News & Events
LANCET DIGITAL HEALTH PAPER – Lancet Digit Health. 2021 Apr 9;S2589-7500(21)00040-6.
Long-term mortality risk stratification of liver transplant recipients: real-time application of deep learning algorithms on longitudinal data
Osvald Nitski, Amirhossein Azhie, Fakhar Ali Qazi-Arisar, Xueqi Wang, Shihao Ma, Leslie Lilly, Kymberly D Watt, Josh Levitsky, Sumeet K Asrani, Douglas S Lee, Barry B Rubin, Mamatha Bhat, Bo Wang
PMID: 33858815
Abstract
Background: Survival of liver transplant recipients beyond 1 year since transplantation is compromised by an increased risk of cancer, cardiovascular events, infection, and graft failure. Few clinical tools are available to identify patients at risk of these complications, which would flag them for screening tests and potentially life-saving interventions. In this retrospective analysis, we aimed to assess the ability of deep learning algorithms of longitudinal data from two prospective cohorts to predict complications resulting in death after liver transplantation over multiple timeframes, compared with logistic regression models.
Methods: In this machine learning analysis, model development was done on a set of 42 146 liver transplant recipients (mean age 48·6 years [SD 17·3]; 17 196 [40·8%] women) from the Scientific Registry of Transplant Recipients (SRTR) in the USA. Transferability of the model was further evaluated by fine-tuning on a dataset from the University Health Network (UHN) in Canada (n=3269; mean age 52·5 years [11·1]; 1079 [33·0%] women). The primary outcome was cause of death, as recorded in the databases, due to cardiovascular causes, infection, graft failure, or cancer, within 1 year and 5 years of each follow-up examination after transplantation. We compared the performance of four deep learning models against logistic regression, assessing performance using the area under the receiver operating characteristic curve (AUROC).
Findings: In both datasets, deep learning models outperformed logistic regression, with the Transformer model achieving the highest AUROCs in both datasets (p<0·0001). The AUROC for the Transformer model across all outcomes in the SRTR dataset was 0·804 (99% CI 0·795-0·854) for 1-year predictions and 0·733 (0·729-0·769) for 5-year predictions. In the UHN dataset, the AUROC for the top-performing deep learning model was 0·807 (0·795-0·842) for 1-year predictions and 0·722 (0·705-0·764) for 5-year predictions. AUROCs ranged from 0·695 (0·680-0·713) for prediction of death from infection within 5 years to 0·859 (0·847-0·871) for prediction of death by graft failure within 1 year.
Interpretation: Deep learning algorithms can incorporate longitudinal information to continuously predict long-term outcomes after liver transplantation, outperforming logistic regression models. Physicians could use these algorithms at routine follow-up visits to identify liver transplant recipients at risk for adverse outcomes and prevent these complications by modifying management based on ranked features.
FASEB J. 2021 May;35(5):e21570.
The hippo pathway: A master regulator of liver metabolism, regeneration, and disease
Anh Thu Nguyen-Lefebvre, Nazia Selzner, Jeffrey L Wrana, Mamatha Bhat
PMID: 33831275
Abstract
The liver is the only visceral organ in the body with a tremendous capacity to regenerate in response to insults that induce inflammation, cell death, and injury. Liver regeneration is a complicated process involving a well-orchestrated activation of non-parenchymal cells in the injured area and proliferation of undamaged hepatocytes. Furthermore, the liver has a Hepatostat, defined as adjustment of its volume to that required for homeostasis. Understanding the mechanisms that control different steps of liver regeneration is critical to informing therapies for liver repair, to help patients with liver disease. The Hippo signaling pathway is well known for playing an essential role in the control and regulation of liver size, regeneration, stem cell self-renewal, and liver cancer. Thus, the Hippo pathway regulates dynamic cell fates in liver, and in absence of its downstream effectors YAP and TAZ, liver regeneration is severely impaired, and the proliferative expansion of liver cells blocked. We will mainly review upstream mechanisms activating the Hippo signaling pathway following partial hepatectomy in mouse model and patients, its roles during different steps of liver regeneration, metabolism, and cancer. We will also discuss how targeting the Hippo signaling cascade might improve liver regeneration and suppress liver tumorigenesis.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY PAPER.Clin Gastroenterol Hepatol. 2021 Jan 16;S1542-3565(21)00071-9.
Predicting Long-Term Survival After Liver Transplantation in Patients With NASH Cirrhosis
Ravikiran S Karnam, Nicholas Mitsakakis, Giovanna Saracino, Leslie Lilly, Sumeet K Asrani, Mamatha Bhat
PMID: 33465480
Abstract
Nonalcoholic steatohepatitis (NASH) cirrhosis is the second most common indication for liver transplantation (LT) in the United States.1 Patients are increasingly older at presentation, with higher rates of metabolic syndrome, obesity, hyperlipidemia, diabetes mellitus, and renal failure.2 They are also at higher risk of cardiovascular events and mortality while on the waiting list1 and in the post-transplant period.3,4 We sought to identify predictors of long-term benefit based on 5-year survival post-LT in NASH cirrhosis, thereby delineating those patients that derive a clear benefit from LT versus those in whom LT may be futile.
TACROLIMUS IMPAIRS KUPFFER CELL CAPACITY TO CONTROL BACTEREMIA: WHY TRANSPLANT RECIPIENTS ARE SUSCEPTIBLE TO INFECTION
Carsten Deppermann, Moritz Peiseler, Joel Zindel, Lori Zbytnuik, Woo‐Yong Lee, Elisa Pasini, Cristina Baciu, John Matelski, Yun Lee, Deepali Kumar, Atul Humar, Bas Surewaard, Paul Kubes, Mamatha Bhat
Abstract
Kupffer cells are the resident intravascular phagocyte population of the liver and critical to the capture and killing of bacteria. Calcineurin/Nuclear Factor of Activated T cells (NFAT) inhibitors (CNIs) such as tacrolimus are used to prevent rejection in solid organ transplant recipients. While their effect on lymphocytes has been studied extensively, there is limited experimental data about if and how CNIs shape innate immunity, and whether this contributes to the higher rates of infection observed in patients taking CNIs. Here, we investigated the impact of tacrolimus treatment on innate immunity and more specifically on the capability of Kupffer cells to fight infections. Retrospective analysis of data of more than 2,700 liver transplant recipients showed that taking calcineurin inhibitors such as tacrolimus significantly increased the likelihood of Staphylococcus aureus infection. Using a mouse model of acute methicillin‐resistant Staphylococcus aureus (MRSA) bacteremia, most bacteria were sequestered in liver and we found that bacteria were more likely to disseminate and kill the host in tacrolimus‐treated mice. Using imaging we unveiled the mechanism underlying this observation: the reduced capability of Kupffer cells to capture, phagocytose and destroy bacteria in tacrolimus‐treated animals. Further, in a gene expression analysis of infected Kupffer cells, the TREM‐1 pathway was the one with the most significant downregulation after tacrolimus treatment. TREM‐1 inhibition likewise inhibited Kupffer cell bacteria capture. TREM‐1 levels on neutrophils as well as the overall neutrophil response after infection were unaffected by tacrolimus treatment. Our results indicate that tacrolimus treatment has a significant impact directly on Kupffer cells and on TREM‐1, thereby compromising their capacity to fend off infections.
Awards to Lab Members
2020 June
MITACS Fellowship
Saranya Sivaraj
2019 September
Best Presentation
Osvald Nitski (project co-supervised with Bo Wang)
Annual Sheila Sherlock Hepatology Research day for “Long-Term Risk Stratification of Liver Transplant Recipients: Real-time Application of Deep Learning Algorithms on Longitudinal Data”
2019 August
Best Presentation
Cherie Tang
Toronto Transplant Institute Research Day. Awarded to Cherie Tang for “Molecular Pathogenesis of Post-Transplant NAFLD”
2019 August
Best Overall Trainee Award
Catherine Hu
Awarded to Catherine Hu “Liver Immune Microenvironment”
2019 April
Young Investigator Award
Ravi Kiran
European Association for Study of Liver. Awarded to Mentee Ravi Kiran “Prediction of Post-Transplant Survival for Non-alcoholic Steatohepatitis”.
2018 September
Best Basic Research presentation
Elisa Pasini
University Health Network, Annual Sheila Sherlock Hepatology Research day for “ACOT1 is essential to progression of Non-alcoholic Fatty Liver Disease.”
2017 May
Rising Star Award to Clinical fellow
Dr. Zita Galvin
Dr. Zita Galvin at the International Liver Transplant Society meeting for “Diagnostic Utility of Simple Non-invasive Fibrosis Scores in Post-liver Transplant Patients with Non-alcoholic Fatty Liver Disease (NAFLD)”.
- Amirhossein Azhie – ATC 2022 – Boston, MA, USA – June 4-6, 2022 – Oral presentation – Abstract Title: Real-time Application Of Deep Learning In Diagnosis Of Graft Fibrosis After Liver Transplantation Using Longitudinal Data
- Amirhossein Azhie – ILTS 2022 – Istanbul, Turkey – 4-7 May – Poster presentation: Dynamic detection of graft fibrosis after liver transplantation using deep-learning algorithms
- Cristina Baciu – ILTS 2022 – Istanbul, Turkey – 4-7 May – Poster presentation: Distinctive Methylation Patterns on Circulating DNA as a Novel Non-Invasive Biomarker of Graft Pathology in Liver Transplant Recipients
- Cristina Baciu – Ajmera 1st conference May 2022– Poster presentation: Distinctive Methylation Patterns on Circulating DNA as a Novel Non-Invasive Biomarker of Graft Pathology in Liver Transplant Recipients
- Cristina Baciu – Sheila Sherlock Research Day – October 27th, 2022 – Toronto, Canada: Distinctive Methylation Patterns on Circulating DNA as a Novel Non-Invasive Biomarker of Graft Pathology in Liver Transplant Recipients
- Anh Thu Nguyen-Lefebvre – GI Research Day 2021- June 09th, 2021 – Toronto, Canada – Poster presentation – Delineating the Biological Mechanisms of Liver Regeneration in Murine Fibrotic Liver Model (awarded)
- Anh Thu Nguyen-Lefebvre– ILTS 2022 – Istanbul, Turkey – 4-7 May – Poster presentation: Delineating the Biological Mechanisms of Liver Regeneration in Fibrotic Liver
- Anh Thu Nguyen-Lefebvre – Ajmera 1st conference May 2022– Toronto, Canada – Moderated Poster presentation – Delineating the Biological Mechanisms of Human Liver Regeneration
- Anh Thu Nguyen-Lefebvre – GI Research Day 2022 – June 8th, 2022 – Toronto, Canada – Oral presentation: Delineating the Biological Mechanisms of Human Liver Regeneration
- Anh Thu Nguyen-Lefebvre-TMM Stem Cell Network-October 2-5, 2022 –Vancouver, Canada. Poster presentation: Understanding the Pathways that Modulate Human Liver Regeneration.
- Anh Thu Nguyen-Lefebvre-TMM Stem Cell Network-October 2-5, 2022 –Vancouver, Canada. Poster presentation: Characterization of Signaling Pathways Regulating Liver Regeneration in Fibrotic Liver
- Fakhar Ali Qazi Arisar Development of a Radiomics-based Model to predict Graft Fibrosis in Liver Transplant Recipients: A Pilot Study going to present at The American Transplant Congress, 2022 June 4 – 8, Boston, MA, USA. (oral presentation-Travel Award)
- Fakhar Ali Qazi Arisar Availability of living donor optimizes timing of liver transplant in high-risk waitlisted cirrhosis patients going to present at The International Liver Transplant Society (ILTS) Annual Congress, 2022 May 4 – 7, Istanbul Turkey. (oral presentation Young Investigator Award)
- Fakhar Ali Qazi Arisar Waitlist outcomes of patients with graft cirrhosis listed for liver re-transplantation going to present at The International Liver Transplant Society (ILTS) Annual Congress, 2022 May 4 – 7, Istanbul Turkey. (Oral presentation)
- Nadia Prayitno – GI Research Day 2022 – June 8th, 2022 – Toronto, Canada – Oral presentation: Dysregulated Wound Healing Contributes to the Progression of Post-Transplant Non-Alcoholic Steatohepatitis (won presentation award)
- Nadia Prayitno – EASL NAFLD Summit 2022 – September 15th – 17th, 2022 – Dublin, Ireland – Poster presentation: Transcriptomic Changes in Livers of Transplant Recipients with Non-Alcoholic Steatohepatitis Indicate Dysregulation of Wound Healing
- Nadia Prayitno – Sheila Sherlock Research Day – October 27th, 2022 – Toronto, Canada – Oral presentation: Dysregulated Wound Healing Contributes to the Progression of Post-Transplant Non-Alcoholic Steatohepatitis
- Nadia Prayitno – CDTRP Annual Scientific Meeting 2022 – December 7 – 9th, 2022 – Kewlona, Canada – Oral presentation: Dysregulated Wound Healing Contributes to the Progression of Post-Transplant Non-Alcoholic Steatohepatitis.
- Anh Thu Nguyen-Lefebvre – Sheila Sherlock Research Day – October 27th, 2022 – Toronto, Canada – Oral presentation: In the Discovery of Pathways modulating Human Liver Regeneration.
- Michael Cooper – Sheila Sherlock Research Day – October 27th, 2022 – Toronto, Canada – Oral presentation: DYNAMELD: Accurate, Equitable Modeling Of End-Stage Liver Disease
- Anita Bakrania – Mitacs Elevate Postdoctoral Fellowship
- Nadia Prayitno – Banting & Best Diabetes Centre Postdoctoral Fellowship
- Michael Cooper- (Co –supervised with Dr. Rahul Krishnan) CIHR Health Systems Impact Fellowship
- Soumita Ghosh- (Co –supervised with Prof. Michael Brudno) Eric and Wendy Schmidt AI in Science Postdoctoral Fellowship Award
- Fakhar Ali Qazi Arisar 2020 UHN Transplant Fellowship Competition – CAD 25000 – Development of a Deep Learning Algorithm to Predict Graft Failure using Radiomic features in Liver Transplant Recipients’
- Fakhar Ali Qazi Arisar AASLD Presidential Poster of Distinction – American Association for the study of liver diseases (AASLD) – The Liver Meeting Digital Experience (TLMdX) 2020, November 13 – 16.
- Fakhar Ali Qazi Arisar Early Career Investigator Award in Clinical/Translational Science – American Association for the study of liver diseases (AASLD) – The Liver Meeting Digital Experience (TLMdX) 2021, November 12 – 15.
- Fakhar Ali Qazi Arisar AASLD Presidential Poster of Distinction (2 posters) – American Association for the study of liver diseases (AASLD) – The Liver Meeting Digital Experience (TLMdX) 2021, November 12 – 15.
- Fakhar Ali Qazi Arisar American Society of Transplantation – Living Donor Community of Practice travel award – American Transplant Congress – 2022, June 4 – 8, Boston, MA, USA.
- Fakhar Ali Qazi Arisar Young Investigator Award – Joint International Congress of ILTS, ELITA & LICAGE – 2022, May 4 – 7, Istanbul, Turkey.
- Nadia Prayitno – EASL NAFLD Summit 2022 Young Investigator Bursary
- Nadia Prayitno – CDTRP Rising Star Travel Award to the Annual Scientific Meeting 2022
- Anh Thu Nguyen-Lefebvre – The Stem Cell Network Travel Award 2022 (TMM conference)
- Michael Cooper – Sheila Sherlock Liver Day 2022 (Best Presentation) ( Project Co-supervised with Rahul Krishnan Annual Sheila Sherlock Hepatology Research day
Madhumitha Rabindranath – Canadian Graduate Scholarship – Master (CIHR)
Soumita Ghosh – Schmidt AI in Science (UofT)
Funding
We are grateful for support from the Canadian Liver Foundation, Canadian Donation and Transplantation Research Program, Toronto General & Western Hospital Foundation, American Society of Transplantation, University of Toronto: McLaughlin Centre, and The Natural Sciences and Engineering Research Council of Canada.
