Industry and author awareness of selection bias and milder mutations

Familial hypercholesterolemia, FH scoring system, FH prevalence, selection bias

A selection bias in FH scoring systems was the very conclusion made by three of the authors of the Danish reports, in their Earlier report: scoring systems exaggerate LDL levels to the upside.[1]It then follows: the FH mutations were also milder than previously thought. This is only possible if there is a variability of scores present in the FH. The excerpts below say as much. No one disputes that this variability is also present among the non-FH. And as we have seen, because the variability is present in both populations, there is a “poisoned premise” [2] within FH scoring systems, after which the industry’s recommended diagnostic procedure fails and the swap of patients becomes a mathematical necessity.

2005:“Phenotype of Heterozygotes for Low-Density Lipoprotein Receptor Mutations Identified in Different Background Populations,” Anne Tybjærg-Hansen, Henrik Kjærulf Jensen, Marianne Benn, Rolf Steffensen, Gorm Jensen, Børge G. Nordestgaard DOI: 10.1161/01.ATV.0000149380.94984.f0

They write:

“The effect of mutations on phenotype is often overestimated because of ascertainment bias.”

“Ascertainment bias” is an academic term for the selection bias that concerns the authors. Their conclusion is not possible without two elements of selection bias: first, all those who have been selected for referrals to a clinic tend to have more severe symptoms than those carriers who did not receive referrals, and second, those genuine carriers who do nothave passing clinical scores had been precluded from the tally in previous studies. In short, a group of mutation carriers found by testing a randomly selected population of 10,000 (thus, “unselected”) is compared to a group selectedby the “Simon Broome criteria,” the latter being one of the FH scoring systems.

Here is a comparison of the selected population against the unselected one:

“Furthermore, background population was a significant determinant of the apparent phenotype associated with these mutations: carriers identified among patients with IHD or clinical FH had increasingly higher levels of cholesterol compared with carriers in the general population.“

Here is a threat to Big Pharma profits: evidence that environmental factors play a role in LDL levels. This takes away from the industry’s argument that expensive medications are the only solution for mutation carriers.

“Effect of Background Population on Phenotype: Importance of Ascertainment Bias

Heterozygous carriers of LDLR mutations with IHD or FH had cholesterol levels that were on average 1.2 and 2.0 mmol/L higher than in carriers identified in the general population. Because the type of LDLR mutations were the same in carriers identified in the 3 different background populations, the increase in cholesterol levels in the patient groups was not caused by an effect of the LDLR mutations, but could be attributed to both “environmental factors,” such as dietary intake and obesity, and to other minor mutations that modulate the cholesterol phenotype in the IHD and FH populations in general.”

And …

“In heterozygotes identified in the general population, a different genetic makeup or environmental factors could counteract the effect of LDLR mutations by reducing synthesis or increasing breakdown rates of LDL, resulting in lower cholesterol levels. However, differences in cholesterol levels between probands identified in the general population or among patients with IHD or FH could not be explained by differences in type of LDLR mutation, because these were the same and could also not be explained by differences in the most obvious confounders: age, gender, and body mass index.”

And here is another statement on the effects of selection bias on FH studies.

“In further support of our conclusion that cholesterol levels associated with a given mutation are overestimated among patients with IHD or FH is the fact that we found the exact same results for APOB R3500Q when identified in similar background populations.  Finally, that phenotype associated with a given mutation is overestimated in patients has also clearly been demonstrated by us and others for hemochromatosis mutations, and for factor V Leiden and venous thrombosis.”

The final sentence:

“In conclusion, our results suggest that the phenotype associated with a given mutation should not be determined in patients, but rather in unselected individuals in the general population.”

Other authors prove the cultural awareness of the variability of the characteristics (phenotype) of FH

“FH is a disease that shows great phenotypic variability.”… “A study on 643 Danish probands could not even find a single phenotypic characteristic to predict the existence of a mutation.”  [3]

 “For all other patients with FH caused by LDLR defects, environmental or other inherited factors seem to be more important than the type of mutation in determining the phenotype severity.”[4]

“Consequently, the phenotype of FH individuals is highly variable, probably also due to environmental factors and other genetic polymorphisms influencing the clinical outcome of FH.” .… “We here present a large, descriptive study of 1038 Danish FH individuals, who display a wide variety of phenotype regardless of mutation status.” [5]

Key authors first show awareness of selection bias then reverse themselves later

2005: Anne Tybjærg-Hansen, Marianne Benn, Børge G. Nordestgaard (and others) write their Earlier 2005 report on the selection bias inherent in FH clinical scoring systems. This shows that these three were aware when they later reverse and employ that bias in 2012.

2012: Anne Tybjærg-Hansen, Marianne Benn, and Børge G. Nordestgaard co-author this 1st report and the later 2nd report. They reverse themselves. Three of the 2005 authors completely ignored their own previous exposure of the selection bias and then used it in this 2012 report.  (Gerald F. Watts will join them here.) Watts and Nordestgaard disclose heavy funding from various Pharmaceutical companies, including but not limited to Amgen and Sanofi-Aventis.

2013:Three of the above 2012 authors show up again. Nordestgaard will be the lead author to the industry’s Authoritative report, the 2013 EAS “consensus” report, which claims the 2012 1st Danish report as its source. Tybjærg-Hansen and Watts will be co-authors, among others.  Again, they recommend the scoring systems. There is heavy Pharma funding.

2016: Anne Tybjærg-Hansen, Marianne Benn, Gerald F. Watts and Børge G. Nordestgaard co-author the 2nd Danish report – stating results “comparable” to the 2012 1st Danish report. But this recent 2016 report actually provides the detail with which we can make decisive deductions, refuting their own former 2012 research. The authors again recommend the scoring systems.


[1] For an explanation of selection bias, click here.

[2] For an explanation of the “poisoned premise,” click here.

[3] Familial Hypercholesterolemia: The Lipids or the Genes? Akl C Fahed and Georges M Nemer; 2011

[4] Mechanisms of Disease: genetic causes of familial hypercholesterolemia; Anne K Soutar and Rossi P Naoumova 2007

[5] No certain predictors for mutation status in a Danish cohort with familial hypercholesterolemia: A descriptive study Mads Nybo, Klaus Brusgaard, Annebirthe Bo Hansen; 2007