We Need to Reframe the Way We Think About Rare Diseases
On making medicine more “zebra”-friendly
Medical school students are frequently warned, “When you hear hoofbeats, look for horses, not zebras,” an aphorism that is essentially the diagnostic equivalent of Occam’s razor, telling students to suspect the obvious before the exotic. Admittedly, this adage only makes sense in certain contexts, namely outside of Africa.
Patients with rare diseases are regarded as zebras in the medical vernacular. The disease diagnosis process should begin with the simplest, most commonly encountered answers and proceed methodically from there. Only after eliminating the run-of-the-mill and routine should one probe for the rare and unlikely.
How many rare diseases even exist? A recent analysis by Smith et al. aims to shed some light on the question and estimates the number of rare diseases at around 10,000. The authors also outline criteria for distinguishing between rare, ultra-rare, and hyper-rare diseases, depending on prevalence.
Bayesian inference highlights common maladies instead of rare ones. But diagnosticians themselves warn that probabilistic reasoning cannot be used to quantify the odds of a disease existing in a single patient and advise that “zebra”-like diagnoses must be kept in mind until evidence conclusively rules them out:
“In making the diagnosis of the cause of illness in an individual case, calculations of probability have no meaning. The pertinent question is whether the disease is present or not. Whether it is rare or common does not change the odds in a single patient … If the diagnosis can be made on the basis of specific criteria, then these criteria are either fulfilled or not fulfilled.”
— Harvey, A. M.; et al. (1979). Differential Diagnosis (3rd ed.). Philadelphia: W.B. Saunders.
The well-intentioned advice to look for horses and not zebras necessarily means that large swaths of patients fall through the cracks of the conventional healthcare system. Women and minority patients are often written off once common diagnoses are exhausted.
Instead of digging deeper and continuing to investigate more uncommon possibilities, healthcare practitioners may resort to psychologizing a patient’s symptoms. These behaviors, combined with factors like confirmation bias and availability heuristic, lead to obstructive delays in getting a proper diagnosis. But keeping the facts in mind can help us make progress.
For one, rare diseases are far more common than we think and affect at least 200,000 Americans. The global Ehlers-Danlos patient community adopted the zebra as their mascot in an effort to raise awareness about rare diseases. Ehlers-Danlos Syndrome (EDS) is a connective tissue disorder characterized by double-jointedness, or hypermobility, as well as vascular instability. The condition can present with co-morbidities like postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS), the three of which often form a diagnostic triumvirate.
Secondly, therapies targeted to the average frequently only work for a small proportion of the population due to the heterogeneity inherent among individuals, underlying the importance of precision medicine. Single-person (n-of-1) studies are useful in helping highlight the wide variability in response to treatment methods.
Compiling databases with patient-reported observations can help bridge the gap for underserved medical communities, and companies like Alike Health and StuffThatWorks are leading early efforts to make these services more easily accessible.
