Temporal Order of Disease Pairs Affects Subsequent Disease Trajectories: The Case of Diabetes and Sleep Apnea

Most studies of disease etiologies focus on one disease only and not the full spectrum of multimorbidities that many patients have. Some disease pairs have shared causal origins, others represent common follow-on diseases, while yet other co-occurring diseases may manifest themselves in random order of appearance. We discuss these different types of disease co-occurrences, and use the two diseases "sleep apnea" and "diabetes" to showcase the approach which otherwise can be applied to any disease pair. We benefit from seven million electronic medical records covering the entire population of Denmark for more than 20 years. Sleep apnea is the most common sleep-related breathing disorder and it has previously been shown to be bidirectionally linked to diabetes, meaning that each disease increases the risk of acquiring the other. We confirm that there is no significant temporal relationship, as approximately half of patients with both diseases are diagnosed with diabetes first. However, we also show that patients diagnosed with diabetes before sleep apnea have a higher disease burden compared to patients diagnosed with sleep apnea before diabetes. The study clearly demonstrates that it is not only the diagnoses in the patient's disease history that are important, but also the specific order in which these diagnosis are given that matters in terms of outcome. We suggest that this should be considered for patient stratification.