A systematic review of multi-variate time series approaches to extract predictive asthma biomarkers from routinely collected diary data

ObjectivesLongitudinal data is commonly acquired in asthma studies, to help assess asthma progression in patients, and to determine predictors of future outcomes, including asthma exacerbations and asthma control. Different methods exist for quantifying temporal behaviour in routinely collected diary variables to obtain meaningful predictive biomarkers of asthma outcomes. The aims of this systematic review were to evaluate the methods for extracting biomarkers from longitudinally collected diary data in asthma and investigate associations between the extracted measures and asthma patient reported outcomes (PROs). SettingA systematic review of MEDLINE, EMBASE, CINAHL and the Cochrane Library was conducted, using index terms relating to diary variables and asthma outcomes. Studies that focused on preschool children were excluded, to avoid confounding asthma with multi-factorial preschool wheeze. Study quality and risk of bias were assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) and the Prediction model Risk Of Bias ASessment Tool (PROBAST), respectively. ParticipantsAdults and/or children of school age ([≥]5 years old), with clinician-diagnosed asthma Primary outcomesAsthma PROs, namely asthma exacerbations, asthma control, asthma-related quality of life and asthma severity Results24 full-text articles met the inclusion criteria and were included in the review. Generally, higher levels of variability in the diary variables were associated with poorer outcomes, especially increased asthma exacerbation risk, and poor asthma control. There was increasing interest in nonparametric methods to quantify complex behaviour of diary variables (6/24). TRIPOD and PROBAST highlighted a lack of consistent reporting of model performance measures and potential for model bias. DiscussionRoutinely collected diary variables aid in generating asthma assessment tools, including surrogate endpoints, for clinical trials, and predictive biomarkers of adverse outcomes, warranting monitoring through remote sensors. Studies consistently lacked robust reporting of model performance. Future research should utilise diary variable-derived biomarkers. Article SummaryStrengths and limitations of this study O_LIThis is the first systematic review that explores the different methods applied to time series of diary variables, namely peak flow, reliever use, symptom scores and awakenings. C_LIO_LIThe scope of this review included multiple patient-reported outcomes, including asthma exacerbations, asthma control and asthma severity. C_LI Only one reviewer was involved in screening the titles and abstracts for inclusion into the systematic review.