An Unsupervised Machine Learning Approach to Evaluating the Association of Symptom Clusters With Adverse Outcomes Among Older Adults With Advanced Cancer
Authors: Xu Huiwen , Mohamed Mostafa , Flannery Marie , Peppone Luke , Ramsdale Erika , Loh Kah Poh , Wells Megan , Jamieson Leah , Vogel Victor G. , Hall Bianca Alexandra , Mustian Karen , Mohile Supriya , Culakova Eva 
Published: March 2023

ImportanceOlder adults with advanced cancer who have high pretreatment symptom severity often experience adverse events during cancer treatments. Unsupervised machine learning may help stratify patients into different risk groups.ObjectiveTo evaluate whether clusters identified from baseline patient-reported symptom severity were associated with adverse outcomes.Design, Setting, and ParticipantsThis secondary analysis of the Geriatric Assessment Intervention for Reducing Toxicity in Older Patients With Advanced Cancer (GAP70+) Trial (2014-2019) included patients who completed the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) before starting a new cancer treatment regimen and received care at community oncology sites across the United States. An unsupervised machine learning algorithm (k-means with Euclidean distance) clustered patients based on similarities of baseline symptom severities. Clustering variables included severity items of 24 PRO-CTCAE symptoms (range, 0-4; corresponding to none, mild, moderate, severe, and very severe). Total severity score was calculated as the sum of 24 items (range, 0-96). Whether the clusters were associated with unplanned hospitalization, death, and toxic effects was then examined. Analyses were conducted in January and February 2022.ExposuresSymptom severity.Main Outcomes and MeasuresUnplanned hospitalization over 3 months (primary), all-cause mortality over 1 year, and any clinician-rated grade 3 to 5 toxic effect over 3 months.ResultsOf 718 enrolled patients, 706 completed baseline PRO-CTCAE and were included (mean [SD] age, 77.2 [5.5] years, 401 [56.8%] male patients; 51 [7.2%] Black and 619 [87.8%] non-Hispanic White patients; 245 [34.7%] with gastrointestinal cancer; 175 [24.8%] with lung cancer; mean [SD] impaired Geriatric Assessment domains, 4.5 [1.6]). The algorithm classified 310 (43.9%), 295 (41.8%), and 101 (14.3%) into low-, medium-, and high-severity clusters (within-cluster mean [SD] severity scores: low, 6.3 [3.4]; moderate, 16.6 [4.3]; high, 29.8 [7.8]; P &amp;lt; .001). Controlling for sociodemographic variables, clinical factors, study group, and practice site, compared with patients in the low-severity cluster, those in the moderate-severity cluster were more likely to experience hospitalization (risk ratio, 1.36; 95% CI, 1.01-1.84; P = .046). Moderate- and high-severity clusters were associated with a higher risk of death (moderate: hazard ratio, 1.31; 95% CI, 1.01-1.69; P = .04; high: hazard ratio, 2.00; 95% CI, 1.43-2.78; P &amp;lt; .001), but not toxic effects.Conclusions and RelevanceIn this study, unsupervised machine learning partitioned patients into distinct symptom severity clusters; patients with higher pretreatment severity were more likely to experience hospitalization and death.Trial RegistrationClinicalTrials.gov Identifier: NCT02054741