Using an innovative multiple regression procedure in a cancer population (Part II): fever, depressive affect, and mobility problems clarify an influential symptom pair (pain-fatigue/weakness) and cluster (pain-fatigue/weakness-sleep problems)

Background: Most patients with advanced cancer experience symptom pairs or clusters among pain, fatigue, and insomnia. However, only combinations where symptoms are mutually influential hold potential for identifying patient subgroups at greater risk, and in some contexts, interventions with "cross-over" (multisymptom) effects. Improved methods to detect and interpret interactions among symptoms, signs, or biomarkers are needed to reveal these influential pairs and clusters. I recently created sequential residual centering (SRC) to reduce multicollinearity in moderated regression, which enhances sensitivity to detect these interactions. Methods: I applied SRC to moderated regressions of single-item symptoms that interact to predict outcomes from 268 palliative radiation outpatients. I investigated: 1) the hypothesis that the interaction, pain x fatigue/weakness x sleep problems, predicts depressive affect only when fever presents, and 2) an exploratory analysis, when fever is absent, that the interaction, pain x fatigue/weakness x sleep problems x depressive affect, predicts mobility problems. In the fever context, three-way interactions (and derivative terms) of the four symptoms (pain, fatigue/ weakness, fever, sleep problems) are tested individually and simultaneously; in the non-fever context, a single four-way interaction (and derivative terms) is tested. Results: Fever interacts separately with fatigue/weakness and sleep problems; these comoderators each magnify the pain-depressive affect relationship along the upper or full range of pain values. In non-fever contexts, fatigue/weakness, sleep problems, and depressive affect comagnify the relationship between pain and mobility problems. Conclusion: Different mechanisms contribute to the pain x fatigue/weakness x sleep problems interaction, but all depend on the presence of fever, a sign/biomarker/symptom of proinflammatory sickness behavior. In non-fever contexts, depressive affect is no longer an outcome representing malaise from the physical symptoms of sickness, but becomes a fourth symptom of the interaction. In outpatient subgroups at heightened risk, single interventions could potentially relieve multiple symptoms when fever accompanies sickness malaise and in non-fever contexts with mobility problems. SRC strengthens insights into symptom pairs/clusters.