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[76]. For PRS, if current scores are beneficial, which is led to a long-simmering debate. PRS are likely to re-
under active debate, and if the benefits depend on pre- invigorate both these conversations. The use of bio-
dictive power, then their use would disproportionately markers for psychiatric conditions is not well
benefit those of European ancestry. Similar dangers have established, and in the case of PRS, research is inter-
also been raised for other branches of personalized woven with sociobehavioral outcomes, posing new eth-
medicine [77]. Statistical methodologies have been pro- ical challenges.
posed to help narrow this gap in predictive power, but
they will not be able to fully close it. This poses an im- The relevance of race, ethnicity, and ancestry
mediate issue of whether tests should be restricted by The argument that clinical use of PRS could contribute
ancestry. This is the path taken for example by Ambry to health disparities discussed above stems from the
Genetics, who restrict their prostate cancer test to males current poorer performance of PRS in non-European an-
of European ancestry, and their breast cancer test to fe- cestry individuals, itself largely a result of the lack of rep-
males of Non-Ashkenazi Jewish, Northern European an- resentation of these individuals in the underlying data. A
cestry [6]. One alternative would be to make the test separate set of concerns relates to how the concepts of
available to those of all ancestries, in which case the per- race, ethnicity, and ancestry are used in the development
formance of the test should be reported in as many pop- and deployment of PRS. Outside of genetics, there is no
ulations as possible, and the results suitably caveated. shortage of evidence for racial and ethnic differences in
Which of these alternatives is preferable will be context association between biomarkers and disease or response
dependent, but ideally, it is those negatively impacted to drugs, with attached calls for race-specific cutoffs and
who should have the deciding voice, for example by algorithms [82–84]. A prominent example is the esti-
using focus groups [78]. mated glomerular filtration rate, a surrogate for renal
The medium-term remedy identified is to gather large function, for which a “correction” for race is typically
data sets from populations of diverse ancestries [79]. made [85]. In the risk variant context, the APOE ε4 risk
Several efforts are underway, including the NIH funded allele for Alzheimer’s disease has been reported to have
“All of Us” program, which aims to recruit more than different effects by self-reported race, leading some to
45% of its one million participants from racial and ethnic suggest that use of this allele as a risk factor should “ad-
minorities [80]. It is unclear how we will know if these just for race” [86]. However, the use of “race as a bio-
laudable efforts suitably address the identified issue. The logical variable” is controversial, out of concerns that
predictive power of a biomarker is not guaranteed to be this construct could detract from social determinants of
the same across different groups, even in the presence of health, reinforce racial stereotypes, and contribute to
very large samples, partly because the environment can viewing race—a social construct—as predominantly
differ systematically across these groups. Of course, the based in biology [87, 88]. Adjustments for race might be
routine clinical use of PRS has the potential to exacer- viewed as appropriate if they are tied to underlying gen-
bate health disparities even if equal predictive power is etic differences, suggesting the need for careful attention
obtained across different ancestry groups, for the all too and research into the relationships between ancestry,
familiar structural reasons that cause those disparities in race, racism, and the environment [89]. This is particu-
the first place, including lack of access to care. A larly true for PRS scores, because the portability problem
spectrum of approaches to assessing and addressing in- means that attention to inferred genetic ancestry will be
equities will be needed. necessary to ensure that patients receive accurate and
properly interpreted results. This will not be a straight-
A spotlight on biomarkers for risk forward task, as there are distinct differences in how
Besides the issues raised by the use of PRS in a public those in population genetics, clinical medicine, and epi-
health context, an additional set of concerns that may demiology consider the role of genetic ancestry [90].
arise with the clinical use of PRS are related to long- The use of race, ancestry, and ethnicity in polygenic
standing issues with the use of biomarkers to identify reporting will hence be fraught with both practical diffi-
those at high risk of disease, including the dangers of culties and ethical questions. Urgent interdisciplinary
overtreatment and overdiagnosis [28]. These concerns work to untangle some of these questions is needed.
are linked to how risk biomarkers can change what we
mean by “a disease.” For example, the links between ele- Biomarkers for conditions that present unique challenges
vated blood pressure and heart disease led to the intro- There are at least three reasons to think that PRS for
duction of prehypertension as a disease diagnosis, a psychiatric conditions may raise unique ethical concerns.
classification that applies to vast numbers of asymptom- The first stems from a clinical distinction: the use of any
atic individuals [81]. The ways in which the distributions non-genetic biomarkers for risk for these conditions is
of biomarker values differ across populations have also very limited. The effect of sharing biomarker risk in