Respiratory Phenotypes for Stratifying and Predicting Survival in ALS
Muhannad Seyam, Rachel Thompson, Jiayi Luo, Joan Skelly, Waqar Waheed, Leonard van den Berg, Rup TandanABSTRACT
Introduction/Aims
Phenotypic heterogeneity in amyotrophic lateral sclerosis (ALS) is an obstacle to stratification and survival prediction and is not sufficiently accounted for in clinical practice or trial design. We aimed to identify respiratory phenotypes to allow stratification and survival prediction in ALS.
Methods
We retrospectively analyzed 292 ALS patients. Data included demographics, disease‐related characteristics, and respiratory measurements (initial predicted forced vital capacity [FVC] and 3‐month decline slope). Survival analysis was performed using Kaplan–Meier estimates and Cox regression. We defined four respiratory phenotypes based on dichotomized predicted FVC at the initial visit and its 3‐month decline slope: (1) initial high, slow decline (IHSD), (2) initial high, fast decline (IHFD), (3) initial low, slow decline (ILSD), and (4) initial low, fast decline (ILFD).
Results
Patients with an initial predicted FVC above the median had a median survival of 33 months, compared to 15 months for those below the median ( p < 0.0001). The highest quartile had an almost threefold survival advantage over the lowest quartile (37 vs. 13 months, p < 0.0001). A 3‐month slope at or above the median predicted longer survival (33 vs. 14 months, p < 0.0001). Survival varied across respiratory phenotypes, ranging from 41 months in IHSD to 11 months in ILFD—with all comparisons being significant ( p ≤ 0.0012) except for ILSD vs. IHFD.
Discussion
Defining respiratory phenotypes in ALS may allow tailored research within those subgroups, biomarker correlations, more accurate prognostication, and stratification in clinical trials based on phenotype‐specific disease progression.