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Lewis and Green Genome Medicine (2021) 13:14 Page 3 of 10

disease PRS into absolute risk models found no [30] under which the patient would need to inform family
and a modest [31] statistically significant improve- members [39].
ment in accuracy compared to use of the same It is not clear how these circumstances should be de-
models without the score. Another study found that fined for PRS. The PRS of first degree family members
when incorporated into risk models, highly elevated are correlated [40], but this information is not as clear
PRS were much more predictive of myocardial infarc- cut as in the monogenic case when a precise probability
tion early in life when other risk factors have yet to of carrying a variant can be given. How high would poly-
manifest [32]. In an early randomized controlled trial genic risk need to be to prompt warning to family mem-
of a PRS for coronary heart disease, participants ran- bers? Guidelines developed by professional societies are
domized to receive the PRS had improved lipid levels needed for both patients and providers. These would
as a result of statin use in those with higher scores possibly be condition specific and would need to incorp-
[33]. One meta-analysis found little evidence that gen- orate input from relevant stakeholders including pa-
etic risk information changed behaviors [34]while tients, genetic counselors, epidemiologists, and primary
others have found evidence for positive behavior care physicians. Products to serve the separate use case
change [35, 36]. Finally, a recent study of 7000 indi- of reproductive planning—the analog of carrier screen-
viduals in Finland found those with high PRS were ing for PRS—will likely also surface. Again, guidelines
more likely to take action such as losing weight or will be needed.
stopping smoking [37].
PRS that are commercially available include those Defining how to approach secondary or incidental
from Myriad Genetics for breast cancer risk [7], from findings
Ambry Genetics for breast cancer and prostate cancer In the monogenic, diagnostic setting of exome and gen-
risk [6], and from 23andMe for type 2 diabetes risk [8]. ome sequencing, the American College of Medical Gen-
Several companies will produce polygenic reports based etics and Genomics (ACMG) has recommended that
on a user’s upload of their 23andMe or Ancestry.com laboratories look for a defined set of genetic variation
data. Given that there are already PRS on the market, that, if present, would be medically actionable [41]. Al-
and that large-scale studies investigating the return of though this was initially considered controversial [42], it
PRS have started, reflection on ELSI concerns is urgently has been adopted in some form by almost all diagnostic
needed. sequencing laboratories in the USA. Most PRS are cur-
rently generated from SNP-chips that are not suited to
Are ELSI themes from the monogenic setting capture all of this variation, but it is possible to select
relevant? SNP-chips that contain much of this variation (i.e.,
Genetic information, and its use in the clinic and be- known pathogenic and likely pathogenic variants in the
yond, has long been considered worthy of special reflec- same set of genes). This raises the question of whether
tion. When the widespread reporting of monogenic there is an ethical imperative to use these chips to pro-
variation based on DNA sequencing was on the horizon, vide such secondary findings.
a vast amount of work started under the umbrella of Genome-derived ancestry itself may be considered an
ELSI of human genome research. We consider several of incidental finding under some circumstances. In the
the most prominent themes in this literature, to assess polygenic setting, it is possible that an individual’s gen-
their relevance in the polygenic context. etic ancestry will be calculated to determine which
ancestry-specific PRS to use or to determine which rela-
The relevance of findings to family members tive risk figures to quote for the patient. If so, it is un-
Genetic variation is shared in families, with many ensu- clear whether the laboratory should report which
ing ethical quandaries, running from how to handle sur- calculated genetic ancestry was used. And if it is re-
prises about paternity to what to do if you realize that ported, there is a chance that this is different from how
the mother of a baby is a BRCA carrier [38]. An individ- an individual might self-identify in terms of ancestry. Pa-
ual has a 50% chance to pass a monogenic variant on to tient preferences should be studied about this possible
a child, and this binary inheritance can be traced unexpected finding, including how to contextualize the
through a family tree. The American Medical Associa- information.
tion’s Council on Ethical and Judicial Affairs considered
the responsibility of the physician towards a patient’s The role of expert mediators
family members and concluded that the physician has a Within medicine, clinical genetics is exceptional in that
duty to discuss the significance of genetic information it leverages an allied field of genetic counseling, made up
with family members as part of informed consent for of professionals who are dedicated to helping individuals
genetic testing, including defining the circumstances anticipate and subsequently navigate the genetic