Conflating R3500Q with controversial R3531C does not increase FDB-as-R3500Q.
R3500Q is also known as p.Arg3527Gln, and R3531C is also known as p.Arg3558Cys. (Click here and here.) For the paragraphs below I will defer to Regeneron’s use of p.Arg3527Gln and p.Arg3558Cys. Elsewhere in my report I will defer to the 1st and 2nd Danish report’s synonymous usage of R3500Q, in comparison with which I will use R3531C.
FDB is usually restricted to p.Arg3527Gln. Previous studies of FDB prevalence have not used p.Arg3558Cys. There is no doubt that when it comes to p.Arg3558Cys, there is some in vitro evidence suggesting FDB. However, it has been determined by many scientists that the p.Arg3558Cys is not sufficient to constitute FDB, in vivo. Like the FH and FDB conflation demonstrated in the preceding chapter, an explanation is lacking here as well.
Traditionally, prevalence for FDB-as-p.Arg3527Gln is between 1:1,000 and 1:1,250. In this Regeneron associated study FDB-as-p.Arg3527Gln is 50,726 ÷ 56 = prevalence of 1 in 906.Regeneron’s FDB-as-p.Arg3527Gln prevalence rate appears to be slightly higher than the established rate. However, influences of selection bias are present, and two of them are serious. First, this result enveloped a region known to have the highest p.Arg3527Gln prevalence in the world, due to founder effect. (Click here.) Second, the result was from 98.4% whites of European descent, a group known to have higher prevalence of this APOB mutation than the general population. (Click here.) Once these biases are removed, it is likely that the prevalence will be equal to or lower than the established rate.
Adding the p.Arg3558Cys into a prevalence count feels more like slipping a Canadian quarter into a roll of US coins and then handing them all over to the practical assumptions of a bank teller. If one insists that Canadian quarters should be counted, the controversy should be addressed openly. The fact that a culture may unwittingly circulate foreign coins does not mean that the bank is going to accept them. From the start, customers and merchants alike should be informed, and bankers should be consulted. Likewise, where is the FDA on this? Is FDB “FH”? Is p.Arg3558Cys “FDB”? Does the medical community even know the elements to the debate? How could they? Big Pharma is in control of the publication strategy, and formerly distinct diseases have already been conflated into “FH.”And now we see the same sort of conflation within FDB: a mutation which had previously not been included in FDB prevalence counts is suddenly included. Can I really compare two prevalence studies whose constituents are not identical?
For example, if Study A declares: “10 horses are under a tent,” but Study B stretches that tent further over 10 zebras and calls all of them, “20 horses,” the number of horses has not increased; the number of zebras has not increased, and the total of both has not increased. There is no news here. A claimed “higher prevalence of horses” is really just definition stretching, not discovery. It is simply a linguistic and mathematical manipulation. If p.Arg3558Cys had not been counted before, but are now, then the issue belongs to a linguistic reclassification and an incidental mathematical adjustment. The new accounting should be out in the open. There should not however be a claim that more people were found: separately identified groups have been joined together under one of their names – incidentally, the one most likely to be indicated by the FDA for drug sales: “FH.” That’s it. There should have been nothing new here besides the necessary math after stretching the linguistic definition. But no, FH is first conflated with FDB, which itself is a conflation of the heretofore counted APOB with heretofore uncounted APOB.
Again the issue of whether to include or exclude p.Arg3558Cys as an FDB mutation is an issue for the medical community and the FDA to decide. The violation I outline here is with simple linguistics and math. Stretching the definition of FDB over p.Arg3558Cys and comparing the result to previous studies that did not stretch the definition must be accompanied by both a detailed explanation and a routine breakdown of the mathematical adjustment.FDB-with–p.Arg3558Cysis not an increaseover FDB-without–p.Arg3558Cys; it is just a bad rhyme – or more like a pun, where two meanings are triggered by a single word, “FDB” … but then again, it is unlike a pun in that in this case the listener is not supposed to “get it.”
APOB R3531C were not counted in previous prevalence studies:
- APOB R3531C, AKA, p.Arg3558Cys, were not counted in previous prevalence studies.
- For the FDB prevalence estimates of 1:1,000 and 1:1,250 only R3500Q, AKA p.Arg3527Gln, was counted.