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Background: Exacerbation frequency strongly influences treatment choices in patients with severe asthma., Research Question: What is the extent of the variability of exacerbation rate across countries and its implications in disease management?, Study Design and Methods: We retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥ 18 years who did not initiate any biologics prior to baseline visit. A severe exacerbation was defined as the use of oral corticosteroids for ≥ 3 days or asthma-related hospitalization/ED visit. A series of negative binomial models were applied to estimate country-specific severe exacerbation rates during 365 days of follow-up, starting from a naive model with country as the only variable to an adjusted model with country as a random-effect term and patient and disease characteristics as independent variables., Results: The final sample included 7,510 patients from 17 countries (56% from the United States), contributing to 1,939 severe exacerbations (0.27/person-year). There was large between-country variation in observed severe exacerbation rate (minimum, 0.04 [Argentina]; maximum, 0.88 [Saudi Arabia]; interquartile range, 0.13-0.54), which remained substantial after adjusting for patient characteristics and sampling variability (interquartile range, 0.16-0.39)., Interpretation: Individuals with similar patient characteristics but coming from different jurisdictions have varied severe exacerbation risks, even after controlling for patient and disease characteristics. This suggests unknown patient factors or system-level variations at play. Disease management guidelines should recognize such between-country variability. Risk prediction models that are calibrated for each jurisdiction will be needed to optimize treatment strategies., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. P. has advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, and Thermofisher; has consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, and Theravance; has grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, and UK National Health Service; has received payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and Teva Pharmaceuticals; has received payment for the development of educational materials from Mundipharma and Novartis; has received payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, and Thermofisher; has received funding for patient enrollment or completion of research from Novartis; has stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); has 5% shareholding in Timestamp, which develops adherence monitoring technology; is a peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. E. W. has received honoraria from AstraZeneca, GlaxoSmithKline, and Genentech; and has been an investigator on studies sponsored by AstraZeneca, GlaxoSmithKline, Genentech, Sanofi, Novartis, and Teva Pharmaceuticals, for which her institution has received funding. M. E. W. reports grants and/or personal fees from Novartis, Sanofi, Regeneron, Genentech, Sentien, Restorbio, Equillium, Genzyme, Cohero Health, Teva Pharmaceuticals, Boehringer Ingelheim, AstraZeneca, Amgen, GlaxoSmithKline, Cytoreason, Cerecor, Sound biologic, Incyte, and Kinaset. D. J. J. has received speaker fees and consultancy fees from AZ, GSK, Sanofi Regeneron, and BI; and research funding from AstraZeneca. J. B. has received research grants from AstraZeneca and personnel fees from NuvoAir, outside the submitted work. L. G. H. has received grant funding, participated in advisory boards, and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, Theravance, Evelo Biosciences, Sanofi, and Teva Pharmaceuticals; has received grants from MedImmune, Novartis UK, Roche/Genentech Inc, Amgen, Genentech/Hoffman la Roche, AstraZeneca, MedImmune, Glaxo Smith Kline, Aerocrine, and Vitalograph; has received sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, and Napp Pharmaceuticals; has taken part in asthma clinical trials sponsored by AstraZeneca, Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline for which his institution received remuneration; and is the academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. P. E. P. has attended advisory boards for AstraZeneca, GlaxoSmithKline, and Sanofi; has given lectures at meetings supported by AstraZeneca and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi, for which his institution received remuneration; and has a current research grant funded by GlaxoSmithKline. D.-W. P. received sponsorship to attend or speak at international meetings, honoraria for lecturing or attending advisory boards, and research grants from the following companies: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Daiichi Sankyo, Shionogi, and Orient Pharma. B. G. C. declares grants from Chiesi and GlaxoSmithKline; personal fees for advisory board activities from Chiesi, GlaxoSmithKline, Novartis, Sanofi, Teva Pharmaceuticals, and AstraZeneca; and payment for lectures/speaking engagements from Chiesi, Novartis, GlaxoSmithKline, Menarini, and AstraZeneca, outside the submitted work. L. P.-L. reports grants, personal fees, and nonfinancial support from AstraZeneca, Teva Pharmaceuticals, Sanofi, and FAES; personal fees and nonfinancial support from GlaxoSmithKline and Chiesi; personal fees from MSD, TECHDOW PHARMA, and Leo-Pharma; grants and personal fees from GEBRO; and personal fees from GILEAD, outside the submitted work. R. A.-L. has given lectures at meetings supported by AstraZeneca, Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Sanofi; and participated in advisory board fees from GlaxoSmithKline, AstraZeneca, Novartis, and Abbot. D. L.-L. reports personal fees from ALK-Abelló, AstraZeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GlaxoSmithKline national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, and Carnot; and grants from Abbvie, Bayer, Lilly, Sanofi, Astrazeneca, Pfizer, Novartis, Circassia, UCB, and GlaxoSmithKline, outside the submitted work. M. A.-A. has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline; and received a grant from Kuwait Foundation for the Advancement of Sciences (KFAS). C. K. R. received consulting/lecture fees from MSD, AstraZeneca, GlaxoSmithKline, Novartis, Takeda, Mundipharma, Boehringer Ingelheim, Teva Pharmaceuticals, Sanofi, and Bayer. T. I. received lecture fees from Kyorin, GlaxoSmithKline, Novartis, Boehringer Ingelheim, and AstraZeneca. E. H. declares personal fees from Sanofi, Regeneron, GlaxoSmithKline, Novartis, AstraZeneca, Stallergenes, and Circassia. G. W. C. has received research grants and lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva Pharmaceuticals, Thermo Fisher, and Valeas. R. C. has received honoraria for lectures from Aerogen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva Pharmaceuticals; is a member of advisory boards for GlaxoSmithKline and Novartis; has received grant support from GlaxoSmithKline and Aerogen; and has patents in the use of acoustics in the diagnosis of lung disease, assessment of adherence, and prediction of exacerbations. N. G. P. has been a speaker and/or advisory board member for Abbott, Abbvie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GSK, HAL, Faes Farma, Medscape, Menarini, MSD, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, and Viatris. A. I. P. has received fees and honoraria from Menarini, GSK, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, and Chiesi. C. M. P. has attended advisory boards for AstraZeneca, Novartis, Teva Pharmaceuticals, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, Teva Pharmaceuticals, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, MSD, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Novartis, Teva Pharmaceuticals, GlaxoSmithKline, ALK, and Sanofi-Genzyme. C. A. T.-D. has received fees as advisory board participant and/or speaker from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi-Aventis; has taken part in clinical trials from AstraZeneca, Novartis, and Sanofi-Aventis; and has received unrestricted grants for investigator-initiated studies at Fundacion Neumologica Colombiana from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols, and Novartis. T. A. P. declares relevant research support from Novartis and Chiesi Pharma. M. H. declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi, Teva Pharmaceuticals, and Seqirus, for unrelated projects. M. P. declares personal fees and nonfinancial support from AstraZeneca and GlaxoSmithKline. P. G. G. has received speaker fees and grants to his institution from AstraZeneca, GlaxoSmithKline, and Novartis. J. M. reports speaker fees, grants, or advisory boards for AstraZeneca, Sanofi, GSK, Novartis, Inmunotek, Menarini, and Noucor. C. B. reports advisory boards participation for Sanofi, AstraZeneca, Takeda, and ValeoPharma; honorarium for presentations for GlaxoSmithKline, AstraZeneca, Amgen, Grifols, Sanofi, Regeneron, and ValeoPharma; and clinical trials paid to University of British Columbia sponsored by AstraZeneza, GlaxoSmithKline, BioHaven, and Sanofi. S. C. declares receiving conference fees from Novartis S.A de C.V, Glaxosmithkline Mexico, AstraZeneca Mexico, and Sanofi Mexico. M. S. has received honoraria from AstraZeneca, Boehringer Ingelheim, Teva Pharmaceuticals, and GlaxoSmithKline for purposes unrelated to the content of this manuscript; and has received research funding from AstraZeneza and Boehringer Ingelheim directly into his research account from AstraZeneza for unrelated projects. None declared (T. Y. L., C. P. Y., R. R., L. H. M. L., B. M., G. C. C., E. A. C.-C., W. C.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Severe asthma is associated with a disproportionally high disease burden, including the risk of severe exacerbations. Accurate prediction of the risk of severe exacerbations may enable clinicians to tailor treatment plans to an individual patient. This study aims to develop and validate a novel risk prediction model for severe exacerbations in patients with severe asthma, and to examine the potential clinical utility of this tool., Methods and Analysis: The target population is patients aged 18 years or older with severe asthma. Based on the data from the International Severe Asthma Registry (n=8925), a prediction model will be developed using a penalised, zero-inflated count model that predicts the rate or risk of exacerbation in the next 12 months. The risk prediction tool will be externally validated among patients with physician-assessed severe asthma in an international observational cohort, the NOVEL observational longiTudinal studY (n=1652). Validation will include examining model calibration (ie, the agreement between observed and predicted rates), model discrimination (ie, the extent to which the model can distinguish between high-risk and low-risk individuals) and the clinical utility at a range of risk thresholds., Ethics and Dissemination: This study has obtained ethics approval from the Institutional Review Board of National University of Singapore (NUS-IRB-2021-877), the Anonymised Data Ethics and Protocol Transparency Committee (ADEPT1924) and the University of British Columbia (H22-01737). Results will be published in an international peer-reviewed journal., Trial Registration Number: European Union electronic Register of Post-Authorisation Studies, EU PAS Register (EUPAS46088)., Competing Interests: Competing interests: DBP has advisory board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrolment or completion of research from Novartis; stock/stock options from AKL Research and Development which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline, outside the submitted work. RB reports grants and personal fees from AstraZeneca, grants from Genentech, grants and personal fees from Health Research Council NZ, personal fees from Cipla, personal fees from Avillion, outside the submitted work. MSK reports grants and personal fees from Astra-Zeneca, personal fees from GlaxoSmithKline, personal fees from Sanofi, personal fees from Novartis, outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

When the same type of event is experienced by a subject more than once it is called recurrent event, which possess two important characteristics, namely "within-subject correlation" and "time-varying covariate." As a result, the traditional statistical methods do not work well on recurrent event data. Over the past few decades, many alternatives methods have been proposed for the analysis of recurrent event data. In this article, the six most prominent methods for recurrent event analysis have been compared on pediatric asthma data. Three variance corrected models (viz "Anderson and Gill [AG] model," "Prentice, William, and Peterson-Counting Process [PWP-CP] model," and "Prentice, William, and Peterson-Gap Time [PWP-GT] model") and three corresponding frailty variants (AG-frailty, PWP-CP-frailty, and PWP-GT-frailty) were compared using three mathematical criterion (AIC, BIC, and log-likelihood) and one graphical criteria (Cox-Snell goodness of fit, visual test). All model comparison indices showed the PWP-GT model as the most appropriate model on asthma data over other models. By using PWP-GT model, seven predictors of asthma exacerbation (viz "abdominal pain at previous visit," "Z5 (%) at previous visit," "diagnosis of asthma at previous visit," "calendar month of exacerbation," "history of maternal asthma," "monthly per capita income," and "emotional stress") were identified. The PWP-GT model was identified as the most appropriate model over other models on pediatrics asthma data., (© 2020 John Wiley & Sons Ltd.)