 protein is associated with venous thromboembolism
Improved biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE) are needed. Here, the authors show that Complement Factor H Related 5 protein, a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker in 5 independent cohorts.
- Maria Jesus Iglesias
- , Laura Sanchez-Rivera
- & Jacob Odeberg
-
Article
| Open AccessThe blood proteome of imminent lung cancer diagnosis
Lung cancer screening could enhance early diagnosis and treatment. Here, the authors used proteomic analysis of pre-diagnosis samples across 6 cohorts to identify 36 proteins associated with imminent lung cancer diagnosis.
- Demetrius Albanes
- , Karine Alcala
- & Wei Zheng
-
Article
| Open AccessWhole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations
Here, the authors perform a whole-genome sequencing association analysis of genetic variants in ≤11,840 multi-ethnic participants with ≤1666 circulating metabolites, discovering 1985 novel variant-metabolite associations and insights into human disease.
- Elena V. Feofanova
- , Michael R. Brown
- & Bing Yu
-
Article
| Open AccessPlasma metabolite profile for primary open-angle glaucoma in three US cohorts and the UK Biobank
Primary open-angle glaucoma is a leading cause of blindness. Here, the authors report higher plasma levels of diglycerides and triglycerides in samples collected prior to diagnosis, particularly in cases presenting with vision loss near fixation.
- Oana A. Zeleznik
- , Jae H. Kang
- & Louis R. Pasquale
-
Article
| Open AccessPrioritization of potential causative genes for schizophrenia in placenta
The placenta has been proposed to be potentially relevant to schizophrenia risk. Here, the authors use the genetically predicted transcriptome to identify genes expressed in the placenta that could be involved in schizophrenia.
- Gianluca Ursini
- , Pasquale Di Carlo
- & Daniel R. Weinberger
-
Article
| Open AccessIdentification of CircRNA signature associated with tumor immune infiltration to predict therapeutic efficacy of immunotherapy
Circular RNAs are known to be linked to cancer regulation. Here, the authors identify a circular RNA signature associated with immune checkpoint response in melanoma.
- Yu Dong
- , Qian Gao
- & Youqiong Ye
-
Article
| Open AccessSingle-cell metabolic fingerprints discover a cluster of circulating tumor cells with distinct metastatic potential
Circulating tumor cells (CTCs) are the tumor cells responsible for metastasis. Here, the authors develop a home-built single-cell quantitative mass spectrometric platform and discover a cluster of CTCs with distinct metastatic potential using a molecular typing system based on the single-cell metabolic fingerprints.
- Wenjun Zhang
- , Feifei Xu
- & Yun Chen
-
Article
| Open AccessAccelerated biological aging and risk of depression and anxiety: evidence from 424,299 UK Biobank participants
Theory indicates that biological aging may contribute to poor mental health in late life. Here, authors show advanced biological aging may represent a potential risk factor for incident depression/anxiety in midlife and older adults and a potential target for risk assessment and intervention.
- Xu Gao
- , Tong Geng
- & Tao Huang
-
Article
| Open AccessClinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease
This study characterizes expression of pharmacogenes across the histological NAFLD severity spectrum. Here, the authors show the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.
- Nicholas R. Powell
- , Tiebing Liang
- & Naga Chalasani
-
Article
| Open AccessClinical and biomarker analyses of sintilimab plus gemcitabine and cisplatin as first-line treatment for patients with advanced biliary tract cancer
Chemotherapeutic agents and immune checkpoint inhibitors have shown modest efficacy in patients with advanced biliary tract cancers (BTCs). Here the authors report the results of a phase II trial of the anti-PD1 antibody sintilimab plus chemotherapy (gemcitabine and cisplatin) as first-line treatment for patients with advanced BTCs.
- Tian-mei Zeng
- , Guang Yang
- & Zhen-gang Yuan
-
Article
| Open AccessCirculating tumor DNA reveals complex biological features with clinical relevance in metastatic breast cancer
Plasma ctDNA is a promising method to determine patient outcome in multiple cancer types. Here, the authors use shallow WGS to create machine learning signatures to identify tumor phenotypes and predict therapy response in patients with metastatic breast cancer.
- Aleix Prat
- , Fara Brasó-Maristany
- & Ana Vivancos
-
Article
| Open AccessLong-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy.
- Jenniffer Linares
- , Anna Sallent-Aragay
- & Alexandre Calon
-
Article
| Open AccessAngiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice
ACE inhibitors are widely used to treat cardiovascular diseases and promote angiogenesis. Here, the authors show a central role for endothelial USP7-Sp1/Sp3-Notch1 signalling in pathophysiological angiogenesis in response to ACE inhibitor treatment.
- Hanlin Lu
- , Peidong Yuan
- & Wencheng Zhang
-
Article
| Open AccessAtlas of plasma NMR biomarkers for health and disease in 118,461 individuals from the UK Biobank
The authors report a systematic analyses of blood biomarkers for metabolism against the whole spectrum of diseases in 100,000 individuals and reveals a prominent role of numerous metabolic biomarkers as risk markers beyond heart disease and diabetes.
- Heli Julkunen
- , Anna Cichońska
- & Peter Würtz
-
Article
| Open AccessEstimation and implications of the genetic architecture of fasting and non-fasting blood glucose
Most genetic studies of glucose levels have been done on fasting samples, which can be difficult to obtain. Here, the authors identify 156 genetic loci controlling the physiological variation of glucose levels in healthy non-fasting individuals, demonstrating that the results non-fasting samples can be used to predict fasting glucose levels.
- Zhen Qiao
- , Julia Sidorenko
- & Loic Yengo
-
Article
| Open AccessHigh-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform
There exist challenges in quantifying the length of individual telomeres at single nucleotide resolution. Here the authors report a method to capture telomeres and accurately analyse their length in human cell lines and patient peripheral blood leukocyte samples using single-molecule real-time sequencing.
- Cheng-Yong Tham
- , LaiFong Poon
- & Shang Li
-
Article
| Open AccessEarly response evaluation by single cell signaling profiling in acute myeloid leukemia
The molecular mechanisms underlying response to chemotherapy in Acute myeloid leukemia (AML) remain to be explored. Here, the authors perform 36-dimensional mass cytometry in 32 AML patients during intensive chemotherapy and suggest functional signalling analysis for prognosis prediction early after treatment in AML.
- Benedicte Sjo Tislevoll
- , Monica Hellesøy
- & Bjørn Tore Gjertsen
-
Article
| Open AccessPhosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A
Phosphoproteomics is a promising tool for identifying biomarkers of treatment response in cancer. Here, the authors analyse proteomics profiling of HER2-negative female breast cancer patients and identify potential predictors of paclitaxel response.
- S. Mouron
- , M. J. Bueno
- & M. Quintela-Fandino
-
Article
| Open AccessLY6D marks pre-existing resistant basosquamous tumor subpopulations
The identification of distinct cell populations with cellular plasticity in skin basal cell carcinoma is important for understanding treatment resistance mechanisms. Here, the authors identify the resistant LY6D+ basosquamous population that correlates with poor clinical outcomes.
- Daniel Haensel
- , Sadhana Gaddam
- & Anthony E. Oro
-
Article
| Open AccessCXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease
Idiopathic multicentric Castleman disease (iMCD) is a life-threatening inflammatory disease requiring immediate intervention, for which the recommended first-line therapy is the Interleukin-6 pathway inhibitor siltuximab. Authors here show that the change in levels of the chemokine CXCL13 shortly following the start of siltuximab treatment is predictive of response.
- Sheila K. Pierson
- , Laura Katz
- & David C. Fajgenbaum
-
Article
| Open AccessSevere Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study
Both acute and chronic COVID-19 disease (also known as long-COVID) may affect the central nervous system. Here authors characterize the immunological profile of peripheral blood and cerebrospinal fluid of COVID-19 patients in order to identify the main factors that contribute to neurological impairment and the severity of neurological symptoms in Sars-CoV-2 infection.
- Manina M. Etter
- , Tomás A. Martins
- & Gregor Hutter
-
Article
| Open AccessDeep learning-based image analysis predicts PD-L1 status from H&E-stained histopathology images in breast cancer
Programmed death ligand-1 (PD-L1) has been recently adopted for breast cancer as a predictive biomarker for immunotherapies. Here, the authors show that PD-L1 expression can be predicted from H&E-stained images using deep learning.
- Gil Shamai
- , Amir Livne
- & Ron Kimmel
-
Article
| Open Access2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability
Maintaining optimal eNOS levels is important during cardiovascular events, although little is known regarding the mechanism of eNOS protection. Here, the authors show a regulatory role of endothelial OASL1 in maintaining eNOS mRNA stability and vascular biology under atheroprone conditions.
- Tae Kyeong Kim
- , Sejin Jeon
- & Goo Taeg Oh
-
Article
| Open AccessDeep transfer learning of cancer drug responses by integrating bulk and single-cell RNA-seq data
Single-cell RNA-seq data provide the opportunity to predict drug response in cancer while considering intratumour heterogeneity. Here, the authors develop a deep transfer learning framework - scDEAL - to predict single-cell drug responses in cancer by integrating single-cell and bulk RNA-seq data.
- Junyi Chen
- , Xiaoying Wang
- & Qin Ma
-
Article
| Open AccessExploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics
Immunoglobulin light chain amyloidosis is a lethal hematologic disorder driven by clonal plasma cells producing abnormal light chains that damage healthy tissues. Fraser et al. show that BH3 mimetics, which inhibit pro-survival proteins BCL-2 or MCL-1, can effectively eliminate diseased cells.
- Cameron S. Fraser
- , Johan K. E. Spetz
- & Kristopher A. Sarosiek
-
Article
| Open AccessTP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma
Inhibition of the protein arginine methyltransferase PRMT5 has been suggested as a promising therapy for lymphoma. Here, the authors show that TP53 loss of function and MUSASHI-2 (MSI2) expression are biomarkers of resistance to PRMT5-targeted therapy in B-cell lymphoma. Moreover, combining PRMT5 inhibition with MSI2 or BCL-2 inhibitors blocks the translation of key drivers of lymphoma, c-MYC and BCL-2, inhibiting cell growth.
- Tatiana Erazo
- , Chiara M. Evans
- & Michael G. Kharas
-
Article
| Open AccessTargeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors
A substantial proportion of HER2+ breast cancer patients do not benefit from HER2-targeted therapy. Here, the authors identify a population of cancer-associated fibroblasts involved in the suppression of trastuzumab-induced ADCC that can be pharmacologically targeted to raise treatment effectiveness in unresponsive tumors.
- Elisa I. Rivas
- , Jenniffer Linares
- & Alexandre Calon
-
Article
| Open AccessCAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies
The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.
- Yongxian Hu
- , Jingjing Li
- & He Huang
-
Article
| Open AccessPharmacogenomics polygenic risk score for drug response prediction using PRS-PGx methods
To try to predict an individual’s drug response using genetic data, most studies have used traditional polygenic risk score (PRS) methods. Here, the authors develop a pharmacogenomics-specific PRS method, which can improve drug response prediction and patient stratification in pharmacogenomics studies.
- Song Zhai
- , Hong Zhang
- & Judong Shen
-
Article
| Open AccessBiomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
Biomarkers predictive of response to T cell therapy remain to be better defined. This study identifies potential predictive and pharmacodynamic markers of response to NY-ESO-1 T-cell therapy in a solid tumor that may inform lymphodepletion, cell dose, and strategies to enhance anticancer efficacy.
- Alexandra Gyurdieva
- , Stefan Zajic
- & Ioanna Eleftheriadou