Appendix: key reports, etc

Review of key scientific reports

The “1st report” See footnote [1]   2012: 1st report by four authors: The authors used lowered standards of diagnosis to an extreme, inflating the count with false positives. They also printed “6” in the text as the diagnostic cutoff while using 5 off-text in the actual calculation, claiming 1:137 prevalence. (The established prevalence is 1:500.) Key authors received funding from big pharma. This paper is cited in the Authoritative report (below) as the “source” for the dramatically new and improved prevalence rate. Not quite.  Although this is the source for understanding the means of deriving the eventual results, it is not the source for the actual results used by Nordestgaard, et al. The results here are incorrect and only used by those unaware of the published Corrigendum (see below).  During my analysis, when I refer to the 1st report in reconciliation with the 2nd report, I refer to the methodology of this 1st report, while using the criteria and results of the Corrigendum. Among at least two of the authors, collectively, money has been received from AstraZeneca, Merck, Pfizer, Abbott, Sanofi-Aventis, Roche, Amgen, Novartis, Boehringer-Ingelheim, GlaxoWellcome, Genfit, Karo Bio, Omthera, and Regeneron. This report also appended genetic results to clinical results, and did not present the breakdown of the genetic results into their original clinical scores. They then later claimed that this was a solely phenotypic result, but this was so only because the genotypic were given a phenotypic score. As we shall see, this demotion of the genotypic to the phenotypic in this 1st report obscures the existence of off-target mutations below the clinical cutoff and replaces them with false positives.
The “Authoritative Report” See footnote [2]   2013: Three of the authors of the 1st report (above) join a larger team and write this “consensus report” — funded by Big-Pharma: Amgen, Aegerion, AstraZeneca, Genzyme, HoffmanLa Roche, Kowa Europe, Novartis, and SanofiAventis/Regeneron. This report is widely cited and has influenced FDA and Insurance formulary perceptions.  In a caption to one of the charts in the selfsame Authoritative report, we find the key prevalence information and correction to the 1st report: “This was originally reported as 1/137 but recalculation suggested that the prevalence of definite or probable familial hypercholesterolaemia combined is closer to 1/200 (personal communication Børge G Nordestgaard).” This is the only contemporary source for this widely influential increase in FH prevalence.[3] This 2013 paper is nonetheless now regarded as authoritative and is cited in FDA documents for the doubled prevalence count.  It did not conduct a prevalence study of its own. The Authoritative report simply printed a total and that total was not even from the external source cited.  Again, the only contemporary“source” for the new prevalence is found in this self-same report, as a personal communication, found within a caption to an illustration. The prevalence rate, it claims, has doubled. The corrigendum (see below) does not yet exist.
The “Corrigendum” to the 1st report See footnote [4]   2014: This is the only external, detailed accounting using the new and improved prevalence rate, and yet it is not cited in the Authoritative report. But the authors have a good excuse.  It would have required a time machine. The Corrigendum did not yet exist at the time the Authoritative report was published. Its total is highly cited by regulators, investors, and the industry.  But almost all cite … the Authoritative report … as if it were the source, even though the Authoritative report did not conduct a prevalence study of its own. The exaggerated numbers had been shouted loud and clear in the 1st report; this later Corrigendum was relatively quiet.  In the correction, the authors issued an apology, moved the diagnostic standard up one notch, and still doubledthe prevalence to 1:223. My analysis estimates that half of the corrected results were still made up of false positives.[5]  With health and billions of dollars at stake, why not insist that real sources be cited when extreme increases in prevalence are declared in FDA submitted documents?
The “2nd report” See footnote [6]   2016: The same four authors appear to verify the prevalence of their 1st report but actually provide the greater detail that refutes it deductively.  The same 60,000 people are shared between the two reports. Data from this later report provides an inside view to a constituent population used in its entirety in the 1st report and shows that even after granting the highest molecular results mathematically possible, the 1st report was, at a minimum, 51% inflated with false positives. Using real-world estimates, and considering the addressable market, the actual false positive percentage was probably closer to 80%. Reconciliation of the two reports also shows that two different constituents are passed off to the reader as if the same people, and as if the coincidental similarity in their total number proves the 1st report. From the 2nd to the 1st report, genuine mutation carriers are swapped out, and false positives, swapped in.  In sum: Under careful scrutiny the 2nd report decisively refutes the 1st report, upon which the Authoritative report depends.  Red Flag:  After some authors disclosed receipt of pharma-money in the 1st and Authoritative reports, the authors declare no financial interest in the 2nd report, as if they’d never been financially interested in the Big-pharma agenda.
The “Regeneron report” See footnote [7] 2016: It adds evidence to my analysis of the preceding reports and provides an outline of the whole publication strategy. (1) It repeats the linguistic conflation of separate diseases. (2) It repeats the targeting of advantageous geography, what I call, “Geno-mandering.” (3) It again inserts an inflated group into the results. (4) It continues the engineering of a social condition, the outcome of which is off-label marketing: from genetic message to recommended clinical diagnosis, genuine carriers are swapped out and false positives swapped in.

Other Significant Reports

Cuchel See footnote [8] 2014: Report promoted by Aegerion (now Novelion) in SEC filed 10-Ks.  Its source for prevalence is the Authoritative report, even though the Authoritative report’s source was supposed to be the 1st report (above). It also cites the Sjouke report (below), which is a study of The Netherlands – a country whose FH population was earlier reported to be influenced by founder effect. (See Kusters report below.)  Cuchel was involved in Aegerion’s Juxtapid/lomitapide studies. Funding by pharma.
Sjouke See footnote [9] 2014: Molecular study of The Netherlands. Used in Cuchel’s report (above). Even though Kusters and Defesche had already joined an earlier study (below) which concluded founder effect in The Netherlands, they join the team here which claims that the prevalence rate can be extrapolated to the USA. The study also finds that most mutation carriers score below the clinical profile. Funding by pharma.
Kusters See footnote [10] 2011: An earlier study of founder effect in The Netherlands. Defesche is also one of the authors. Founder effect is an anomaly where genetically inherited diseases can have inordinately high prevalence rates. A population influenced by founder effect cannot reasonably be used as a proxy for the general population or the USA.
The “Earlier Report” See footnote [11] 2005: Three out of four of the same authors of the 1st and 2nd reports published an earlier report. These authors show an understanding of the variability of mutation phenotypes and the significance of environmental factors. (Also, click here.)
Damgaard 2004 (online 2005): The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population: Dorte Damgaard, Mogens L. Larsen, Peter H. Nissen, Jesper M. Jensena, Henrik K. Jensen, Vibeke R. Soerensen, Lillian G. Jensen, Ole Faergeman | Atherosclerosis 180 (2005) 155–160
Brusgaard 2006: Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia: Brusgaard K, Jordan P, Hansen H, Hansen AB, Horder M. | Clin. Genet 2006: 69: 277-283. Blackwell Munksgaard, 2006

[1] 2012: Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication: Marianne Benn, Gerald F. Watts, Anne Tybjaerg-Hansen,and Børge G. Nordestgaard J Clin Endocrin Metab. First published ahead of print August 14, 2012 as doi:10.1210/jc.2012-1563

[2] 2013: Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society: Børge G. Nordestgaard, M. John Chapman, Steve E. Humphries, Henry N. Ginsberg, Luis Masana, Olivier S. Descamps, OlovWiklund, Robert A. Hegele, Frederick J. Raal, Joep C. Defesche, AlbertWiegman, Raul D. Santos, Gerald F.Watts, Klaus G. Parhofer, G. Kees Hovingh, PetriT.Kovanen, Catherine Boileau, MaurizioAverna, JanBore´n, EricBruckert, Alberico L. Catapano, Jan Albert Kuivenhoven, Pa¨ivi Pajukanta, Kausik Ray, Anton F. H. Stalenhoef, Erik Stroes, Marja-Riitta Taskinen, and Anne Tybjærg-Hansen, for the European Atherosclerosis Society Consensus Panel European Heart Journal doi:10.1093/eurheartj/eht273

[3] See “Citation Kiting” here.

[4] 2014: Corrigendum to (doi: 10.1210/jc.2014-3926) “Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication” by Marianne Benn, Gerald F. Watts, Anne Tybjærg-Hansen, and Børge G. Nordestgaard J Clin Endocrinol Metab, December 2014, 99(12):4758–4759

[5] “New management, same old tricks: how the promotion of manipulated science is misrepresentation of market and off-label promotion”

[6] 2016: Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217: Marianne Benn, Gerald F.Watts, Anne Tybjærg-Hansen, and Børge G. Nordestgaard (Note, this includes the supplementary material) 2016: Supplementary Material: How to identify persons with mutations causative for familial hypercholesterolemia: Screening of 98,098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217 European Heart Journal (2016) 37, 1384–1394 doi:10.1093/eurheartj/ehw028

[7] 2016: Genetic identification of familial hypercholesterolemia within a single U.S. health care system: Noura Abul-Husn, et al.

[8] Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society; Marina Cuchel, Eric Bruckert, Henry N. Ginsberg, Frederick J. Raal, Raul D. Santos, Robert A. Hegele, Jan Albert Kuivenhoven, Børge G. Nordestgaard, Olivier S. Descamps, Elisabeth Steinhagen-Thiessen, Anne Tybjærg-Hansen, Gerald F. Watts, Maurizio Averna, Catherine Boileau, Jan Boren, Alberico L. Catapano, Joep C. Defesche, G. Kees Hovingh, Steve E. Humphries, Petri T. Kovanen, Luis Masana, Paivi Pajukanta, Klaus G. Parhofer, Kausik K. Ray, Anton F. H. Stalenhoef, Erik Stroes, Marja-Riitta Taskinen, Albert Wiegman, Olov Wiklund, and M. John Chapman, for the European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. (Jul 2014)

[9] Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome; Barbara Sjouke, D. Meeike Kusters, Iris Kindt, Joost Besseling, Joep C. Defesche, Eric J.G. Sijbrands, Jeanine E. Roeters van Lennep, Anton F.H. Stalenhoef, AlbertWiegman, Jacqueline de Graaf, SigridW. Fouchier, John J.P. Kastelein and G. Kees Hovingh (Feb. 2014)

[10] Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes; D. Meeike Kusters, Roeland Huijgen; Joep C. Defesche; Maud N. Vissers, Iris Kindt, Barbara A. Hutten and John .J.P. Kastelein (2011)

[11] 2004: 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 Arterioscler Thromb Vasc Biol. is available at DOI: 10.1161/01.ATV.0000149380.94984.f0