Causal inference can lead us to modifiable mechanisms and informative archetypes in sepsis.

Autor:	Baillie JK; Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. j.k.baillie@ed.ac.uk.; Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh, UK. j.k.baillie@ed.ac.uk.; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK. j.k.baillie@ed.ac.uk.; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK. j.k.baillie@ed.ac.uk.; International Sepsis Forum, Murphy, NC, USA. j.k.baillie@ed.ac.uk., Angus D; International Sepsis Forum, Murphy, NC, USA.; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, USA.; UPMC Health System, Pittsburgh, PA, USA., Burnham K; Wellcome Sanger Institute, Hinxton, UK., Calandra T; International Sepsis Forum, Murphy, NC, USA.; Service of Immunology and Allergy, Department of Medicine, Lausanne, Switzerland.; Department of Laboratory Medicine and Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland., Calfee C; International Sepsis Forum, Murphy, NC, USA.; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Departments of Medicine and Anesthesia, University of California San Francisco, San Francisco, CA, USA., Gutteridge A; Computational Biology, Novo Nordisk, Oxford, UK., Hacohen N; Harvard University, Boston, USA., Khatri P; Institute for Immunity, Transplantation and Infection, Palo Alto, CA, USA.; Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA., Langley R; College of Medicine, University of New Mexico, Albuquerque, NM, USA., Ma'ayan A; Icahn School of Medicine at Mount Sinai, New York, NY, USA., Marshall J; International Sepsis Forum, Murphy, NC, USA.; Unity Health Toronto, Toronto, ON, Canada., Maslove D; Department of Critical Care Medicine, Queen's University, Kingston, ON, Canada., Prescott HC; International Sepsis Forum, Murphy, NC, USA.; University of Michigan, Ann Arbor, MI, USA., Rowan K; International Sepsis Forum, Murphy, NC, USA.; Intensive Care National Audit & Research Centre, London, UK., Scicluna BP; Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei hospital, University of Malta, Msida, Malta.; Centre for Molecular Medicine and Biobanking, Biomedical Sciences bldg., University of Malta, Msida, Malta., Seymour C; International Sepsis Forum, Murphy, NC, USA.; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, USA., Shankar-Hari M; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.; International Sepsis Forum, Murphy, NC, USA.; Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK., Shapiro N; International Sepsis Forum, Murphy, NC, USA.; Harvard University, Boston, USA., Joost Wiersinga W; International Sepsis Forum, Murphy, NC, USA.; Division of Infectious Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands., Singer M; International Sepsis Forum, Murphy, NC, USA.; University College London, London, UK., Randolph AG; International Sepsis Forum, Murphy, NC, USA.; Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA.; Departments of Anaesthesia and Pediatrics, Harvard Medical School, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	Intensive care medicine [Intensive Care Med] 2024 Dec; Vol. 50 (12), pp. 2031-2042. Date of Electronic Publication: 2024 Oct 21.
DOI:	10.1007/s00134-024-07665-4
Abstrakt:	Medical progress is reflected in the advance from broad clinical syndromes to mechanistically coherent diagnoses. By this metric, research in sepsis is far behind other areas of medicine-the word itself conflates multiple different disease mechanisms, whilst excluding noninfectious syndromes (e.g., trauma, pancreatitis) with similar pathogenesis. New technologies, both for deep phenotyping and data analysis, offer the capability to define biological states with extreme depth. Progress is limited by a fundamental problem: observed groupings of patients lacking shared causal mechanisms are very poor predictors of response to treatment. Here, we discuss concrete steps to identify groups of patients reflecting archetypes of disease with shared underlying mechanisms of pathogenesis. Recent evidence demonstrates the role of causal inference from host genetics and randomised clinical trials to inform stratification analyses. Genetic studies can directly illuminate drug targets, but in addition they create a reservoir of statistical power that can be divided many times among potential patient subgroups to test for mechanistic coherence, accelerating discovery of modifiable mechanisms for testing in trials. Novel approaches, such as subgroup identification in-flight in clinical trials, will improve efficiency. Within the next decade, we expect ongoing large-scale collaborative projects to discover and test therapeutically relevant sepsis archetypes. Competing Interests: Conflicts of interest: The International Sepsis Forum has been generously sponsored by Cytosorbents, Genentech, GE, BD, deepull, Gentian, Inflammatix, Oxford Nanopore Technologies, Sanofi, and Baxter. JKB reports research funding from Wellcome, MRC, BBSRC, UKRI, Baillie Gifford, and NIHR. JM reports grants from the Canadian Institutes of Health Research and has served as chair of data and safety monitoring boards for AM Pharma and Adrenomed. MS-H reports funding from NIHR. TvdP has received grants from the EU's Horizon 2020 research and innovation funding programme. All other authors declare no competing interests. AG is a shareholder of and has received salaries from GSK and Novo Nordisk. AGR is the Chair of the International Sepsis Forum and has received consultancy fees from Inotrem, Thermo Fisher and Volition, and receives funding from the US National Institute of Allergy and Infectious Diseases and Centers for Disease Control. TC reports grants from the Swiss Academy of Medical Sciences, the Swiss Federal Institute of Technology Zurich and the EU's Horizon 2020 research and innovation funding programme, and consulting, speaker’s bureau, data safety monitoring boards from Basilea, Cidara, Gilead Sciences, MSD Merck Sharp & Dohme, Moderna, Novartis, Pfizer, Shionogi (payments made to his institution.) CSC reports grant funding from the NIH, Roche-Genentech, and Quantum Leap Healthcare Collaborative, and has served as a consultant or advisor to Vasomune, Gen1e Life Scienes, Arrowhead, Cellenkos, Calcimedica, EnliTISA, Novaris, Aerogen, Fisher-Paykel, and Boehringer. BPS received funds from the European Society of Intensive Care Medicine (ESICM) and Xjenza Malta Research Excellence Program (REP-2023-049). CWS reports grants from the US National Institutes of Health National Institute of General Medical Sciences, during the conduct of the study, and personal fees from Inotrem and Beckman Coulter, outside of the submitted work. (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze:	MEDLINE
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