Real-world treatment trajectories of adults with newly diagnosed asthma or COPD.

BACKGROUND: There is a lack of knowledge on how patients with asthma or chronic obstructive pulmonary disease (COPD) are globally treated in the real world, especially with regard to the initial pharmacological treatment of newly diagnosed patients and the different treatment trajectories. This knowledge is important to monitor and improve clinical practice. METHODS: This retrospective cohort study aims to characterise treatments using data from four claims (drug dispensing) and four electronic health record (EHR; drug prescriptions) databases across six countries and three continents, encompassing 1.3 million patients with asthma or COPD. We analysed treatment trajectories at drug class level from first diagnosis and visualised these in sunburst plots. RESULTS: In four countries (USA, UK, Spain and the Netherlands), most adults with asthma initiate treatment with short-acting ß2 agonists monotherapy (20.8%-47.4% of first-line treatments). For COPD, the most frequent first-line treatment varies by country. The largest percentages of untreated patients (for asthma and COPD) were found in claims databases (14.5%-33.2% for asthma and 27.0%-52.2% for COPD) from the USA as compared with EHR databases (6.9%-15.2% for asthma and 4.4%-17.5% for COPD) from European countries. The treatment trajectories showed step-up as well as step-down in treatments. CONCLUSION: Real-world data from claims and EHRs indicate that first-line treatments of asthma and COPD vary widely across countries. We found evidence of a stepwise approach in the pharmacological treatment of asthma and COPD, suggesting that treatments may be tailored to patients' needs.

Challenges of Estimating Global Feature Importance in Real-World Health Care Data.

Feature importance is often used to explain clinical prediction models. In this work, we examine three challenges using experiments with electronic health record data: computational feasibility, choosing between methods, and interpretation of the resulting explanation. This work aims to create awareness of the disagreement between feature importance methods and underscores the need for guidance to practitioners how to deal with these discrepancies.

Characterising the treatment of thromboembolic events after COVID-19 vaccination in 4 European countries and the US: An international network cohort study.

Background: Thrombosis with thrombocytopenia syndrome (TTS) has been identified as a rare adverse event following some COVID-19 vaccines. Various guidelines have been issued on the treatment of TTS. We aimed to characterize the treatment of TTS and other thromboembolic events (venous thromboembolism (VTE), and arterial thromboembolism (ATE) after COVID-19 vaccination and compared to historical (pre-vaccination) data in Europe and the US. Methods: We conducted an international network cohort study using 8 primary care, outpatient, and inpatient databases from France, Germany, Netherlands, Spain, The United Kingdom, and The United States. We investigated treatment pathways after the diagnosis of TTS, VTE, or ATE for a pre-vaccination (background) cohort (01/2017-11/2020), and a vaccinated cohort of people followed for 28 days after a dose of any COVID-19 vaccine recorded from 12/2020 onwards). Results: Great variability was observed in the proportion of people treated (with any recommended therapy) across databases, both before and after vaccination. Most patients with TTS received heparins, platelet aggregation inhibitors, or direct Xa inhibitors. The majority of VTE patients (before and after vaccination) were first treated with heparins in inpatient settings and direct Xa inhibitors in outpatient settings. In ATE patients, treatments were also similar before and after vaccinations, with platelet aggregation inhibitors prescribed most frequently. Inpatient and claims data also showed substantial heparin use. Conclusion: TTS, VTE, and ATE after COVID-19 vaccination were treated similarly to background events. Heparin use post-vaccine TTS suggests most events were not identified as vaccine-induced thrombosis with thrombocytopenia by the treating clinicians.

Assessing Trustworthy AI in Times of COVID-19: Deep Learning for Predicting a Multiregional Score Conveying the Degree of Lung Compromise in COVID-19 Patients.

This article's main contributions are twofold: 1) to demonstrate how to apply the general European Union's High-Level Expert Group's (EU HLEG) guidelines for trustworthy AI in practice for the domain of healthcare and 2) to investigate the research question of what does "trustworthy AI" mean at the time of the COVID-19 pandemic. To this end, we present the results of a post-hoc self-assessment to evaluate the trustworthiness of an AI system for predicting a multiregional score conveying the degree of lung compromise in COVID-19 patients, developed and verified by an interdisciplinary team with members from academia, public hospitals, and industry in time of pandemic. The AI system aims to help radiologists to estimate and communicate the severity of damage in a patient's lung from Chest X-rays. It has been experimentally deployed in the radiology department of the ASST Spedali Civili clinic in Brescia, Italy, since December 2020 during pandemic time. The methodology we have applied for our post-hoc assessment, called Z-Inspection®, uses sociotechnical scenarios to identify ethical, technical, and domain-specific issues in the use of the AI system in the context of the pandemic.

TreatmentPatterns: An R package to facilitate the standardized development and analysis of treatment patterns across disease domains.

BACKGROUND AND OBJECTIVES: There is an increasing interest to use real-world data to illustrate how patients with specific medical conditions are treated in real life. Insight in the current treatment practices helps to improve and tailor patient care, but is often held back by a lack of data interoperability and a high-level of required resources. We aimed to provide an easy tool that overcomes these barriers to support the standardized development and analysis of treatment patterns for a wide variety of medical conditions. METHODS: We formally defined the process of constructing treatment pathways and implemented this in an open-source R package TreatmentPatterns (https://github.com/mi-erasmusmc/TreatmentPatterns) to enable a reproducible and timely analysis of treatment patterns. RESULTS: The developed package supports the analysis of treatment patterns of a study population of interest. We demonstrate the functionality of the package by analyzing the treatment patterns of three common chronic diseases (type II diabetes mellitus, hypertension, and depression) in the Dutch Integrated Primary Care Information (IPCI) database. CONCLUSION: TreatmentPatterns is a tool to make the analysis of treatment patterns more accessible, more standardized, and more interpretation friendly. We hope it thereby contributes to the accumulation of knowledge on real-world treatment patterns across disease domains. We encourage researchers to further adjust and add custom analysis to the R package based on their research needs.

Use of unstructured text in prognostic clinical prediction models: a systematic review.

OBJECTIVE: This systematic review aims to assess how information from unstructured text is used to develop and validate clinical prognostic prediction models. We summarize the prediction problems and methodological landscape and determine whether using text data in addition to more commonly used structured data improves the prediction performance. MATERIALS AND METHODS: We searched Embase, MEDLINE, Web of Science, and Google Scholar to identify studies that developed prognostic prediction models using information extracted from unstructured text in a data-driven manner, published in the period from January 2005 to March 2021. Data items were extracted, analyzed, and a meta-analysis of the model performance was carried out to assess the added value of text to structured-data models. RESULTS: We identified 126 studies that described 145 clinical prediction problems. Combining text and structured data improved model performance, compared with using only text or only structured data. In these studies, a wide variety of dense and sparse numeric text representations were combined with both deep learning and more traditional machine learning methods. External validation, public availability, and attention for the explainability of the developed models were limited. CONCLUSION: The use of unstructured text in the development of prognostic prediction models has been found beneficial in addition to structured data in most studies. The text data are source of valuable information for prediction model development and should not be neglected. We suggest a future focus on explainability and external validation of the developed models, promoting robust and trustworthy prediction models in clinical practice.

Seek COVER: using a disease proxy to rapidly develop and validate a personalized risk calculator for COVID-19 outcomes in an international network.

BACKGROUND: We investigated whether we could use influenza data to develop prediction models for COVID-19 to increase the speed at which prediction models can reliably be developed and validated early in a pandemic. We developed COVID-19 Estimated Risk (COVER) scores that quantify a patient's risk of hospital admission with pneumonia (COVER-H), hospitalization with pneumonia requiring intensive services or death (COVER-I), or fatality (COVER-F) in the 30-days following COVID-19 diagnosis using historical data from patients with influenza or flu-like symptoms and tested this in COVID-19 patients. METHODS: We analyzed a federated network of electronic medical records and administrative claims data from 14 data sources and 6 countries containing data collected on or before 4/27/2020. We used a 2-step process to develop 3 scores using historical data from patients with influenza or flu-like symptoms any time prior to 2020. The first step was to create a data-driven model using LASSO regularized logistic regression, the covariates of which were used to develop aggregate covariates for the second step where the COVER scores were developed using a smaller set of features. These 3 COVER scores were then externally validated on patients with 1) influenza or flu-like symptoms and 2) confirmed or suspected COVID-19 diagnosis across 5 databases from South Korea, Spain, and the United States. Outcomes included i) hospitalization with pneumonia, ii) hospitalization with pneumonia requiring intensive services or death, and iii) death in the 30 days after index date. RESULTS: Overall, 44,507 COVID-19 patients were included for model validation. We identified 7 predictors (history of cancer, chronic obstructive pulmonary disease, diabetes, heart disease, hypertension, hyperlipidemia, kidney disease) which combined with age and sex discriminated which patients would experience any of our three outcomes. The models achieved good performance in influenza and COVID-19 cohorts. For COVID-19 the AUC ranges were, COVER-H: 0.69-0.81, COVER-I: 0.73-0.91, and COVER-F: 0.72-0.90. Calibration varied across the validations with some of the COVID-19 validations being less well calibrated than the influenza validations. CONCLUSIONS: This research demonstrated the utility of using a proxy disease to develop a prediction model. The 3 COVER models with 9-predictors that were developed using influenza data perform well for COVID-19 patients for predicting hospitalization, intensive services, and fatality. The scores showed good discriminatory performance which transferred well to the COVID-19 population. There was some miscalibration in the COVID-19 validations, which is potentially due to the difference in symptom severity between the two diseases. A possible solution for this is to recalibrate the models in each location before use.

Trends in the conduct and reporting of clinical prediction model development and validation: a systematic review.

OBJECTIVES: This systematic review aims to provide further insights into the conduct and reporting of clinical prediction model development and validation over time. We focus on assessing the reporting of information necessary to enable external validation by other investigators. MATERIALS AND METHODS: We searched Embase, Medline, Web-of-Science, Cochrane Library, and Google Scholar to identify studies that developed 1 or more multivariable prognostic prediction models using electronic health record (EHR) data published in the period 2009-2019. RESULTS: We identified 422 studies that developed a total of 579 clinical prediction models using EHR data. We observed a steep increase over the years in the number of developed models. The percentage of models externally validated in the same paper remained at around 10%. Throughout 2009-2019, for both the target population and the outcome definitions, code lists were provided for less than 20% of the models. For about half of the models that were developed using regression analysis, the final model was not completely presented. DISCUSSION: Overall, we observed limited improvement over time in the conduct and reporting of clinical prediction model development and validation. In particular, the prediction problem definition was often not clearly reported, and the final model was often not completely presented. CONCLUSION: Improvement in the reporting of information necessary to enable external validation by other investigators is still urgently needed to increase clinical adoption of developed models.

Implementation of the COVID-19 Vulnerability Index Across an International Network of Health Care Data Sets: Collaborative External Validation Study.

BACKGROUND: SARS-CoV-2 is straining health care systems globally. The burden on hospitals during the pandemic could be reduced by implementing prediction models that can discriminate patients who require hospitalization from those who do not. The COVID-19 vulnerability (C-19) index, a model that predicts which patients will be admitted to hospital for treatment of pneumonia or pneumonia proxies, has been developed and proposed as a valuable tool for decision-making during the pandemic. However, the model is at high risk of bias according to the "prediction model risk of bias assessment" criteria, and it has not been externally validated. OBJECTIVE: The aim of this study was to externally validate the C-19 index across a range of health care settings to determine how well it broadly predicts hospitalization due to pneumonia in COVID-19 cases. METHODS: We followed the Observational Health Data Sciences and Informatics (OHDSI) framework for external validation to assess the reliability of the C-19 index. We evaluated the model on two different target populations, 41,381 patients who presented with SARS-CoV-2 at an outpatient or emergency department visit and 9,429,285 patients who presented with influenza or related symptoms during an outpatient or emergency department visit, to predict their risk of hospitalization with pneumonia during the following 0-30 days. In total, we validated the model across a network of 14 databases spanning the United States, Europe, Australia, and Asia. RESULTS: The internal validation performance of the C-19 index had a C statistic of 0.73, and the calibration was not reported by the authors. When we externally validated it by transporting it to SARS-CoV-2 data, the model obtained C statistics of 0.36, 0.53 (0.473-0.584) and 0.56 (0.488-0.636) on Spanish, US, and South Korean data sets, respectively. The calibration was poor, with the model underestimating risk. When validated on 12 data sets containing influenza patients across the OHDSI network, the C statistics ranged between 0.40 and 0.68. CONCLUSIONS: Our results show that the discriminative performance of the C-19 index model is low for influenza cohorts and even worse among patients with COVID-19 in the United States, Spain, and South Korea. These results suggest that C-19 should not be used to aid decision-making during the COVID-19 pandemic. Our findings highlight the importance of performing external validation across a range of settings, especially when a prediction model is being extrapolated to a different population. In the field of prediction, extensive validation is required to create appropriate trust in a model.

The role of explainability in creating trustworthy artificial intelligence for health care: A comprehensive survey of the terminology, design choices, and evaluation strategies.

Artificial intelligence (AI) has huge potential to improve the health and well-being of people, but adoption in clinical practice is still limited. Lack of transparency is identified as one of the main barriers to implementation, as clinicians should be confident the AI system can be trusted. Explainable AI has the potential to overcome this issue and can be a step towards trustworthy AI. In this paper we review the recent literature to provide guidance to researchers and practitioners on the design of explainable AI systems for the health-care domain and contribute to formalization of the field of explainable AI. We argue the reason to demand explainability determines what should be explained as this determines the relative importance of the properties of explainability (i.e. interpretability and fidelity). Based on this, we propose a framework to guide the choice between classes of explainable AI methods (explainable modelling versus post-hoc explanation; model-based, attribution-based, or example-based explanations; global and local explanations). Furthermore, we find that quantitative evaluation metrics, which are important for objective standardized evaluation, are still lacking for some properties (e.g. clarity) and types of explanations (e.g. example-based methods). We conclude that explainable modelling can contribute to trustworthy AI, but the benefits of explainability still need to be proven in practice and complementary measures might be needed to create trustworthy AI in health care (e.g. reporting data quality, performing extensive (external) validation, and regulation).