Part 2: The Patient Swap

The fact that mutations are milder is both a health benefit and a financial problem

There is a health benefit with Cascade Screening[1] — and a financial benefit too, albeit for insurance carriers and Medicaid, not for pharmaceutical companies. Cascade Screening is highly effective in locating genuine FH. That’s a big problem for commercial medicine. The patient identification procedure with the greatest efficiency is an unmentioned obstacle. Identifying the genuine FH presents several threats to Pharma’s marketing interests.

  1. First, those with mild mutations are the majority of carriers.
  2. Their mildness undermines the marketing message of “urgency.”
  3. They are milder, it is speculated, because environmental factors often do play a role in cholesterol levels. Thus, there are other remedies. Even when these milder mutations are found, doctors will be less likely to prescribe risky and expensive drugs.
  4. Lastly, “Precision Medicine” is the future, leaving these Pharma profits vulnerable to increased public exposure to the fact that mutations are milder, threatening to expose all of the above and more: “Underdiagnosis” is not only proven, but given awareness of the problem, touting the scoring system as sufficient causes underdiagnosis.

When the medical solution is a financial problem, ethical conduct needs to step forward. Should the industry mitigate the risks of selling off-label? If the genuine carriers are milder than previously thought and if environmental factors do play a role, then there is an overlap of carriers and non-carriers, both above and below clinical passing scores. Setting aside Cascade Screening, if Pharma is truly concerned with “precision medicine” then they should use the two procedures, not as a choice between alternatives, but as two necessary steps in a procedure of elimination.

  1. It is prohibitively expensive and structurally impossible to genetically test entire populations. So the first step is practical: scoring systems.  But with this, the milder mutation carriers are eliminated from consideration – the majority of carriers.
  2. Also, most of those with passing scores will not be FH carriers. So genetic testing is the second step. We want to eliminate the non-carriers, just as a detective uses forensic DNA matching to eliminate the innocent from his list of suspects. The non-mutation carriers are eliminated here – the majority of those who survived the 1st step.
FH genetic testing, Familial hypercholesterolemia,  FH prevalence

“Commercial Medicine” is full of irony. For a CEO, the solution to the problem of finding the FH mutation carrierscomes with the problem of finding them. They are milder than previously thought.  Mitigating the risks of off-label sales through the diagnostic scoring systems, as always, presents a problem for profits.  Drug sales are now a fraction of what they were. Pharma’s problem with genetic approaches to FH is not the severity of the disease, but the mildness – not medical, but financial. However, Pharma has found a financial solution to the problem of diagnostic accuracy: inaccuracy.

Lowering identification standards increases the resulting population

The potential conflict between genetic testing and the scoring systems is parallel to that of the two types of evidence within legal judgments: the weaker forms of circumstantial evidence and the forensic DNA match.[2]  With the circumstantial, the fewer characteristicsthere are, the larger our pool of suspects … but we also increase the number of innocent included. When it comes to weighting circumstantial evidence, the error-rate is scalable, every notch lower in the standard for evaluation (threshold) increases the number of innocent in our pool, disproportionately — because the number of the actual guilty remains fixed. On the other hand, a forensic DNA match, when done correctly, is not scalable. It is 1 match for 1 criminal.

In medicine, the terminology is different but the epistemological conflict is the same.This linguistic unfamiliarity is what Pharma-funded FH reports are trying to exploit. They reduce the standards of the scalable, circumstantial, scoring systems, while discouraging the more forensic genetic testing. They instruct the medical community to regard the results of these lower standards as something more than suspects: these are said to be the actual FH patients, in need of expensive, risky, new medicines. But if we lower the standards for accuracy we do not end up putting more FH on these risky drugs; we disproportionately prescribe the drugs to false positives.

We might as well give the gold medal to the archer who can paint the largest bull’s eye rather than to the one with the better aim.In FH research, we find a target-painting contest, not archery. 

pharma profit versus accuracy,  Familial hypercholesterolemia,  FH prevalence

Here’s the big, unexpected problem when it comes to FH. Genetics, like forensics, is strong and precise. It reduces errors, settling for fewer FH determinations.  A clinical scoring system, like circumstantial evidence, is weak and error-prone. It inflates the count with errors. This is why the accuracy of genetics works against the industry’s aim on profits, while the inaccuracy of the scoring system works for it.  

This brings us to an apparent dilemma. Because the disease is milder than previously thought, if genetics is emphasized, Pharma loses the marketing message of “severity.” On the other hand, because environmental factors are at play (contrary to Pharma’s main message), there is an overlap of Non-FH with FH, and so lowering the standard of the scoring system captures morepeople. But at the same time, it actually increases the decibels behind the bias of “Severity!”  How does this work?


[1] Cascade Screening is a strategy for genetic testing: it traces family lines and uses centralized databases to improve the odds of finding genetic matches. Cascade Screening has been used in the Netherlands with great success. Pharma’s publications do mention Cascade Screening, but they keep the more profitable scoring systems front and center. (The USA is not equipped for widespread Cascade screening. For example, “There are currently no systematic approaches to the identification of FH patients or to cascade screening of their relatives in the United States. In addition, our health care system lacks key structural elements to facilitate the collection of national longitudinal data to measure and track the clinical progress of diagnosed patients.” ~ Am Heart J. 2014 December; 168(6): 807–811. doi:10.1016/j.ahj.2014.09.001. )

[2] Academically, it can be argued that ultimately all evidence is circumstantial. When I speak of “circumstantial” evidence, I mean the weaker forms of circumstantial evidence. When I use the term, “forensic,” I mean a decisive fact, such as finding a DNA match. For the current analysis, I intend a distinction between these two terms according to their base rate. For example, a characteristic associated with a bank robber — a red baseball cap — may be shared with other suspects. There are five people with red baseball caps in the vicinity. Thus, the odds of any given wearer of red baseball caps being the actual criminal is 1 out 5 suspects. These are very poor odds if sighting someone with a red baseball cap is my only criteria. I dismiss this single, isolated fact because it is “merely circumstantial.” On the contrary, if DNA evidence was left behind, and competently analyzed, we would say that the odds of a suspect with the same DNA being the actual criminal is 1 out of 1. That particular DNA is a characteristic unshared with all other suspects in the vicinity. So when I use the words, “circumstantial evidence,” I mean a weaker base rate which is relies upon characteristics shared with others, and when I say forensic, I mean the strongest base rate: 1 in 1. It relies on a characteristic unshared with all others.