A few months ago, I wrote about an article on the challenges for patients seeking a timely XLH diagnosis: “The diagnostic odyssey children and adolescents with X-linked hypophosphataemia.” The article was intended to show how data could help clinicians predict the diagnosis based on certain symptoms, but in my reading, it just showed how messy health records are, which makes historic data and even an individual’s past data less than useful for diagnostic purposes.
A similar article was published in September: “Epidemiological analysis to identify predictors of X-linked hypophosphatemia (XLH) diagnosis.”
The authors were looking for a way to improve the timely diagnosis of XLH by creating an algorithm that could sort through large patient databases (electronic health records, EHRs) to look for a missed diagnosis. To create an algorithm, they needed to establish a number of individual symptoms/tests that correlated with an XLH diagnosis. The obvious ones are prescription of appropriate treatment (although that requires a correct diagnosis already, no need for the algorithm to suggest a diagnosis), and lower-body x-rays (indicating that the caregiver and/or clinician was concerned with lower limb issues). No surprises there!
Another not-surprising result was an almost universal pattern of misdiagnosis for XLH patients (at least the spontaneous ones) early on in the process. This too isn’t surprising to patients, since we’ve lived it: the patient is initially misdiagnosed with a more common condition, which has to be ruled out before the correct diagnosis is found. The whole thing becomes circular, when the early misdiagnosis that the algorithm is trying to prevent actually gets built into a predictive factor in the algorithm. So the first correlating factor for predicting a future diagnosis of XLH is one you can probably guess: large numbers of past vitamin D prescriptions, because the clinician has incorrectly diagnosed nutritional rickets. The algorithm basically concedes that the initial diagnosis will be wrong and can’t be addressed.
The second correlation factor was more interesting to me, in that it has nothing to do with actual symptoms of XLH, as far as anyone knows, and I can’t imagine why it’s so common among pediatric XLHers. It was the prescription of antihistamines (and a high number of upper respiratory infections).
I’d love to see someone followup on that correlation. The article goes on to speculate about it, but the discussion seems to be based on the assumption that we have universally low amounts of vitamin D in our blood, and that’s not necessarily true. We can have perfectly normal vitamin D levels in our blood, but be unable to transform it into calcitriol, an active form of vitamin D. The authors do discuss calcitriol as well, and that explanation makes more sense, although apparently the science of vitamin D (including calcitriol) and allergies is unclear and needs more research. (Hey, researchers: the XLH community would be a great starting point for understanding this issue better for everyone, not just us!)
While we might not understand the correlation between XLH and upper respiratory infections, the data (if borne out in additional studies; this one included a small number of patients) could still be useful. Assuming the correlation exists, and assuming we had robust databases to study, it would be relatively easy for to look for patients who had that high number of upper respiratory infections, and then refer them to an expert to look for more XLH-specific issues (the lower limb x-rays, in particular) and perhaps automatically request a phosphorus blood test if it hadn’t already been done.
I’m not sure what entity would be motivated to do that kind of research (and who would have access to the databases; pharma would have a motive, but not access), but I can envision a slightly different scenario that would be more likely. Consider a patient (or parents, most likely) whose child has bowed legs and delayed mobility, who’s convinced there’s something wrong, but the clinician can’t figure out what it is. A program, perhaps loaded with misdiagnosis-searching algorithms for each of hundreds of rare diseases, could compare that patient’s data with its algorithms and generate leads for the clinician to pursue. Including, when a patient has had a lot of vitamin D and/or antihistamine prescriptions, the recommendation to run a phosphorus blood test (and related things like calcium and alkaline phosphatase). It all comes back to getting clinicians to order phosphorus blood tests EARLY in the diagnostic journey. Because once a clinician sees the low number, it’s a relatively easy diagnosis to make (or at least an easy decision to refer to an endocrinologist who could make the diagnosis).
Wouldn’t that be great? Not just for XLH but for the thousands of rare disorders that have some sort of relatively straightforward tests for diagnosis? First, we need more research like in the article above, for XLH and all the other rare diseases, to create the algorithms for each one. And then we’d need to convince clinicians to use it. Neither of which is an easy task, but it gives me hope that we will find new approaches to early diagnosis, using tools and knowledge that we’re just beginning to discover now.
And now for a bit of ad hoc research, since I’m curious — did you have a lot of upper respiratory infections (sinus or ears) as a kid or an adult? I don’t recall having them in childhood, but I had a lot of them (both sinus and ears) as a young adult, and then seemed to age out of them in my forties. What about you?
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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