David Ledbetter at Collège de France

Earlier today, I saw a class by David H Ledbetter at Collège de France who was invited by Jean-Louis Mandel who holds the human genetics chair in that glorious institution.

He talked about his experience of building a large cohort with Whole Exome Sequencing(WES) at Geisinger Health System. He used to work in academia but was recruited by Glenn D Steele another former academic to lead a large genomics program at Geisinger.

What is Geisinger ?

Geisinger is a not for profit organisation that offers health insurance and also runs large hospitals. It covers mainly a rural area of Pennsylvania where the biggest city is Scranton, a city were the tv series The Office was located to symbolize small-town America. However, the headquarters of Geisinger are not even in Scranton, but in Danville with a population of around 5000 habitants. So, not the most glamorous place!

Geisinger seems to have many advantages for the success of a large cohort:

  • The area has relatively small population turn-over which means that many patients are available for follow-up and sometimes even several generations are living in the area. Furthermore, There is a low turn-over in insurance, people stay with Geisinger. This allows to follow  patients longitudinally over time. This also means that Geisinger has an interest in preventing diseases which is not the case when people change health insurance every 2 years.
  • There is a lot of trust between Geisinger and its clients/patients. Geisinger is the largest employer in the area and people are satisfied with the care they are provided. This is seen in that there is a 90% consent rate for inclusion in the study!
  • The phenotypic data i.e. Electronic Health Records have been in place since 1996 and special care has been given to make it as tidy as possible. This means that on average they have health records for over 12 years easily accessible. Data quality is of course absolutely primordial for the success of such a large scientific endeavour.

Ledbetter joined Geisinger in 2010 anticipating that Francis Collins director of the NIH would soon convince the federal administration to launch a large precision medicine cohort. However, this did not happen until 2015. In the meantime, they partnered with Regeneron therapeutics a New York pharmaceutical company and they have already sequenced over 50000 patients! Regeneron wants to discover variants linked to diseases to find therapeutical targets and they have offered to sequence the samples.

Geisinger now has applied for the precision medicine grants. The precision medicine initiative will fund 7 healthcare providers to sequence each 150000 patients in order to obtain a cohort of over 1 million subjects. A lot of remarkable science will come from that dataset ! Similar efforts are conducted in the UK with 100K genomes or UK Biobank.

Consent forms and involvement of subjects in clinical research

Ledbetter talked a fair bit about consent forms that subjects of a study have to sign to be included. Most of the time, consent forms forbids the researchers to return results to subjects. However, after conducting focus groups with subjects, it became apparent that most people expected their health care provider to not respect that part and tell them if they had anything important. The IRB (International Review Board) therefore changed the consent forms to allow return of information. This means that subjects of the study will benefit from the findings of the study. Ledbetter described the process as building the plane while flying it.

He also described an evolution in terminology occurring in the US, subjects of a study stopped being referred to as subjects but as participants and now they are called partners. This is linked to a turn to greater implication of subjects in advisory boards of the studies meaning that they can influence the health outcomes to be studied. Indeed, they do not always have the same interest as physicians or scientists. This seems rather positive as it allows more trust and implication as well as science more suited to the patients’ needs.

What will patients be told ?

It transpired of the focus groups that the patients trusted Geisinger to decide what was worth telling them and what was not. To begin with, Ledbetter settled on the list proposed by the American College of Medical Geneticists. It regroups 56 genes for which a non-sense mutation is dominant and has a high penetrance. This includes BRCA 1 and 2 of Angelina Joli’s fame. It also includes variants for familial hypercholesterolemia. It is estimated that the variants of the list are present in 2-4% of the healthy adult population. As more and more information on variants becomes available through ClinVar (a central database that regroups all known variants), more patients will receive genetic counselling. For a variant to be reported, it has to be clinically actionable i.e. some prevention scheme or treatment must be available to improve outcome.


This is all very exciting. The focus is very much on monogenic disorders where the most immediate consequences of WES are. For complex diseases, it seems harder to use WES as the difference between GWAS and WES is a lot of variants present in very few people. And it is hard to increase prediction accuracy with variables that have such a low variance.  However, the potential of GWAS+machine learning for complex diseases with such large cohorts is underappreciated by the scientific community cf earlier post.


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