Caroline Gombault

Guillaume Grenet

Laure Ségurel

Laurent Duret

François Gueyffier

Pascal Cathébras

Dominique Pontier

MD Sabine Mainbourg

Alicia Sanchez-Mazas

Jean-Christophe Lega
email: jean-christophe.lega@chu-lyon.fr

Sanchez-Mazas Alicia

Laure Segurel

Population designations in biomedical research: limitations and perspectives

Keywords: biomedical translational science, cultural diversity, ethnicity, genetic variation, racial groups

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Population differences are of central interest in biomedical research. Variations in the frequency and severity of diseases among human population groups have been shown in many medical conditions, [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF] including type 2 diabetes, obesity, 2 cardiovascular diseases, [START_REF] Sullivan | Representation of black patients in randomized clinical trials of heart failure with reduced ejection fraction[END_REF][START_REF] Henderson | Established risk factors account for most of the racial differences in cardiovascular disease mortality[END_REF][START_REF] Brewster | Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review[END_REF] prostate cancer, [START_REF] Rotimi | Ancestry and disease in the age of genomic medicine[END_REF] transplantation, [START_REF] Sanchez-Mazas | Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations[END_REF][START_REF] Nunes | The HLA-net GENE[RATE] pipeline for effective HLA data analysis and its application to 145 population samples from Europe and neighbouring areas[END_REF][START_REF] Morishima | Race and Survival in Unrelated Hematopoietic Cell Transplantation[END_REF] asthma, [START_REF] Ortega | Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine[END_REF] systemic lupus erythematosus, [START_REF] Falasinnu | The Representation of Gender and Race/Ethnic Groups in Randomized Clinical Trials of Individuals with Systemic Lupus Erythematosus[END_REF] and neonatal morbidities. [START_REF] Janevic | Association of Race/Ethnicity With Very Preterm Neonatal, et al. Association of Race/Ethnicity With Very Preterm Neonatal Morbidities [Internet][END_REF] Similarly, a number of investigations have provided insights into differences observed after exposure or in response to a given medicine [START_REF] Osei-Assibey | Pharmacotherapy for overweight/obesity in ethnic minorities and White Caucasians: a systematic review and meta-analysis[END_REF][START_REF] Brewster | Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review[END_REF][START_REF] Ramamoorthy | Racial/ethnic differences in drug disposition and response: Review of recently approved drugs[END_REF][START_REF] Mcleod | Pharmacogenetics: more than skin deep[END_REF][START_REF] Li | Racial differences in blood pressure response to angiotensinconverting enzyme inhibitors in children: a meta-analysis[END_REF][START_REF] Wilson | Population genetic structure of variable drug response[END_REF] as well as after tissue transplantation 9 across various populations. While many efforts are made to enhance our understanding of the mechanisms explaining differences in treatment effects, such as that of dipeptidyl peptidase-4 inhibitors in diabetes [START_REF] Kim | Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis[END_REF] and antihypertensive drugs, [START_REF] Brewster | Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review[END_REF] most of the time it remains empirical. It is important to note that, since humans share over 99.9% of their genomes, the phenotypic differences between them are related to a 0.1% genome variation. [START_REF] Lander | Initial sequencing and analysis of the human genome[END_REF] Consequently, with the aim of developing individually-tailored healthcare strategies, the Food and Drug Administration (FDA) states that "Collecting data on race and/or ethnicity is critical to identifying population-specific signals." [START_REF]Collection of Race and Ethnicity Data in Clinical Trials[END_REF] Ramamoorthy et al. found that, in all the new molecular entities approved by the American agency between 2008 and 2013, 21% of them demonstrated population differences. [START_REF] Ramamoorthy | Racial/ethnic differences in drug disposition and response: Review of recently approved drugs[END_REF] Along the same lines, the guidance "Ethnic Factors in the Acceptability of Foreign Clinical Data" of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH E5) states that "any candidate medicine for global development should be characterized as ethnically sensitive or insensitive". [START_REF] Falasinnu | The Representation of Gender and Race/Ethnic Groups in Randomized Clinical Trials of Individuals with Systemic Lupus Erythematosus[END_REF] As a result, and in a holistic spirit, assigning an alleged affiliation to a particular population to participants in clinical studies is seen as a normal methodological choice, and the terminologies used to name the different human population groups are now being used extensively in health research.

Numerous systematic reviews on this topic have been performed, aiming to evaluate the use of these population denominations in biomedical research nowadays. A brief comparison of them reveals that the reporting of population differences in clinical research is characterized by a large disparity in practices, and fraught with methodological issues and inconsistencies. A systematic review of the use of "race/ethnicity" in three top medical journals reported 100 different population labels employed to describe study samples. [START_REF] Kanakamedala | Characterization of clinical study populations by race and ethnicity in biomedical literature[END_REF] In another study reviewing a sample of 995 articles reporting "race/ethnicity", only 4.5% of them formally defined race/ethnicity and only 10.5% reported the method used to attribute the respective "racial/ethnic" designations. [START_REF] Bokor-Billmann | The reporting of race and/or ethnicity in the medical literature: a retrospective bibliometric analysis confirmed room for improvement[END_REF] These findings point out the limitations concerning the practices in terms of population labeling in medical research. The aim of this narrative review is to explain the origins of such a haphazard approach to human diversity and its impact on biomedical research.

About the high heterogeneity in population designations

The dizzying array of terms can be partly explained by the origins of human classifications.

Colonization first led to the advent of the folk idea of "race", when European armies started to encounter populations that differed from them in terms of both physical and cultural features. [START_REF] Cooper | Race and Genomics[END_REF][START_REF] Smedley | Race as biology is fiction, racism as a social problem is real: Anthropological and historical perspectives on the social construction of race[END_REF] For the purpose of standardizing "racial" classifications, modern human categories emerged from the work of European naturalists in the 18 th Century, [START_REF] Cathébras | Pour en finir avec les « Caucasiens ». Catégories raciales et ethniques dans la littérature médicale[END_REF][START_REF] Nobles | History counts: a comparative analysis of racial/color categorization in US and Brazilian censuses[END_REF] leading to the labels "Mongoloid", "Negroid", or "Australoid", depending on the geographical area of origin. [START_REF] Braun | Racial categories in medical practice: how useful are they?[END_REF][START_REF] Winker | Measuring race and ethnicity: why and how?[END_REF][START_REF] Gravlee | How race becomes biology: embodiment of social inequality[END_REF] In order to support the speculations of polygenists and advocates of "racial" ideology, [START_REF] Mathur | Availability and use of UK based ethnicity data for health research -NCRM EPrints Repository[END_REF][START_REF] Cooper | Race in Biological and Biomedical Research[END_REF] scientists began searching for evidence of natural racial distinctions, notably through craniometry, biology, anthropology, and medicine. [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF][START_REF] Braun | Racial categories in medical practice: how useful are they?[END_REF][START_REF] Oppenheimer | Paradigm lost: race, ethnicity, and the search for a new population taxonomy[END_REF][START_REF] Goodman | Why genes don't count (for racial differences in health)[END_REF] Some populations were then considered to be more vulnerable to illness and became commonly associated with it -for instance, diabetes was called "Judenkrankheit" (Jewish disease) in Germany at the beginning of the 20 th Century. [START_REF] Duster | A post-genomic surprise. The molecular reinscription of race in science, law and medicine[END_REF] Such racial classifications became ingrained in biomedical research, which slowly led to a common acceptance of "race" as a biological variable. [START_REF] Oppenheimer | Paradigm lost: race, ethnicity, and the search for a new population taxonomy[END_REF][START_REF] Lee | Race" and "ethnicity" in biomedical research: how do scientists construct and explain differences in health?[END_REF][START_REF] Schwartz | Racial profiling in medical research[END_REF][START_REF] Sankar | Reporting Race and Ethnicity in Genetics Research: Do Journal Recommendations or Resources Matter?[END_REF] It is also important to examine the origins of the human classifications currently used.

Terminology has evolved since the classification systems proposed by naturalists. [START_REF] Bhopal | European, Western, Caucasian, or what? Inappropriate labeling in research on race, ethnicity, and health[END_REF] Nowadays, population classification schemes are widely inspired by the legal and social classification systems of the countries in which the research is conducted. [START_REF] Cooper | Race in Biological and Biomedical Research[END_REF] Many biomedical scientists adopted official census categories in their trial designs and sampling strategies. [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF][START_REF] Nunes | NO to obsolete definitions: YES to blanks[END_REF][START_REF] Ellison | Racial Categories in Medicine: A Failure of Evidence-Based Practice?[END_REF] However, the definitions and the systems used to define population subgroups vary considerably from one country to another, [START_REF] Nobles | History counts: a comparative analysis of racial/color categorization in US and Brazilian censuses[END_REF][START_REF] Gagnon | IMISCOE Research Series -Social Statistics and Ethnic Diversity -IMISCOE Publications Catalogue[END_REF][START_REF] Farkas | Report on Equality Data based on Racial and Ethnic Origin[END_REF] which partly explains the wide diversity of terms and approaches that can be observed in the international biomedical literature. [START_REF] Braun | Racial categories in medical practice: how useful are they?[END_REF][START_REF]Demographic and Social Statistics[END_REF] The United States of America (USA), heavyweight of international biomedical research, refers to the Office of Management and Budget (OMB) Directive No. 15, 19 adopted in 1977 and revised in 1997. [START_REF] Bhopal | European, Western, Caucasian, or what? Inappropriate labeling in research on race, ethnicity, and health[END_REF][START_REF] Perez | The Changing Racial and Ethnic Composition of the US Population: Emerging American Identities[END_REF][START_REF] Gennaro | Racial and Ethnic Identity in Nursing Research[END_REF] The present day classification includes five "racial" groups based on geographical origin or skin color: "American Indian or Alaska Native", "Asian", "Black or African American", "Native Hawaiian or Other Pacific Islander", and "White", with a "Hispanic or Latino" category for ethnicity, [START_REF]Collection of Race and Ethnicity Data in Clinical Trials[END_REF] added in 1970. [START_REF] Gagnon | IMISCOE Research Series -Social Statistics and Ethnic Diversity -IMISCOE Publications Catalogue[END_REF] Multiple choice is permitted, and allows a total of 126 possible combinations. [START_REF] Winker | Measuring race and ethnicity: why and how?[END_REF][START_REF] Perez | The Changing Racial and Ethnic Composition of the US Population: Emerging American Identities[END_REF] In the UK, the classification approach has evolved over time. [START_REF] Gagnon | IMISCOE Research Series -Social Statistics and Ethnic Diversity -IMISCOE Publications Catalogue[END_REF][START_REF] Aspinall | What kind of mixed race/ethnicity data is needed for the 2020/21 global population census round: the cases of the UK, USA, and Canada[END_REF] Currently, the Office for National Statistics (ONS) provides 18 options for England and Wales grouped into five main groups, and these are commonly found in the scientific literature -including, to cite a few examples, "White and Black Caribbean", "White and Asian", "Indian", "Black British", and "Arab". [START_REF] Mathur | Availability and use of UK based ethnicity data for health research -NCRM EPrints Repository[END_REF] In France, often regarded as an "ethnicity-blind" nation, there is no official demographic categorization scheme due to the almost complete prohibition of ethnic-based statistics. [START_REF] Gagnon | IMISCOE Research Series -Social Statistics and Ethnic Diversity -IMISCOE Publications Catalogue[END_REF][START_REF] Farkas | Report on Equality Data based on Racial and Ethnic Origin[END_REF]46,[START_REF] Guerrier | Adequate clinical practice limited by the ethnic French taboo[END_REF] These three cases are sufficient to give an insight into why population denominations are far from being uniform on a global scale.

The issues raised by the current standards

Blurred concepts

The limitations concerning the use of "race/ethnicity" as variables in research are more and more acknowledged by scientists, [START_REF] Winker | Measuring race and ethnicity: why and how?[END_REF][START_REF] Megyesi | A critical review of racial/ethnic variables in osteoporosis and bone density research[END_REF] as well as the complexity of defining adequate labels for different human populations. The work of convincingly deconstructing the legitimacy of common designations, considered by some as reflecting a "biological naivety of researchers", [START_REF]Teaching "race" at medical school: social scientists on the margin[END_REF] has led to an increasing amount of publications in biomedical journals, resulting in numerous controversies and a passionate debate within the scientific community. [START_REF] Cooper | Race and Genomics[END_REF] The first issue concerns the breadth of potential interpretations regarding the concepts related to human diversity, since they are imprecise and lack clear-cut boundaries. [START_REF] Goodman | Why genes don't count (for racial differences in health)[END_REF][START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF] The most obvious concept attached to human diversity is "race". "Race" has no standard definition. [START_REF] Braun | Racial categories in medical practice: how useful are they?[END_REF] It is historically seen as a tool to subdivide the human species into groups of relatively homogenous people, sharing inborn physical characteristics that distinguish them from other groups, and which would reflect their "ancestry" and "geographical origins". [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF][START_REF] Ramamoorthy | Racial/ethnic differences in drug disposition and response: Review of recently approved drugs[END_REF][START_REF] Cathébras | Pour en finir avec les « Caucasiens ». Catégories raciales et ethniques dans la littérature médicale[END_REF] The change in mentalities led to a broadening of its scope to include social and cultural features, [START_REF] Ortega | Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine[END_REF] making its differentiation with the concept of "ethnicity" unclear, as evidenced by the increasing use of the combined terminology "race/ethnicity". [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF][START_REF] Bhopal | European, Western, Caucasian, or what? Inappropriate labeling in research on race, ethnicity, and health[END_REF] "Ethnicity" is seen as a construct combining geographical origin and social dimensions, [START_REF] Gennaro | Racial and Ethnic Identity in Nursing Research[END_REF][START_REF]ICH E5 (R1) Ethnic factors in the acceptability of foreign clinical data[END_REF][START_REF] Rosendaal | Race[END_REF] encompassing a broad range of socially constructed characteristics derived from a shared history and a shared heritage, such as language, religion, habits, traditions, values, relational styles, and customs. [START_REF] Ortega | Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine[END_REF][START_REF] Ramamoorthy | Racial/ethnic differences in drug disposition and response: Review of recently approved drugs[END_REF][START_REF] Kreatsoulas | The impact of social determinants on cardiovascular disease[END_REF][START_REF] Burchard | The importance of race and ethnic background in biomedical research and clinical practice[END_REF][START_REF] Eisenhower | Which Box Should I Check?": Examining Standard Check Box Approaches to Measuring Race and Ethnicity[END_REF] It is a multifaceted quality, [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF][START_REF] Farkas | Report on Equality Data based on Racial and Ethnic Origin[END_REF] "achieved" but "not ascribed", [START_REF] Lee | Race" and "ethnicity" in biomedical research: how do scientists construct and explain differences in health?[END_REF] a flexible cultural construct that can have biological implications. [START_REF] Smedley | Race as biology is fiction, racism as a social problem is real: Anthropological and historical perspectives on the social construction of race[END_REF] It is increasingly employed, especially in Europe, as it is seen as more politically correct than "race". [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF][START_REF] Cathébras | Pour en finir avec les « Caucasiens ». Catégories raciales et ethniques dans la littérature médicale[END_REF][START_REF] Mathur | Availability and use of UK based ethnicity data for health research -NCRM EPrints Repository[END_REF][START_REF] Lee | Race" and "ethnicity" in biomedical research: how do scientists construct and explain differences in health?[END_REF] The terms "population" and "ancestry" appear to be less controversial. [START_REF] Fullwiley | The biologistical construction of race: "admixture" technology and the new genetic medicine[END_REF] However, their use is also subject to caution, given their lack of clear definition and their wide range of possible interpretations. [START_REF] Fujimura | Different differences: The use of 'genetic ancestry' versus race in biomedical human genetic research[END_REF] Their "neutral" appearance is a smokescreen: George Ellison reminds us that "population group" was the term used during apartheid in South Africa. [START_REF] Ellison | Population profiling' and public health risk: When and how should we use race/ethnicity?[END_REF] Some see the notion of "shared ancestry" as merely overlaying "racial" categories. [START_REF] Fujimura | Different differences: The use of 'genetic ancestry' versus race in biomedical human genetic research[END_REF] Additionally, although recent generations of ancestors are easy to identify, defining and interpreting deeper genealogical information is highly complex. [START_REF] Fujimura | Different differences: The use of 'genetic ancestry' versus race in biomedical human genetic research[END_REF] In a study addressing the correlation between multiple self-identification measures and classifications based on ancestry informative markers (AIM) and human leukocyte antigen (HLA) genes in the USA, the geographical ancestry of grandparents was more closely correlated with AIM and HLAdefined genetic ancestries than with "race/ethnicity", especially for subjects with African and Latin American ancestry. [START_REF] Hollenbach | Race, Ethnicity and Ancestry in Unrelated Transplant Matching for the National Marrow Donor Program: A Comparison of Multiple Forms of Self-Identification with Genetics[END_REF] Collecting information on the grandparents of donors may thus improve the chances of finding HLA-compatible donors in hematopoietic stem cell transplantation (HSCT), where HLA matches are essential. However, the correlation with the geographical origin of grandparents still remains imperfect for estimating deep genetic ancestry. [START_REF] Hollenbach | Race, Ethnicity and Ancestry in Unrelated Transplant Matching for the National Marrow Donor Program: A Comparison of Multiple Forms of Self-Identification with Genetics[END_REF] "Continent of origin" is also a very broad term that sounds neutral. Touted as the solution to old notions of "race" and "ethnicity", it refers to extremely large clusters, which in the end makes it useless for any proper study of human diversity. Continental population labels actually reinvigorate ideas about "major races", which would be "Africans" or "Europeans". [START_REF] Fujimura | Different differences: The use of 'genetic ancestry' versus race in biomedical human genetic research[END_REF] Finally, the categories may change according to the set of reference populations used in a study, which are often poorly described in studies. [START_REF] Ellison | Racial Categories in Medicine: A Failure of Evidence-Based Practice?[END_REF][START_REF] Mathieson | What is ancestry?[END_REF] A high inconsistency regarding "racial" and "ethnic" classifications across papers as well as between countries have also been reported in a number of biomedical research fields, including pharmacogenomics. [START_REF] Zhang | Inconsistency in race and ethnic classification in pharmacogenetics studies and its potential clinical implications[END_REF] The concept of "ancestry" is also ambiguous and encompasses distinct approaches, framed as "genetic ancestry": (i) methods to infer ancestral relationships between populations, (ii) methods that allow an individual genomes to be represented as a combination of reference populations, and (iii) methods that an infer a degree of similarity between individuals. [START_REF] Mathieson | What is ancestry?[END_REF] However, only the third approach allows showing the continuous, i.e. category-free, nature of genetic variation. [START_REF] Mathieson | What is ancestry?[END_REF]

Imprecise designations

The current designations refer to broad, heterogeneous groups. [START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF] The epithet "Europeans" encompasses an extremely wide range of different phenotypes with, for instance, hair, eye, and skin color varying from relatively dark in Southern Europe to very light in the North. [START_REF] Candille | Genome-Wide Association Studies of Quantitatively Measured Skin, Hair, and Eye Pigmentation in Four European Populations[END_REF] Metabolic pathways and culture also vary considerably as demonstrated by the fact that the main allele (-13,910*T) conferring lactose tolerance varies from less than 10% to more than 95% in Europeans [START_REF] Itan | The Origins of Lactase Persistence in Europe[END_REF] and more than 200 languages (despite 24 official) are spoken in Europe. [START_REF] Eberhard | Languages of the World [Internet[END_REF] Similarly, the term "African" is a crude simplification. More than 1.2 billion humans live in Africa, which is also the continent with the greatest amount of genetic variation on the planet. 65 Although other labels appear to be more accurate, they are not -the category "American Indians and Alaska Natives", also known as "Native Americans", actually refers to more than 500 federally recognized tribes, which are too different from each other to be grouped in one single "pan-Indian" group. [START_REF] Burhansstipanov | Office of Management and Budget racial categories and implications for American Indians and Alaska Natives[END_REF] The breadths of these terms make them inadequate for their use in medical research.

Many used terms are simplistic, and represent, for most, obsolete terms. [START_REF] Oppenheimer | Paradigm lost: race, ethnicity, and the search for a new population taxonomy[END_REF][START_REF] Schwartz | Racial profiling in medical research[END_REF][START_REF] Bhopal | European, Western, Caucasian, or what? Inappropriate labeling in research on race, ethnicity, and health[END_REF][START_REF] Nunes | NO to obsolete definitions: YES to blanks[END_REF] The wellknown "Caucasian" label, for instance, is an unfortunate relic of an old classification of humankind created by a German naturalist named Johann Friedrich Blumenbach in the 18 th Century, who derived Europeans from the region of Caucasus. [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF][START_REF] Sanchez-Mazas | Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations[END_REF][START_REF] Cathébras | Pour en finir avec les « Caucasiens ». Catégories raciales et ethniques dans la littérature médicale[END_REF][START_REF] Fullwiley | The biologistical construction of race: "admixture" technology and the new genetic medicine[END_REF][START_REF] Popejoy | Too many scientists still say Caucasian[END_REF] The label "Black", while being a legacy of colonial anthropology encouraging the division of society by skin color, [START_REF] Sanchez-Mazas | Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations[END_REF] is meaningless in terms of genetic ancestry -dark-skinned people are observed in many areas of the globe, from Africa to India, as well as in Southeast Asia and Australia. [START_REF] Relethford | Hemispheric difference in human skin color[END_REF] The term "mixed" is in itself a nonsense. This category would be of major importance given the increasing rates of mixed sexual unions between distantly related people, particularly in countries such as the USA. [START_REF] Perez | The Changing Racial and Ethnic Composition of the US Population: Emerging American Identities[END_REF] However, the number of potential combinations is so large that the willingness of capturing any "mixed" identity generates substantial reporting issues. [START_REF] Aspinall | What kind of mixed race/ethnicity data is needed for the 2020/21 global population census round: the cases of the UK, USA, and Canada[END_REF] Grouping data of all "mixed" individuals in a single category has, in the end, the same effectiveness as having no data. [START_REF] Bhopal | European, Western, Caucasian, or what? Inappropriate labeling in research on race, ethnicity, and health[END_REF][START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF][START_REF] Burchard | The importance of race and ethnic background in biomedical research and clinical practice[END_REF][START_REF] Burhansstipanov | Office of Management and Budget racial categories and implications for American Indians and Alaska Natives[END_REF] In addition, the term "trans-ethnic" is debated in genomics research because of its imprecision and ambiguity. This term encompasses heterogeneous studies including meta-analytic genome-wide association studies, fine-mapping, and assessment of genetic architecture across populations, or calculation of polygenic risk scores. Kamariza et al. suggested the use of the terms "cross-ancestry", "multi-population" or "multi-ancestry" instead. [START_REF] Kamariza | Misuse of the term 'trans-ethnic' in genomics research[END_REF] These concepts are subjective, and therefore not easily assigned. [START_REF] Gennaro | Racial and Ethnic Identity in Nursing Research[END_REF][START_REF] Hahn | Inconsistencies in coding of race and ethnicity between birth and death in US infants. A new look at infant mortality, 1983 through 1985[END_REF] Penner et al. reported in 2008, from a sample of 12,686 American individuals, that 20% had been affiliated to at least two different "racial" categories by interviewers over a 19-year period. [START_REF] Penner | How social status shapes race[END_REF] According to distinct reporting formats (self-identification of "race/ethnicity" using single or multiple choices, geographical ancestry using single or multiple choices, classification by others), inconsistencies may occur between "race/ethnicity" and geographical ancestry as well as between self-identification and identification by others. [START_REF] Hollenbach | Race, Ethnicity and Ancestry in Unrelated Transplant Matching for the National Marrow Donor Program: A Comparison of Multiple Forms of Self-Identification with Genetics[END_REF] Most often, a lack of concordance between geographical ancestry and "race/ethnicity" reporting occurs when individuals acknowledge particular geographical ancestries but do not explicitly identify with a corresponding "racial/ethnic" group. Less common is "race/ethnicity" self-identification without reporting a corresponding geographical ancestry. [START_REF] Hollenbach | Race, Ethnicity and Ancestry in Unrelated Transplant Matching for the National Marrow Donor Program: A Comparison of Multiple Forms of Self-Identification with Genetics[END_REF] Many dimensions must be taken into consideration when defining identity, and terminology fails to embrace them all -"Hispanic" invokes language, "American Indian" invokes ancestral groups, "Asian" invokes continental origin, "White" invokes skin color. [START_REF] Hunt | Genes, race and research ethics: who's minding the store?[END_REF] The United Nations stated about "ethnicity": "the subjective nature of the term [...] requires that information on ethnicity be acquired through self-declaration of a respondent". [START_REF] Farkas | Report on Equality Data based on Racial and Ethnic Origin[END_REF] This principle is sometimes circumvented by the use of name recognition softwares, such as the "Ethnicolr" program. [START_REF] Henderson | Established risk factors account for most of the racial differences in cardiovascular disease mortality[END_REF][START_REF] Marschke | Last Place? The Intersection of Ethnicity, Gender, and Race in Biomedical[END_REF] However, "ethnicity" reflects, above all, the feeling of belonging to a chosen community, which is subject to change. [START_REF] Winker | Measuring race and ethnicity: why and how?[END_REF][START_REF] Mathur | Availability and use of UK based ethnicity data for health research -NCRM EPrints Repository[END_REF][START_REF] Cooper | Race in Biological and Biomedical Research[END_REF][START_REF] Goodman | Why genes don't count (for racial differences in health)[END_REF][START_REF] Duster | A post-genomic surprise. The molecular reinscription of race in science, law and medicine[END_REF][START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF] Census categories, for instance, can take on new social or political meanings. An example concerns the restoration of Aboriginal people's pride in Canada which led to a major increase in the affiliations of individuals to this category in censuses at the end of the 20 th Century. [START_REF] Gagnon | IMISCOE Research Series -Social Statistics and Ethnic Diversity -IMISCOE Publications Catalogue[END_REF] Conversely, latent racism may influence self-identification in favor of a better socially-perceived group. [START_REF] Gennaro | Racial and Ethnic Identity in Nursing Research[END_REF] Since context influences categorization, [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF][START_REF] Mathur | Availability and use of UK based ethnicity data for health research -NCRM EPrints Repository[END_REF] population designations are interchangeable.

The current use of population designations is ethically questionable. [START_REF] Winker | Measuring race and ethnicity: why and how?[END_REF] Census categories were originally intended only for social and pragmatic reasons, but their widespread use in research unintentionally implies their adequacy for describing so-called "natural" patterns of diversity. [START_REF] Braun | Racial categories in medical practice: how useful are they?[END_REF][START_REF] Gravlee | How race becomes biology: embodiment of social inequality[END_REF][START_REF] Sankar | Reporting Race and Ethnicity in Genetics Research: Do Journal Recommendations or Resources Matter?[END_REF][START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF][START_REF] Ellison | Population profiling' and public health risk: When and how should we use race/ethnicity?[END_REF] Even though the Nazi crimes of World War II largely tempered the previously facile acceptance of "race" as deeply and unalterably biogenetic, [START_REF] Bhopal | European, Western, Caucasian, or what? Inappropriate labeling in research on race, ethnicity, and health[END_REF] and forced scientists to reexamine their thinking on "race", the 21 st Century has surprisingly witnessed a resurgence of "race" through genetics. [START_REF] Smedley | Race as biology is fiction, racism as a social problem is real: Anthropological and historical perspectives on the social construction of race[END_REF][START_REF] Sankar | Reporting Race and Ethnicity in Genetics Research: Do Journal Recommendations or Resources Matter?[END_REF][START_REF] Hunt | Genes, race and research ethics: who's minding the store?[END_REF] Relying on contemporary genomic findings, many researchers see "racial" categories as "reflecting genetic", argue that DNA variations between geographically distinct individuals confirm the existence of biological human "races", [START_REF] Smedley | Race as biology is fiction, racism as a social problem is real: Anthropological and historical perspectives on the social construction of race[END_REF][START_REF] Baer | Concepts of race and ethnicity among health researchers: patterns and implications[END_REF] or believe that race is a valid and reliable proxy for the clustering of genetic diversity. [START_REF]Teaching "race" at medical school: social scientists on the margin[END_REF] Some academics have found "new grist for the racial differences mill". [START_REF] Smedley | Race as biology is fiction, racism as a social problem is real: Anthropological and historical perspectives on the social construction of race[END_REF] This renewed interest in clustering human beings genetically, and the attempts to link this clustering to biological outcomes, regrettably led to a normalization of the use of population designations in an uncritical manner in biomedical research. [START_REF] Gravlee | How race becomes biology: embodiment of social inequality[END_REF][START_REF] Duster | A post-genomic surprise. The molecular reinscription of race in science, law and medicine[END_REF] The numerous consequences of the use of "race/ethnicity" in medical research

The use of "race/ethnicity" as a cause of human heterogeneity can distract from investigating other factors that are really related to a medical condition. In 2013, Braun et al. observed that the majority of the literature studying lung function differences in "racial groups" ignored the importance of socioeconomic factors, despite their well-established influence on pulmonary conditions. [START_REF] Braun | Defining race/ethnicity and explaining difference in research studies on lung function[END_REF] Yet, slavery and colonial history left a legacy of social and economic inequalities, inextricably linked to a greater exposure of immigrant populations to what Kreatsoulas and Anand called "the causes of the causes". [START_REF] Kreatsoulas | The impact of social determinants on cardiovascular disease[END_REF] It refers to the social determinants of disease risk factors such as poor living conditions, low purchasing power, diminished access to healthcare, and health education. [START_REF] Cooper | Race and Genomics[END_REF][START_REF] Smedley | Race as biology is fiction, racism as a social problem is real: Anthropological and historical perspectives on the social construction of race[END_REF][START_REF] Cathébras | Pour en finir avec les « Caucasiens ». Catégories raciales et ethniques dans la littérature médicale[END_REF][START_REF] Beck | Racial disparities in self-rated health: trends, explanatory factors, and the changing role of socio-demographics[END_REF][START_REF] Nazroo | The Black diaspora and health inequalities in the US and England: does where you go and how you get there make a difference?[END_REF][START_REF] Krieger | Living and Dying at the Crossroads: Racism, Embodiment, and Why Theory Is Essential for a Public Health of Consequence[END_REF] Diet and exercise, smoking, cultural and religious practices, compliance with medication, and other behavioral factors also result in health disparities. [START_REF] Henderson | Established risk factors account for most of the racial differences in cardiovascular disease mortality[END_REF][START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF] To highlight the salience of considering environmental factors rather than relying on a self-defined "ancestry" designations, Cooper et al. compared rates of hypertension in several populations of West African "ancestry". [START_REF] Cooper | An international comparative study of blood pressure in populations of European vs. African descent[END_REF] Their findings showed substantial differences in the prevalence of hypertension depending on location, rising from 16% for populations living in Nigeria and Cameroon to 26% in the Caribbean and 33% in metropolitan Chicago. Similarly, the prevalence of diabetes varies greatly among populations with comparable "ancestral background" but different environments. 33,80 6,26,29 To prevent misunderstandings, we should make clear that claiming the inadequacy of the most common human classifications does not amount to asserting that biological and genetic differences among humans of various origins do not exist. The aim here is to shed light on the illogicality of trying to explain differences in disease between humans using such crude concepts and categories. The use of such classifications as shortcuts for the prevalence of a few rare genetic mutations such as that of sickle cell trait in populations of African, Southern European, and Caribbean origin, or of the BRCA gene in individuals self-identifying as "Ashkenazi Jews", may be useful in practice, if cautiously used. [START_REF] Rotimi | Ancestry and disease in the age of genomic medicine[END_REF][START_REF] Braun | Racial categories in medical practice: how useful are they?[END_REF][START_REF] Mathur | Availability and use of UK based ethnicity data for health research -NCRM EPrints Repository[END_REF] However, as soon as we consider complex diseases such as asthma, cancer, diabetes, or cardiovascular diseases, they may become scientifically inadequate and dangerously misleading. Therefore, their use in research raises concerns, and the trivialization of their reporting in biomedical literature has serious consequences.

The need for transnational collaborative research

International research relies on data portability and reproducibility. [START_REF] Megyesi | A critical review of racial/ethnic variables in osteoporosis and bone density research[END_REF] In the reviews aforementioned, population labels are not treated as requiring further clarification in publications, which opens the door to every possible interpretation. The lack of explanation suggests that they are selfevident, that the reader will simply recognize and understand them. Yet, unfortunately, the latter will develop his own understanding of who falls into these designations and who does not. Catherine Lee notes, "when we [researchers] use prototype theory, we have a ''broad picture'' in our minds about what we think we are classifying. Different social groups have different prototypes in mind." [START_REF] Lee | Race" and "ethnicity" in biomedical research: how do scientists construct and explain differences in health?[END_REF] As long as investigators fail to render the labeling of population designations transparent to readers, it will prevent making valid comparisons across clinical trials, even those conducted in the same country. [START_REF] Winker | Measuring race and ethnicity: why and how?[END_REF][START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF][START_REF]The unexamined "Caucasian[END_REF] Additionally, notwithstanding that current global standards are based on the societal stratification of the USA and, hence, do not adequately reflect other nations' migration histories, non-American researchers tend to adopt these standards in their own countries, [START_REF]Collection of Race and Ethnicity Data in Clinical Trials[END_REF][START_REF] Braun | Racial categories in medical practice: how useful are they?[END_REF] which can result in misinterpretations. The term "Asian", for instance, generally refers to people from the Indian subcontinent in the UK, but to Far Eastern Asians in the USA. [START_REF] Bhopal | Glossary of terms relating to ethnicity and race: for reflection and debate[END_REF] Similarly, the term "White" is meant to include Scottish, New Zealander, Greek, Spanish, English, Canadian, Welsh, and Irish altogether, but also includes Iranians and Moroccans in the USA. [START_REF] Bhopal | European, Western, Caucasian, or what? Inappropriate labeling in research on race, ethnicity, and health[END_REF] Communication issues can also arise from the fact that presumably similar groups can be exposed to completely different confounding factors according to the country. For example, Nazroo et al. showed that Caribbean immigrants have very different social and economic positions in the UK and in the USA, impacting their health differently both in positive and negative ways. [START_REF] Nazroo | The Black diaspora and health inequalities in the US and England: does where you go and how you get there make a difference?[END_REF] Accordingly, this haphazard use and reporting of human diversity is at odds with the fundamental requirements of transnational research, which are based on rigorous practices and valid data. [START_REF] Baer | Concepts of race and ethnicity among health researchers: patterns and implications[END_REF][START_REF] Sankar | Race and Ethnicity in Genetic Research[END_REF] In the domain of histocompatibility, such as HSCT where matching HLA genotypes between recipients and donors is essential, the chances of finding a compatible donor is expected to be greater among individuals sharing a greater level of genetics. [START_REF] Nunes | How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians [Internet[END_REF] In some cases (e.g. in Brazil), it may correlate with government-defined broad racial categories such as "Black", "Mixed", and "White", because the latter reflect different amounts of African and European ancestry. [START_REF] Maróstica | How HLA diversity is apportioned: influence of selection and relevance to transplantation[END_REF] However, the use of such categories in transplantation may stigmatize the idea that graft success is race-dependent, which is not. Most HLA alleles encoding functional molecules at the protein level (known as alleles defined at the 2 nd -field level of resolution) [START_REF] Robinson | IPD-IMGT/HLA Database[END_REF] and hence, crucial in transplant matching, are shared across continents. This thus provides chances of finding compatible donors among distantly-related populations, although identifying a fully-matched donor at multiple HLA loci (ideally both alleles at five loci, known as 10/10 matching) remains challenging when no HLA-identical sibling donor is available. [START_REF] Tiercy | How to select the best available related or unrelated donor of hematopoietic stem cells?[END_REF]

Reinforcing stereotypes in medicine and biology

Many researchers claim that even if societal categories are ill-defined, they remain fairly correlated with economic factors and behavioral traits. But one should not minimize the potential social costs of this reasoning. [START_REF] Rotimi | Ancestry and disease in the age of genomic medicine[END_REF][START_REF] Cathébras | Pour en finir avec les « Caucasiens ». Catégories raciales et ethniques dans la littérature médicale[END_REF][START_REF] Schwartz | Racial profiling in medical research[END_REF][START_REF] Hunt | Genes, race and research ethics: who's minding the store?[END_REF] Human classification is by nature associated with stigmatization, marginalization, and prejudice, even though these concepts may be useful to address the effect of inequities on population health. [START_REF] Goodman | Why genes don't count (for racial differences in health)[END_REF][START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF][START_REF] Yudell | Science a,nd society. Taking race out of human genetics[END_REF] In research, it has been proven that "ancestry" or "origins" are poor proxies for sociocultural variables and, besides being a distraction from other relevant causes of disease, [START_REF] Winker | Measuring race and ethnicity: why and how?[END_REF][START_REF] Goodman | Why genes don't count (for racial differences in health)[END_REF] their use emphasizes the alleged biological underpinnings of health inequalities. [START_REF] Ellison | Population profiling' and public health risk: When and how should we use race/ethnicity?[END_REF] It has been demonstrated that the use of certain human categories in medical research influences the behavior of physicians, and reifies these categories by contributing to the perpetuation of healthcare disparities. [START_REF] Ellison | Racial Categories in Medicine: A Failure of Evidence-Based Practice?[END_REF][START_REF] Burchard | The importance of race and ethnic background in biomedical research and clinical practice[END_REF] As a brief example, a study showed that patients with cystic fibrosis seen as being of "African origin" have a diagnostic disadvantage, because historically this affection was seen as being limited to "Europeans". [START_REF] Stewart | Cystic Fibrosis in the African Diaspora[END_REF] A similar situation was observed in women with osteoporosis. [START_REF] Megyesi | A critical review of racial/ethnic variables in osteoporosis and bone density research[END_REF]

The pitfalls of "racial-genetic determinism"

One of the main consequences of the trivialization of human classifications in research is the spread of "racial-genetic determinism" [START_REF] Gravlee | How race becomes biology: embodiment of social inequality[END_REF] or "genetic reductionism" [START_REF]Teaching "race" at medical school: social scientists on the margin[END_REF][START_REF] Hunt | Genes, race and research ethics: who's minding the store?[END_REF] among researchers. Nancy Kieger denounces the "still dominant ahistorical and decontextualized biomedical and lifestyle theories of disease distribution, which reduce causes of disease to individuals' genetic constitution and 'personal tastes'". [START_REF] Krieger | Living and Dying at the Crossroads: Racism, Embodiment, and Why Theory Is Essential for a Public Health of Consequence[END_REF] Alan Goodman also warns us about "geneticization", which he defines as "the belief that most biology and behavior are located in the 'genes'". [START_REF] Goodman | Why genes don't count (for racial differences in health)[END_REF] Indeed, studies looking for "running genes" in Kenyan sprinters, [START_REF] Holden | Peering under the hood of Africa's runners[END_REF] or linking the prevalence of diabetes in Pima Indians and asthma therapy efficiency in "Hispanic ascendance" to their retrospective degree of European admixture, [START_REF] Ortega | Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine[END_REF] contribute to legitimizing simplistic conclusions on complex genetic and social processes.

Of course, some genetic variants do correlate with an individual's geographical origin, especially those which confer an adaptation to a specific local environment. It is the case for lactase persistence in pastoral populations, [START_REF] Ségurel | On the Evolution of Lactase Persistence in Humans[END_REF][START_REF] Vicente | Population history and genetic adaptation of the Fulani nomads: inferences from genome-wide data and the lactase persistence trait[END_REF][START_REF] Gerbault | Impact of Selection and Demography on the Diffusion of Lactase Persistence[END_REF] and dark skin pigmentation which protects humans from sunburn and skin cancer, and also light skin pigmentation which facilitates the synthesis of vitamin D3 in northerly latitudes. [START_REF] Tang | Skin color variation in Africa[END_REF][START_REF] Sulem | Genetic determinants of hair, eye and skin pigmentation in Europeans[END_REF] It is then commonplace to connect certain phenotypic features with specific areas of the globe. However, although some striking differences are observed concerning hair and eye color, the label "continental populations" has been proven to not be informative for other common heritable traits such as height, [START_REF] Lanktree | Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height[END_REF] which is subject to substantial differences between Maasai and Biaka people in sub-Saharan Africa, Swedish and Sicilians in Europe, and even new generations of Japanese compared to older generations. [START_REF] Cooper | Race and Genomics[END_REF] The non-concordant patterns followed by genetic variations are so complex that attempting to graft them onto labeled delimited populations is misleading. [START_REF] Goodman | Why genes don't count (for racial differences in health)[END_REF][START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF][START_REF] Hunt | Genes, race and research ethics: who's minding the store?[END_REF][START_REF] Sankar | Race and Ethnicity in Genetic Research[END_REF] Alan Goodman said that "traits tend to vary independently of other traits" and that, consequently, human clustering schemes change according to the trait chosen: a classification based on sickle cell trait groups Africans, Greeks, and Turks together, while a classification based on lactase enzyme deficiency gathers southern Africans with Japanese and Native Americans. [START_REF] Goodman | Why genes don't count (for racial differences in health)[END_REF] The incidence of sickle cell traits in West Africa was about 4% in the Mandinka people, 14% in the Wolof people, rose to around 30% in the Fula people, but was also very high in India, with an incidence of 35% in the Oktar people. [START_REF] Braun | Defining race/ethnicity and explaining difference in research studies on lung function[END_REF] Surprisingly, the determining role of genetics for visible "skin deep" variations and marked population differences for a few rare traits led many biomedical scientists to apply the same reasoning to all diseases, thus undervaluing the complexity of human genetic variation and of genotype-phenotype links. [START_REF] Kanakamedala | Characterization of clinical study populations by race and ethnicity in biomedical literature[END_REF][START_REF] Gravlee | How race becomes biology: embodiment of social inequality[END_REF][START_REF] Schwartz | Racial profiling in medical research[END_REF][START_REF]Teaching "race" at medical school: social scientists on the margin[END_REF][START_REF] Goldstein | Common genetic variation and human traits[END_REF] This is highly problematic for research since, according to the WHO, the great majority of trials registered globally between 1999 and 2018 concern complex multigenic chronic affections such as diabetes, cancer, obesity, and hypertension. In these cases, the influence of genetic variants on incidence of disease or response to treatment is often associated with small effect sizes with low to moderate clinical consequences. [START_REF] Cooper | Race and Genomics[END_REF][START_REF] Mountain | Assessing genetic contributions to phenotypic differences among "racial" and "ethnic" groups[END_REF][START_REF] Kaufman | Socioeconomic status and health in blacks and whites: the problem of residual confounding and the resiliency of race[END_REF] This reasoning is also frequently found in pharmacology, especially in pharmacogenetics. Over the last decades, single nucleotide polymorphisms (SNPs) have been at the core of investigations, since they are known to have a great impact on pharmacokinetics and pharmacodynamics if located in some genes, specifically those encoding drug metabolizing cytochromes P450, phase II enzymes, and drug transporters. Factors influencing the emergence of these specific SNPs are still under deep investigation, and, ineluctably, "racial" considerations became center-stage, and prompted the FDA and other agencies to set up "population-specific recommendations" based on the genetic results observed in samples of individuals. For instance, the agency states that 7% to 10% of "Caucasians" and 3% to 8% of "Black/African Americans" are poor metabolizers for CYP2D6, [START_REF] Ramamoorthy | Racial/ethnic differences in drug disposition and response: Review of recently approved drugs[END_REF] which can lead them to a higher exposure than others when taking certain medicines such as iloperidone. These low percentages show well that these phenomena are everything but "all-or-none". [START_REF] Mcleod | Pharmacogenetics: more than skin deep[END_REF] Cytochromes P450 also displayed wide variations within populations. [START_REF] Shah | Precision medicine: does ethnicity information complement genotype-based prescribing decisions?[END_REF] In short, while identifying poor metabolizers is essential, such shortcuts have no place in pharmacogenetics, especially when a patient's safety is at stake. [START_REF] Mcleod | Pharmacogenetics: more than skin deep[END_REF] To conclude, it is widely acknowledged that all human beings do not have the exact same genetic makeup, and that genomics plays a great role in disease diagnosis and personalized treatments.

However, commonly inferred genetic clusters, based on geographical arguments, are inaccurately represented by widely used "racial/ethnic" labels, and have been shown to inherently present a great and significant variance in drug-metabolizing profiles, on which target-oriented medicine largely relies on. [START_REF] Wilson | Population genetic structure of variable drug response[END_REF]

How can we durably improve practices in research?

Enhance the involvement of biomedical journals to enforce "good practices" guidelines

Recommendations on how to handle population terminology in biomedical research have existed for many years. [START_REF] Winker | Measuring race and ethnicity: why and how?[END_REF][START_REF] Sankar | Race and Ethnicity in Genetic Research[END_REF]100 At the beginning of their use, the FDA clearly stated that OMB categories, which now dominate scientific literature, were intended to ensure consistency in population data reporting, and specified that they should not be interpreted as being scientific or anthropological in nature. [START_REF]Collection of Race and Ethnicity Data in Clinical Trials[END_REF] Biomedical editors who are members of the International Committee of Medical Journal Editors (ICMJE) provided instructions to authors on the proper use of terminology for research on "race/ethnicity" in the fifth edition of their "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" (renamed as "Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals") including the justification and definition of "race/ethnicity" and the relevance of the use of such concepts in regards to the aim of the study. [START_REF] Lee | Race" and "ethnicity" in biomedical research: how do scientists construct and explain differences in health?[END_REF][START_REF] Bhopal | European, Western, Caucasian, or what? Inappropriate labeling in research on race, ethnicity, and health[END_REF]101 In 2000, Nature Genetics published a policy stating that authors must explain why they make use of particular ethnic groups or populations, and how classification was achieved. 102 Unfortunately, these recommendations are rarely enforced by the reviewers' of biomedical journals or respected by the authors [START_REF] Bokor-Billmann | The reporting of race and/or ethnicity in the medical literature: a retrospective bibliometric analysis confirmed room for improvement[END_REF][START_REF] Cathébras | Pour en finir avec les « Caucasiens ». Catégories raciales et ethniques dans la littérature médicale[END_REF][START_REF] Ellison | Racial Categories in Medicine: A Failure of Evidence-Based Practice?[END_REF][START_REF] Sankar | Race and Ethnicity in Genetic Research[END_REF]103,104 including Nature Genetics itself. [START_REF] Hunt | Genes, race and research ethics: who's minding the store?[END_REF] This global unheeding of guidance may be partly explained by the fact that calls for improving practices were made only in an intermittent and disjointed fashion, which consequently perpetuated ambiguity on this topic and made addressing change more challenging. [START_REF] Yudell | Science a,nd society. Taking race out of human genetics[END_REF] If all biomedical journals agree to strengthen the control of manuscripts' compliance with requirements on proper population labeling practices, improvements will surely be observed. Among the 486 reporting guidelines available on the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) website, searching for the words 'ethnicity' retrieved no result, and searching for 'race' gave three results but focused on specific situations (forensic context). 105

Changes in the mentalities of authors and their personal involvement

The profusion of "race/ethnicity" variables in biomedical research is partly rooted in the requirements established in 1993 by American regulatory bodies and funding agencies [START_REF]Collection of Race and Ethnicity Data in Clinical Trials[END_REF]106,107 to promote the inclusion of participants of all origins in study samples. [START_REF] Sullivan | Representation of black patients in randomized clinical trials of heart failure with reduced ejection fraction[END_REF][START_REF] Falasinnu | The Representation of Gender and Race/Ethnic Groups in Randomized Clinical Trials of Individuals with Systemic Lupus Erythematosus[END_REF][START_REF] Ramamoorthy | Racial/ethnic differences in drug disposition and response: Review of recently approved drugs[END_REF][START_REF] Lee | Race" and "ethnicity" in biomedical research: how do scientists construct and explain differences in health?[END_REF][START_REF] Megyesi | A critical review of racial/ethnic variables in osteoporosis and bone density research[END_REF]103,104,[107][108][109] Reporting is therefore more frequent in the USA than in other countries 110 but, as mentioned before, is now accepted and expected internationally. [START_REF] Kanakamedala | Characterization of clinical study populations by race and ethnicity in biomedical literature[END_REF] Beyond the fact that legal requirement is not a valid scientific argument, [START_REF] Nunes | NO to obsolete definitions: YES to blanks[END_REF] the main concern here is that the use of "race/ethnicity" categories is often only required as a "descriptive" tool meant to observe differences in inclusion or failures of randomization, but routinely drifts to an inappropriate "attributive" use of these labels as explanatory arguments. [START_REF] Braun | Racial categories in medical practice: how useful are they?[END_REF][START_REF] Ellison | Racial Categories in Medicine: A Failure of Evidence-Based Practice?[END_REF][START_REF] Kaplan | Use of race and ethnicity in biomedical publication[END_REF] Initially based on the well-intentioned goal of addressing underrepresentation of minorities in research, these requirements have unintendedly contributed to a further reifying of the census categories as genetic entities, and their continued use perpetuates the idea of them being adequate to explain patterns of human genetic variation. [START_REF] Baer | Concepts of race and ethnicity among health researchers: patterns and implications[END_REF] There is a clear contradiction in the research field: many studies showed that the limitations of common population designations is well-known and accepted by the research community, and, surprisingly, it is still extensively used and routinely reported in health research. 111 Many emphasize the need of reporting this variable for the sake of research, and affirm that "race" is the best proxy available for studying human diversity. [START_REF] Yudell | Science a,nd society. Taking race out of human genetics[END_REF] It is seen as useful, "in the meantime", until better surrogates are found. [START_REF] Braun | Racial categories in medical practice: how useful are they?[END_REF][START_REF] Burchard | The importance of race and ethnic background in biomedical research and clinical practice[END_REF][START_REF] Hunt | Genes, race and research ethics: who's minding the store?[END_REF][START_REF] Mountain | Assessing genetic contributions to phenotypic differences among "racial" and "ethnic" groups[END_REF] The lack of proper education concerning the question of human diversity is salient in biomedical education. [START_REF] Baer | Concepts of race and ethnicity among health researchers: patterns and implications[END_REF] Behavior and genetic explanations are prioritized over discriminatory and environmental ones. Medical students traditionally learn that patients' histories begin with "this is a [insert patient's age, presumed race, sex] who presents with a chief complaint of…." -though they receive little or no training on these concepts. [START_REF] Winker | Measuring race and ethnicity: why and how?[END_REF] Some researchers, who explicitly defend the racial labeling of participants, qualify debates about the use of "race/ethnicity" in health as political correctness, denounce the "color-blind" approach to biomedical research as "[flying] in the face of clinical reality", [START_REF]Teaching "race" at medical school: social scientists on the margin[END_REF]112 and claim that these practices are appropriate in the scientific area as soon as any value system is attached to it. Troy Duster reacts to the latter point by saying that "while the sentiment is admirable, this formulation constitutes a fundamentally flawed notion of a firewall between 'science' and 'politics'". [START_REF] Duster | A post-genomic surprise. The molecular reinscription of race in science, law and medicine[END_REF] As an example, when the South African National Blood Service was blamed for classifying donors on the basis of "racial/ethnic" categories in order to estimate their risk of HIV infection, some clinicians found it regrettable to face political sensitivities for what they considered to be a risk-based approach founded on medical realities. [START_REF] Ellison | Population profiling' and public health risk: When and how should we use race/ethnicity?[END_REF] However, rather than blaming political correctness, underlining the role that apartheid and its socioeconomic consequences played in the differential spread of HIV virus could have explained more adequately the approach undertaken. [START_REF] Ellison | Population profiling' and public health risk: When and how should we use race/ethnicity?[END_REF] Lastly and briefly, other researchers are unfortunately reluctant to follow recommendations for the simple reason that it would require a revision of previous results, or a renunciation of the use of old databases built on OMB categories or on vague continental designations. 113 In conclusion, practices regarding the labeling of subpopulations do not exhibit a level of rigor one would expect in biomedical research. Attempts of resolving these issues are not facilitated by the wide range of opinions among researchers, and, most of all, the quandary surrounding this topic.

"Race", "ethnicity", "ancestry", "geographical origin", and other similar concepts are saturated with meanings and are increasingly considered as being non-acceptable due to their history of misuse and injustice -Cooper says that "race" is "the unwelcome guest in the disciplines of science". [START_REF] Cooper | Race in Biological and Biomedical Research[END_REF] The debate on whether reporting "race/ethnicity"-related outcomes is useful in research has persisted over many decades. Even if the feasibility of a global consensus regarding labeling is unclear, [START_REF] Farkas | Report on Equality Data based on Racial and Ethnic Origin[END_REF] sociologists, geneticists, anthropologists, and ethicists may help develop policies and practices for the biomedical field. For now, the priority for research publications are the following.

First, the use of outdated concepts such as "Caucasian" should be banned, while precise and adequate labeling (e.g. "African diaspora from the 15 th Century to the present', 'grandparents born in Turkey') need to be promoted according to the objectives and the setting of the study. [START_REF]The unexamined "Caucasian[END_REF] To reduce stereotypes in biomedical research, educational efforts are required during biological, medical, and pharmaceutical training to improve knowledge on human evolution, by including courses on human migration, demographic history, environmental adaptation, as well as genetic structure and diversity between individuals and populations. Multidisciplinary approaches are needed to propose new consensus [START_REF] Kamariza | Misuse of the term 'trans-ethnic' in genomics research[END_REF] which would require the engagement of the communities concerned and international societies. 114 Second, when it is legally required to ask patients to self-identify as being part of a particular population group in a study, it should, as much as possible, not appear in the study findings. Journal editors should promote adequate statistical methods (e.g. subgroup analysis in clinical trials 115,116 ) (Figure 1) and develop new sets of standards in accordance with modern concepts. In 2021, the editors of the Journal of the American Medical Association (JAMA) acknowledged, as we do here, that "race" and "ethnicity" are social constructs without scientific or biological meaning and proposed guidance on how to report such designations in medical and science journals. 117 Among their recommendations, to provide explanations on the source and reasons of the classifications used and to prioritize the use of specific over collective terms (e.g. "underrepresented populations" rather than "minorities"; descriptions according to country or regional areas of origin rather than broad terms referring to continental areas, etc) represent an important step forward. However, other JAMA advices remain limited to the US context and are hardly exportable internationally: for example, the proper term of "race" is unaccepted in many countries like France 118 , and US government-defined descriptors like "Black" or "American Indian" are inadequate in non-US countries (e.g. "populations of African descent" is suggested for populations of African origin not living in Africa by the European HLA-NET network [START_REF] Sanchez-Mazas | Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations[END_REF][START_REF] Nunes | NO to obsolete definitions: YES to blanks[END_REF] and "First Nations" is used for indigenous people in Canada). A main challenge for scientific journals is thus sill to adapt their guidance for population designations to an international context.

Finally, the reporting of patients' origins should not be tolerated if not justified, particularly if it is employed as a proxy for cultural habits, diet, or environmental exposure in regards to the high risk of false positive results (Figure 1). If all biomedical researchers adopt a critical view on how they handle and report human diversity, and invest themselves in adopting the right practices, real improvements can be made. However, for now sadly, the concepts of "race" and "ethnicity" remain deeply ingrained in biomedical research.

Acknowledgement:

The authors thank Véréna Landel for her valuable help in proofreading the manuscript.

Funding: This work was supported by the Swiss National Science Foundation (Grants Nos. 1003A_144180 and 310030_188820 to A.S.-M.).

Conflict of interest statement: none of the authors declared any conflict of interest


Zhengyu Zhang

Arnaud Brosseau

Margaux Elie

Jean-Luc Renaud

Matthieu Hamel

Sylvain Gaillard

Robert Bernard Pansu

Burning TADF Solids Reveals their Excitons' Mobility

Keywords: Luminescence decay, solid state luminescence, FRET, TADF, Perrin, exciton mobility, Copper complex luminescence

HIGHLIGHTS

The luminescence decays of solid samples are often complex due in part to the presence of defects. In the case of these TADF molecular solids, the analysis of the decays after the addition of defects provides the quenching distance of the triplet and singlet states.

ABSTRACT Nowadays, Thermally Activated Delayed Fluorescence (TADF) compounds have proven to be attractive for highly efficient optoelectronic devices as they can exploit both singlet and triplet excited states generated by charge recombinations that occur in such devices.

However, quenching of excited states limits such benefits at high current densities. We have studied the quenching in the case of cationic copper(I) complexes coordinated by both Nheterolytic carbene (NHC) and 2,2'-dipyridylamine (dpa) ligands. Defects are created in their crystals by a strong laser irradiation. Then we have investigated, by analysing their fluorescence decay as a function of temperature, the quenching mechanism and the exciton mobility. Using a time-resolved version of the Perrin's quenching model, we show that the quenching volume depends on temperature according to the singlet/triplet equilibrium. At room temperature, the singlet states are responsible for 75% of the quenching although they contribute for 2% to the excited states population. From the analysis of the decay curves, we show that the excitons are not mobile in the crystals and are quenched through Förster Resonant Energy Transfer (FRET).

INTRODUCTION

The luminescence decay in solids is always complex. This has been attributed to sample heterogeneity 1 and to distance-dependent quenching of the excited state by the defects or impurities [START_REF] Főrster | Transfer mechanisms of electronic excitation[END_REF] . Local environment heterogeneity is often dominated by the presence of a few defects close to the excited state. The decay without quenchers is significantly different from that with one quencher. To the opposite, in solution, the Brownian motion averages out distances and numbers of quenchers before the emission of the photon. In solution, all emitters can be considered to have the same environment and the same lifetime. Thus, it is often assumed that the lifetimes are associated with species. In solid, even if crystallized samples are quite clean and neat, the population of the excited states is a mixture of excitons with zero, one, two, … a few defects with different quenching rates. This multiplicity of lifetimes explains why nowadays, decays in solid are often overlooked. In solid, the description of the fluorescence requires the calculation of the numbers of defects and their corresponding distribution. The calculation of the number of defects that are within the quenching volumes around the excited states is known as the Perrin model. [START_REF] Perrin | Loi de décroissance du pouvoir fluorescent en fonction de la concentration[END_REF][START_REF] Blumen | On the concentration and time dependence of the energy transfer to randomly distributed acceptors[END_REF][START_REF] Hartmann | Quenching Dynamics in CdSe Nanoparticles: Surface Induced Defects upon Dilution[END_REF] In particular, the fraction of the excitons that have no quenchers in their surroundings (Fig. 1a), have an exponential decay with the longest lifetime and was expressed by F. Perrin as: 3

𝑭 𝒑𝒖𝒓 = 𝐞𝐱𝐩 &-[𝑸]𝑽 𝑸 (𝑻)/ , (1)
where [Q] is the density of the quenching defects and 𝑉 % (𝑇) is the quenching volume. In this contribution, we shall measure the number of defects within the quenching volume (Fig. 1b) and determine the quenching process from the analysis of the shape of the fluorescence decay curves. For that we create defects by burning the sample at high laser fluences. Electroluminescence, used in OLED (Organic Light Emitting Diode) or LEC (Light-Emitting Electrochemical Cell) technologies, is an emission of light resulting from the excited state, generated by the recombination of an electron and a hole in the emitting layer, of the emissive compound. However, spin statistics implies that 75% of the electrically generated pairs are triplets, which have most of the time a low luminescence yield for the majority of organic compounds. Compounds that exhibit a delayed fluorescence after thermal activation of the triplets (TADF) can also convert efficiently triplet states into light. [START_REF] Uoyama | Highly efficient organic lightemitting diodes from delayed fluorescence[END_REF] Among the known TADF emitters, copper(I) complexes are one of the most attractive. 7,8,[START_REF] Leitl | Phosphorescence versus thermally activated delayed fluorescence. Controlling singlet-triplet splitting in brightly emitting and sublimable Cu(I) compounds[END_REF] It is noteworthy that the highest yields in OLEDs, although reaching ~100%, are achieved at low current densities only, whereas above 100 mA/cm 2 , this yield is reduced and a roll-off of the luminescence is observed because of the quenching of excited states by charges or by their mutual annihilations. [START_REF] Sandanayaka | Exciton Quenching Behavior of Thermally Activated Delayed Fluorescence Molecules by Charge Carriers[END_REF] The operation of OLEDs at high luminescence thus requires the control of these losses.

In this paper, we study the quenching of [Cu(IPr)(dpa)][PF 6 ]

(IPr: 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene; dpa: 2,2'dipyridylamine), shown on Fig. 2, in its crystalline form 11 (see experimental section and the paragraph a of the Supplementary Information (SIa)). Indeed, we have reported a family of [Cu(NHC)(N^N)] + complexes (NHC = N-Heterocyclic Carbene, and N^N = bridged bis-pyridyl derivatives) that exhibit a TADF behavior and some of them have been successfully applied in LEC devices. [START_REF] Elie | Designing NHC-Copper(I) Dipyridylamine Complexes for Blue Light-Emitting Electrochemical Cells[END_REF][START_REF] Elie | Role of the bridging group in bis-pyridyl ligands: Enhancing both photo-and electro-luminescent features of cationic (IPr)Cu(I) complexes[END_REF][START_REF] Leitl | Copper(I) Complexes for Thermally Activated Delayed Fluorescence: From Photophysical to Device Properties[END_REF] degradation to investigate the mobility of the excitons and the quenching mechanism in this solid.

In TADF materials, the excited states equilibrate between the singlets and triplets according to equation (2): 15

𝑅(𝑇) = [' ! ] [* ! ] = + "#$ , 𝑒𝑥𝑝 &- -. %& /* / (2)
where [S 1 ] and [T 1 ] are the concentrations of singlets and triplets, ∆E ST is the energy difference between singlet and triplet states per luminescence site, k is the Boltzmann constant, T is the

temperature. 𝜙 012 = / "#$ / "#$ 3/ ' 3/ () 3/ *+,&
is the yield of the intersystem conversion to the triplet state compared to the other desactivation rates of the singlet. 𝜙 012 is 1 when the intersystem conversion is fast compared to the decay rate of singlet state. [START_REF] Etherington | Revealing the spin-vibronic coupling mechanism of thermally activated delayed fluorescence[END_REF] This temperature dependence of the singlet/triplet equilibrium allows the observation of the impact of the nature of the excited states on the quenching, in the same TADF sample, with the same concentration and distribution of defects. From equation (1) a measure and an analysis of the quenching volume as a function of temperature is possible. We show that the Förster energy transfer is the path of the quenching of both triplet and singlet states but with a larger quenching volume in the case of singlets (2.4 times larger for [Cu(IPr)(dpa)][PF 6 ] crystals). The dynamics of the quenching in [Cu(IPr)(dpa)][PF 6 ] crystals show that excitons are trapped, which prevent the triplet-triplet and singlet-singlet annihilations and limit the quenching by charge carriers.

MATERIAL AND METHODS

Crystals of [Cu(IPr)(dpa)][PF 6 ] were obtained from a slow gas diffusion of hexane into a chloroform solution of the copper complex. Crystals were then crunched to prepare crystals with thickness smaller than the extinction length of the laser into individual particle. 17 They were then dispersed into a KBr powder at a dispersion of 5% by weight to form a homogeneous sample that fits with the laser beam diameter. The mixture was inserted into an Oxford Instrument cryostat and the temperature was controlled by a nitrogen gas flow between 77 K and 310 K. The sample was excited with the third harmonic of a NdYAG laser Surelite from Continuum. The energy was 2 mJ per pulse over an area of 0.25 cm 2 . The pulse duration was 5 ns and the repetition rate was 10 Hz. The luminescence was collected at 90° and analyzed with a transient absorption setup, LP920 from Edinburgh Instrument at 500±2.5 nm. The setup was previously described. [START_REF] Wrona-Piotrowicz | Efficient synthesis of pyrene-1-carbothioamides and carboxamides. Tunable solid-state fluorescence of pyrene-1-carboxamides[END_REF]

RESULTS AND DISCUSSION

Generation of defects

We think that the photo-transformation of luminescent molecules in solids (burning) is a suitable way to probe the mobility and the quenching volume of the excitons. In the excited state, molecules have an excess of energy that can lead to their destruction and thus the formation of photoproducts that will quench the luminescence. Consequently, a

[Cu(IPr)(dpa)][PF 6 ] sample was bleached by strong laser irradiations (80 pulses of 8 mJ/cm 2 of the third harmonic of a NdYAG laser for each measurement) to create quenchers in the crystals. This is ten times more than the power typically used to study such samples. 11 The proportionality of the decay rate with the quencher concentration is a very general property. [START_REF] Hartmann | Quenching Dynamics in CdSe Nanoparticles: Surface Induced Defects upon Dilution[END_REF] More significant is the observation of a safe population with a constant lifetime during the "burning process". From the fraction of the safe population, the number of quenchers in the quenching volume around the excitons is extracted using equation (1). The number of quenchers ∆Ln(I long ) versus the loss of the initial intensity was plotted on the inset of Figure 3. The proportionality shows a constant yield for the photoproduction of quenchers at the expense of the original molecules. The complex decay observed before bleaching can be ascribed to the presence of some quenchers in the neat sample with the same quenching rate as the photoproducts (see SI(g)). In some cases, a cautious recrystallization leads to crystals without fast initial decay (see Fig. S8).

Below 240 K, the burning of the sample by the laser is not efficient (see SI(o)). Therefore, the "burning process" cannot be operated at cryogenic temperatures. But still the effect of temperature can be studied on partially burned samples.

The singlet-triplet equilibrium

Figure 4 shows the luminescence decays recorded as a function of temperature. 20 Laser shots were used to record the decays in order to limit the bleaching.

The common lifetime of the excited states depends on temperature and is given by: 8

𝟏 𝝉 = 𝟏 𝝉 𝑻 6 3 𝑹(𝑻) 𝝉 𝑺 6 𝟏3𝑹(𝑻) , (3)
where 𝜏 * is the triplet decay time, 𝜏 ' is the singlet decay time, R(T) is the ratio of singlets to triplets as a function of temperature in equation ( 2). The decays at all temperatures are complex and multi-exponentially shaped. However, the long-lived population gives a well-defined exponential contribution to the luminescence decay.

A biexponential fit allows us to extract safely the lifetime and the fraction of the long component. The long-lived population is the fraction of the excitons that are safe from quenching ( a b

Figure 1).

The decay rates of the long component at different temperatures are represented in Figure 5, as well as the number of quenchers derived from the long component's relative contributions (equation (1)). 𝜙 012 was set equal to 1. The singlet/triplet splitting agrees with the calculations according to the time-dependent density functional theory. [START_REF] Elie | Designing NHC-Copper(I) Dipyridylamine Complexes for Blue Light-Emitting Electrochemical Cells[END_REF] At 77 K, the probability for the luminescent site to be a singlet exciton is only 10 -8 whereas at room temperature [Cu(IPr)(dpa)][PF 6 ] spends 2% of its time as a singlet. The singlet will induce an increased quenching through a faster FRET.

The size of the quenching volume

Figure 5 shows the relationship between the quenching volume and the temperature. In this experiment, only the number of quenchers n Q in the quenching volume

V Q (n Q = [Q]V Q , where
[Q] is the density of quenchers) were measured and not directly V Q . The quencher concentration is constant, thus the higher number of quenchers involved in the quenching reflects the increase of the quenching volume. At low temperature, the excited TADF unit spends most of its time as a triplet. At room temperature, the singlet state contributes as well. We shall assume a FRET for both the triplet state and the singlet state. [START_REF] Főrster | Transfer mechanisms of electronic excitation[END_REF][START_REF] Charbonniere | Lanthanides to quantum dots resonance energy transfer in time-resolved fluoro-immunoassays and luminescence microscopy[END_REF] Whatever the quenching mechanism, we want to express the presence of a characteristic distance for that mechanism. To assume a FRET for both the singlet and triplet state makes the equation easier to handle. Let's define the quenching volume V Q of a TADF compound by the distance at which the transfer rate coefficient to the quencher equals the decay rate coefficient of the non-quenched population. [START_REF] Blumen | Quenching of luminescence by non-radiative tunnelling[END_REF] The quenching rate is the sum of the rates by the two forms of the excited state weighted by their respective probabilities. If V QT and V QS are respectively the quenching volumes of the triplet and singlet, V Q will verify equation ( 4): .

(

) 5
The experimental values and the fit according to equation ( 5) are presented on Figure 5. The factors ∆E ST /k, t S , t T are in common in equation ( 4) and ( 5 3) and ( 5), a minority of singlet states (2%) at room temperature are responsible for most of the quenching (75%). On Figure 5 an increase of the number of quenchers between room temperature and 240 K is seen that is not described by our model. It could be due to the burning of the sample during the measurement process. It cannot be due to a quenching of the triplets through a Dexter electron exchange (See SI(m)).

The quenching dynamics

Equation (6) was proposed by Millar et al. for the fluorescence decay of a quenched population and it has been tested for solutions: [START_REF] Millar | Picosecond dynamics of electronic energy transfer in condensed phases[END_REF] 𝐥𝐧 & 𝑰(𝒕)

𝑰 𝒐 / = -𝒌 𝑭 𝒕 -[𝑸] &𝟒𝝅𝑫𝒓 𝒇 𝒕 + 𝑮𝝅 𝟑 𝟐 𝑹 𝒐 𝟑 D𝒌 𝑭 𝒕 / , (6)
Importantly, the 𝑅 G , D𝑘 H 𝑡 is due to the distance dependence of the FRET quenching in three dimensions. 23,24 This term is obtained as an approximation for short times of the more complex equation using the Perrin model and neglects the existence of a non-quenched population. [START_REF] Charbonniere | Lanthanides to quantum dots resonance energy transfer in time-resolved fluoro-immunoassays and luminescence microscopy[END_REF] The term linear with time, 4𝜋𝐷𝑟 I , describes the diffusion of the excitons and quenchers. In solids, the diffusion can be due to a hopping of the excitation from site to site. As a diffusion rate, it must be positive. 6) and our equation (7). Record number 11 is shown as an example. The residuals are displayed on the top plot for equation (6) and on lower plot for equation (7). The diffusion term is plotted on the inset.

Equation (6) including an offset term for the adjustment of the baseline can be used to fit the data. A global fit of the family of decays produced during the bleaching experiment of Figure 3, where 𝑘 H and the ratio 𝐺𝑅 G , /4𝐷𝑟 I D𝜋𝑘 H are the common parameters. The results are presented in Table 1. The diffusion rate 4𝜋𝐷𝑟 I [𝑄] is free to change among successive curves.

The result is shown on Figure 6 for the eleventh measurement. Residuals are on the top plot and all residuals can be found in SI(k). The fit is numerically satisfying, but with a negative value of -14650 ± 37 s -1 for the diffusion rate. This negative diffusion rate becomes more pronounced as the concentration of quenchers is increased as shown on the inset of Figure 6. the decays observed as due to the presence of a few quenchers per exciton, using an extension to the time-resolved luminescence of the statistical analysis done by Perrin. At room temperature, the quenching rate coefficient is a square root of time. This is that of a FRET from the fixed exciton to a fixed trap. From the analysis of the fraction of non-quenched excitons, the number of quenchers within the FRET distance has been extracted. This fraction that exponentially depends on the quencher concentration can only be measured using spectroscopic technics with a dynamic range of a few orders of magnitude. The same analysis could be performed using light pulses or electrical pulses in OLEDs for the determination of the local number of defects.

With TADF compounds, by changing the temperature we can change the nature of the excitons. We have assumed a FRET for the triplet state quenching. This enables us to define a quenching volume and compare its values with our model. The analysis of the quenching extant offers a second way to measure ∆E ST , the energy gap between the singlet and the triplet states.

In the case of [Cu(IPr)(dpa)][PF 6 ] complex, since the critical temperature at which the quenching shifts (160 K) is more accessible than the critical temperature at which the lifetime shifts, a better measurement of the energy gap between singlet and triplet can be obtained.

Because of the difference between the two critical temperatures, it appears that, at room temperature, even if the singlet states have a very short lifetime and contribute only to 2% the excited states, they dominate the quenching and the quenching dynamics.

As a conclusion, this study shows that a few defects in an almost perfect sample complicate the photo-physics of solids, but they can be used to gain a better knowledge of the excitons behavior. Adding defects by a laser treatment is a useful way to interrogate the photophysics of a solid sample.

Supporting Information

Figure 1 .

 1 Figure 1. Perrin's quenching model. (a) An exciton with no defect in the quenching volume. The

Fig. 2 [

 2 Fig. 2 [Cu(IPr)(dpa)][PF6].

Figure 3 .

 3 Figure 3. Luminescence decay curves recorded during the bleaching of [Cu(IPr)(dpa)][PF 6 ]

Figure 4 .

 4 Figure 4. The fluorescence decays of [Cu(IPr)(dpa)][PF 6 ] crystals as a function of temperature.

Figure 5 .

 5 Figure 5. The decay rates of the long component at different temperatures and the numbers of

  ) and have been obtained by a global fit of the two sets of data of Figure5. The intersystem crossing yield 𝜙 012 was set to 1 for the analysis of the non-quenched population (equation 3) and found to be 0.15 for the quenched population (equation 5) (See SI(l)). This might be because the quenching competes with the intersystem crossing and reduces the 𝜙 012 yield for the quenched population. From the fit by equation(5), two extra values can be extracted, namely the number of quenchers in the triplet quenching volume at low temperature (0.46) and the number of quenchers in the singlet quenching volume (1.1). These two values can be read on Figure5from the values of the plateau at low and room temperatures. Due to the difference in the weighting factors of equation (

Figure 6 .

 6 Figure 6. A global fit of the decays during the bleaching has been performed with Millar et al.'s

From

  the non-positive values of the diffusion coefficient, we assume the absence of diffusion for the excitons and the quenchers in [Cu(IPr)(dpa)][PF 6 ] crystals at low temperatures. Trapped excitons will be less sensitive to singlet-singlet and triplet-triplet annihilations, which is attractive for lightening applications. However, the strictly negative value of the diffusion coefficient obtained from the fit is disturbing. uch specific time dependence of the quenching rate may come from some specific quencher/exciton distribution curve in the case of [Cu(IPr)(dpa)][PF 6 ] crystals. But Equation (6) neglects the presence of an unquenched population. From the presence of an unquenched population, both at room temperature and at liquid nitrogen temperature, we know that we have only a few quenchers per exciton: less than 1.4 quenchers per exciton are seen in Figure3.Thus, different populations of luminescent sites with no, one, two, …, a few quenchers can be envisaged, leading to express the total decay as: 𝒌 𝑭 𝒕 -𝑽 𝑸 [𝑸]T𝟏 -𝐞𝐱𝐩U-D 𝝅𝒌 𝑸 𝒕VW ,(7) where 𝑉 % [𝑄] is the number of quenchers in the Perrin volume. {1 -exp (𝑓(𝑡))} term comes from the distribution of the number of quenchers.[START_REF] Blumen | On the concentration and time dependence of the energy transfer to randomly distributed acceptors[END_REF][START_REF] Hartmann | Quenching Dynamics in CdSe Nanoparticles: Surface Induced Defects upon Dilution[END_REF] expU-D 𝜋𝑘 % 𝑡V is the decay of an ensemble of luminescent sites with only one FRET quencher. The decay with equation (7) was fitted as shown on Figure6and residuals are on the lower plot. The residuals are better than those of equation (6) (see SI(e) for the global residues), but more importantly now the presence of quenchers increases the decay rate as expected. The success of the two models confirms that the complexity of the luminescence decay of such TADF copper complexes is due to the presence of a few defects per luminescent center. The contribution of the population without quencher to the late fluorescence is clearly seen from the data. The presence of this population is often overlooked in solid-state luminescence studies where the short time validity of approximate equations is favored over the late time validity. 25 Both models conclude to the immobility of the luminescent centers in the solid which support that this [Cu(IPr)(dpa)][PF 6 ] complex family is of interest for lightning applications. CONCLUSION The decay of the fluorescence of solids is always complex, but important pieces of information were extracted from the burning of TADF [Cu(IPr)(dpa)][PF 6 ] crystals. In addition to the short component corresponding to the direct fluorescence and the long component ascribed to the thermally activated delayed fluorescence, we have observed and studied an intermediate component that we attribute to the presence of defects in the solids. Burning the sample at high laser fluence amplifies that intermediate component. We successfully analyze

  b) Burning [Cu(IPr)( 3Me dpa)][PF 6 ]at high laser fluence c) The binomial distribution of the number of quenchers around emitters d) Principle Component Analysis e) Building of the decay rates f) The quencher free decay g) Temperature dependence of a defect-less sample h) The production yield of the quenchers i) The shape of the quenching rates j) The global fit of the luminescence decays k) Equation for the temperature dependence of the quenching volume l) The global fit m) Temperature dependence of the bleaching ACKNOWLEDGMENT This work is supported by the CNRS (Centre National de la Recherche Scientifique), the Agence Nationale de Recherche as part of the NESSYNED project (contract ANR-15-CE39-0006). Zhengyu Zhang is grateful for support from the Ecole doctorale INTERFACES of University Paris Saclay. We thanks the "Région Basse-Normandie" for their funding (M.E.). SG thanks Johnson Matthey for the gift of metals. REFERENCES 1 J Macklin, J. J.; Trautman, J. K.; Harris, T. D.; Brus, L. E., Imaging and time resolved spectroscopy of single molecules at an interface. Science 1996, 272, 255-258. DOI: 10.1126/science.272.5259.255

Table 1

 1 Results of the global fit, by Millar's model and by Perrin's model, of the decayscollected during the burning.

	Millar		eq. (6)
	𝒌 𝑭 s -1	Fix	46760.4	𝒌 𝑭 s -1	Common	25500 ± 92
	𝑮𝑹 𝒐 𝟑 /𝟒𝑫𝒓 𝒇 D𝝅𝒌 𝑭 Common 17±1 10 -3	𝒌 𝑸 s -1	Common	13200 ± 400
	𝟒𝝅𝑫𝒓 𝒇 [𝑸]	Free		𝑽 𝑸 [𝑸]	Free

-𝒌 𝑭 𝒕 -[𝑸] &𝟒𝝅𝑫𝒓 𝒇 𝒕 + 𝑮𝝅 𝟑 𝟐 𝑹 𝒐 𝟑 D𝒌 𝑭 𝒕 /

Perrin eq. (

7

)

-𝒌 𝑭 𝒕 -𝑽 𝑸 [𝑸] N𝟏 -𝐞𝐱𝐩 P-Q𝝅𝒌 𝑸 𝒕RS