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COVID-19 related prediction models for
diagnosis and prognosis: living SR
Maarten van Smeden
University Medical Center Utrecht
Julius Center for Health Sciences and Primary Care
The Netherlands
Twitter: @MvanSmeden
Email: M.vanSmeden@umcutrecht.nl
28 May 2020
Julius Seminar
I have no conflicts of interest to declare
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Thanks to
Laure Wynants (Maastricht/Leuven)
Ewoud Schuit (Utrecht)
Gary Collins (Oxford) for the materials for these slides
https://coronavirus.jhu.edu/map.html (26/5/2020)
Utrecht, 28 May 2020 Twitter: @MaartenvSmedenDoi: 10.1136/bmj.m1328
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
The COVID-19 systematic review tsunami
https://www.crd.york.ac.uk/prospero
Utrecht, 28 May 2020 Twitter: @MaartenvSmedenData from: https://ispmbern.github.io/covid-19/ (publications in Pubmed/Embase; preprints in BioRxiv and MedRxiv
Utrecht, 28 May 2020 Twitter: @MaartenvSmedenDoi: 10.1136/bmj.m1328
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
(Clinical) Prediction models
• Support clinical decision-making for individual patients
• Combining and giving appropriate weights to several inputs
(e.g., CT image characteristics, signs & symptoms, lab test
results, demographics, …)
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
What not?
• Virus, contact or transmission models
• “Risk factor” or prognostic factor finding studies
• Diagnostic accuracy studies
• Effects of treatments, policies or vaccines
https://www.crd.york.ac.uk/prospero
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden10.1101/2020.03.05.20031906
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Timeline
Doi: 10.1136/bmj.m1328
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Timeline
Doi: 10.1136/bmj.m1328
1916 titles screened
15 studies included
describing 19 models
(first submitted version)
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Timeline
Doi: 10.1136/bmj.m1328
1st submission
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Timeline
Doi: 10.1136/bmj.m1328
2690 titles screened
27 studies included
describing 31 models
(published version)
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Timeline
Doi: 10.1136/bmj.m1328
Received peer review
feedback
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Timeline
Doi: 10.1136/bmj.m1328
Replied to peer
review + update
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Timeline
Doi: 10.1136/bmj.m1328
Paper accepted
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
How?
• Used existing website to download COVID-19 related TIAB
(Pubmed/Embase/BioRxiv/MedRxiv, we manually added arXiv)
https://zika.ispm.unibe.ch/assets/data/pub/search_beta/
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
How?
• Used existing website to download COVID-19 related TIAB
(Pubmed/Embase/BioRxiv/MedRxiv, we manually added arXiv)
• Used existing RoB and data extraction tool
Doi: 10.7326/M18-1377, 10.1371/journal.pmed.1001744
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
How?
• Used existing website to download COVID-19 related TIAB
(Pubmed/Embase/BioRxiv/MedRxiv, we manually added arXiv)
• Used existing RoB and data extraction tool
• 14 experienced risk modelling reviewers from AT, BE, NL, UK.
Screening and data extraction independently by 2 reviewers
• Pre-submission inquiry (day 1), fast track peer review and
editorial process
• PRISMA and TRIPOD followed for our reporting
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Flow diagram
Doi: 10.1136/bmj.m1328
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Results
• 51 papers describing the development or validation of COVID-
19 related prediction models
• 45 preprints: medRxiv (n=30), arXiv (n=13), bioRxiv (n=2)
• 6 peer-reviewed & published: Clin Infect Dis, Crit Care, Eur
Radiol, Phys Eng Sci Med, PLoS One, Radiology
• 32 studies used data from China, 2 from Italy, 1 from
Singapore, 10 international data, 2 simulated data, 1 Medicare
data, 3 studies unclear
Doi: 10.1136/bmj.m1328
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Results
• 3 models for predicting hospital admission from pneumonia
• 47 diagnosis models for COVID-19 or COVID-19 pneumonia
• 34 based on medical images (deep learning)
• 16 prognosis models for predicting mortality risk, progression
to severe disease, or length of stay
Doi: 10.1136/bmj.m1328
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Results
• Hospital admission models: AUC range 0.73 to 0.81
• Diagnosis models: AUC range 0.85 to 0.99
• Diagnostic imaging models: AUC range 0.81 to 0.998
• Prognosis models: AUC range 0.85 to 0.99
Doi: 10.1136/bmj.m1328
BUT
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
PROBAST
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
PROBAST
• Risk of bias any flaw or shortcoming in the design, conduct or
analysis of a primary study that is likely to distort the predictive
performance of a model
• Assess risk of bias on four domains using “signaling questions”
• Participants (2 questions)
• Predictors (3 questions)
• Outcome (6 questions)
• Analysis (9 questions)
• If risk of bias was high in at least one domain, overall risk of bias
was judged to be high
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
PROBAST - results
• Participants domain: 24/51 at high risk of bias
• Non-representative of the target population (e.g., non-
consecutive patients)
• Predictors domain: 6/51 at high risk of bias
• Predictors not available at time of intended model use
• Outcome domain: 18/51 at high risk of bias
• Subjective or proxy outcomes
• Analysis domain: 50/51 at high risk of bias
• Small sample size (->overfitting & no adjustment), incomplete
reporting of model performance (e.g., no calibration)
All models at high
risk of bias
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Poor reporting
• Unclear study designs
• Lack of clear description of the study population
• Basic characteristics not reported
• Age: not reported in 22 studies
• Sex: not reported in 22 studies
• Often unclear on the intend moment of use of the model, what
and how many predictors were examined, missing data
handling, sample size
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Poor prediction models can make things worse
Doi: 10.1378/chest.1118087
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Conclusion
• COVID-19 prediction models were poorly reported, at high risk of
bias, and their reported performance is probably optimistic
• Application of currently available prediction models not
recommended
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
From systematic review sprint to marathon
• 18 days from conception to paper accept
• BMJ first living review for coming months
• Collaboration with Cochrane Prognosis Methods Group
• April 7 -> 4909 TIAB screened -> 66 models total
(to be published shortly)
• May 4 -> 9306 TIAB screened (semi-automated) -> 148 models
total (analysis underway)
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
COVID-PRECISE
• Large IPD-MA initiative
• Partners in Sweden, UK, Zwitserland, USA and expanding
• Goals
• Develop and validate COVID-19 related prediction models
• Understand and model heterogeneity between healthcare
settings
• Lead also by Thomas Debray and Valentijn de Jong
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden
Team science
Coordination team
Laure Wynants (Maastricht)
Maarten van Smeden (Utrecht)
Carl Moons
Ben Van Calster (Leuven)
Reviewers
Thomas Debray (Utrecht)
Valentijn de Jong
Ewoud Schuit
Hans Reitsma
Toshi Takada
Lotty Hooft
Anneke Damen
Constanza Navarro
Florien van Royen
Pauline Heus
Luc Smits (Maastricht)
Sander van Kuijk
Ewout Steyerberg (Leiden)
Anna Lohmann
Kim Luijken
Georg Heinze (Vienna)
Maria Haller
Christine Wallisch
Nina Kreuzberger (Cologne)
Nicole Skoetz
Darren Dahly (Cork)
Michael Harhay (Philadelphia)
Robert Wolff (York)
Ioana Tzoulaki (London)
Gary Collins (Oxford)
Jie Ma
Paula Dhiman
Richard Riley (Keele)
Kym Snell
Matthew Sperrin (Manchester)
Jamie Sergeant
Glen Martin
Jack Wilkinson
Chunhu Shi
Jan Verbakel (Leuven)
Information specialist
René Spijker (Utrecht)
Advisors
Marc Bonten (Utrecht)
Maarten De Vos (Leuven)
Liesbet Henckaerts
Utrecht, 28 May 2020 Twitter: @MaartenvSmeden

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COVID-19 related prediction models for diagnosis and prognosis - a living systematic review

  • 1. COVID-19 related prediction models for diagnosis and prognosis: living SR Maarten van Smeden University Medical Center Utrecht Julius Center for Health Sciences and Primary Care The Netherlands Twitter: @MvanSmeden Email: M.vanSmeden@umcutrecht.nl 28 May 2020 Julius Seminar I have no conflicts of interest to declare
  • 2. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Thanks to Laure Wynants (Maastricht/Leuven) Ewoud Schuit (Utrecht) Gary Collins (Oxford) for the materials for these slides
  • 4. Utrecht, 28 May 2020 Twitter: @MaartenvSmedenDoi: 10.1136/bmj.m1328
  • 5. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden The COVID-19 systematic review tsunami https://www.crd.york.ac.uk/prospero
  • 6. Utrecht, 28 May 2020 Twitter: @MaartenvSmedenData from: https://ispmbern.github.io/covid-19/ (publications in Pubmed/Embase; preprints in BioRxiv and MedRxiv
  • 7. Utrecht, 28 May 2020 Twitter: @MaartenvSmedenDoi: 10.1136/bmj.m1328
  • 8. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden (Clinical) Prediction models • Support clinical decision-making for individual patients • Combining and giving appropriate weights to several inputs (e.g., CT image characteristics, signs & symptoms, lab test results, demographics, …)
  • 9. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden What not? • Virus, contact or transmission models • “Risk factor” or prognostic factor finding studies • Diagnostic accuracy studies • Effects of treatments, policies or vaccines https://www.crd.york.ac.uk/prospero
  • 10. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden10.1101/2020.03.05.20031906
  • 11. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Timeline Doi: 10.1136/bmj.m1328
  • 12. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Timeline Doi: 10.1136/bmj.m1328 1916 titles screened 15 studies included describing 19 models (first submitted version)
  • 13. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Timeline Doi: 10.1136/bmj.m1328 1st submission
  • 14. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Timeline Doi: 10.1136/bmj.m1328 2690 titles screened 27 studies included describing 31 models (published version)
  • 15. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Timeline Doi: 10.1136/bmj.m1328 Received peer review feedback
  • 16. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Timeline Doi: 10.1136/bmj.m1328 Replied to peer review + update
  • 17. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Timeline Doi: 10.1136/bmj.m1328 Paper accepted
  • 18. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden How? • Used existing website to download COVID-19 related TIAB (Pubmed/Embase/BioRxiv/MedRxiv, we manually added arXiv) https://zika.ispm.unibe.ch/assets/data/pub/search_beta/
  • 19. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden How? • Used existing website to download COVID-19 related TIAB (Pubmed/Embase/BioRxiv/MedRxiv, we manually added arXiv) • Used existing RoB and data extraction tool Doi: 10.7326/M18-1377, 10.1371/journal.pmed.1001744
  • 20. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden How? • Used existing website to download COVID-19 related TIAB (Pubmed/Embase/BioRxiv/MedRxiv, we manually added arXiv) • Used existing RoB and data extraction tool • 14 experienced risk modelling reviewers from AT, BE, NL, UK. Screening and data extraction independently by 2 reviewers • Pre-submission inquiry (day 1), fast track peer review and editorial process • PRISMA and TRIPOD followed for our reporting
  • 21. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Flow diagram Doi: 10.1136/bmj.m1328
  • 22. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Results • 51 papers describing the development or validation of COVID- 19 related prediction models • 45 preprints: medRxiv (n=30), arXiv (n=13), bioRxiv (n=2) • 6 peer-reviewed & published: Clin Infect Dis, Crit Care, Eur Radiol, Phys Eng Sci Med, PLoS One, Radiology • 32 studies used data from China, 2 from Italy, 1 from Singapore, 10 international data, 2 simulated data, 1 Medicare data, 3 studies unclear Doi: 10.1136/bmj.m1328
  • 23. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Results • 3 models for predicting hospital admission from pneumonia • 47 diagnosis models for COVID-19 or COVID-19 pneumonia • 34 based on medical images (deep learning) • 16 prognosis models for predicting mortality risk, progression to severe disease, or length of stay Doi: 10.1136/bmj.m1328
  • 24. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Results • Hospital admission models: AUC range 0.73 to 0.81 • Diagnosis models: AUC range 0.85 to 0.99 • Diagnostic imaging models: AUC range 0.81 to 0.998 • Prognosis models: AUC range 0.85 to 0.99 Doi: 10.1136/bmj.m1328
  • 25. BUT
  • 26. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden PROBAST
  • 27. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden PROBAST • Risk of bias any flaw or shortcoming in the design, conduct or analysis of a primary study that is likely to distort the predictive performance of a model • Assess risk of bias on four domains using “signaling questions” • Participants (2 questions) • Predictors (3 questions) • Outcome (6 questions) • Analysis (9 questions) • If risk of bias was high in at least one domain, overall risk of bias was judged to be high
  • 28. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden PROBAST - results • Participants domain: 24/51 at high risk of bias • Non-representative of the target population (e.g., non- consecutive patients) • Predictors domain: 6/51 at high risk of bias • Predictors not available at time of intended model use • Outcome domain: 18/51 at high risk of bias • Subjective or proxy outcomes • Analysis domain: 50/51 at high risk of bias • Small sample size (->overfitting & no adjustment), incomplete reporting of model performance (e.g., no calibration)
  • 29. All models at high risk of bias
  • 30. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Poor reporting • Unclear study designs • Lack of clear description of the study population • Basic characteristics not reported • Age: not reported in 22 studies • Sex: not reported in 22 studies • Often unclear on the intend moment of use of the model, what and how many predictors were examined, missing data handling, sample size
  • 31. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Poor prediction models can make things worse Doi: 10.1378/chest.1118087
  • 32. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Conclusion • COVID-19 prediction models were poorly reported, at high risk of bias, and their reported performance is probably optimistic • Application of currently available prediction models not recommended
  • 33. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden From systematic review sprint to marathon • 18 days from conception to paper accept • BMJ first living review for coming months • Collaboration with Cochrane Prognosis Methods Group • April 7 -> 4909 TIAB screened -> 66 models total (to be published shortly) • May 4 -> 9306 TIAB screened (semi-automated) -> 148 models total (analysis underway)
  • 34. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden COVID-PRECISE • Large IPD-MA initiative • Partners in Sweden, UK, Zwitserland, USA and expanding • Goals • Develop and validate COVID-19 related prediction models • Understand and model heterogeneity between healthcare settings • Lead also by Thomas Debray and Valentijn de Jong
  • 35. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden Team science Coordination team Laure Wynants (Maastricht) Maarten van Smeden (Utrecht) Carl Moons Ben Van Calster (Leuven) Reviewers Thomas Debray (Utrecht) Valentijn de Jong Ewoud Schuit Hans Reitsma Toshi Takada Lotty Hooft Anneke Damen Constanza Navarro Florien van Royen Pauline Heus Luc Smits (Maastricht) Sander van Kuijk Ewout Steyerberg (Leiden) Anna Lohmann Kim Luijken Georg Heinze (Vienna) Maria Haller Christine Wallisch Nina Kreuzberger (Cologne) Nicole Skoetz Darren Dahly (Cork) Michael Harhay (Philadelphia) Robert Wolff (York) Ioana Tzoulaki (London) Gary Collins (Oxford) Jie Ma Paula Dhiman Richard Riley (Keele) Kym Snell Matthew Sperrin (Manchester) Jamie Sergeant Glen Martin Jack Wilkinson Chunhu Shi Jan Verbakel (Leuven) Information specialist René Spijker (Utrecht) Advisors Marc Bonten (Utrecht) Maarten De Vos (Leuven) Liesbet Henckaerts
  • 36. Utrecht, 28 May 2020 Twitter: @MaartenvSmeden