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The Nature of Genetic Susceptibility to Multiple Sclerosis [article]

Douglas S Goodin, Pouya Khankhanian, Pierre-Antoine Gourraud, Nicolas Vince
2020 bioRxiv   pre-print
OBJECTIVE: To explore the nature of MS-susceptibility and, by extension, other complex-genetic diseases. BACKGROUND Basic-epidemiological parameters of MS (e.g., prevalence, recurrence-risks for siblings and twins, time-dependent changes in sex-ratio, etc.) are well-established. Moreover, >200 genetic-loci are unequivocally MS-associated, especially the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype-association. DESIGN/METHODS: We define the genetically-susceptible subset-(G) to include everyone
more » ... h any non-zero life-time chance of developing MS. We analyze, mathematically, the implications that these epidemiological observations have regarding genetic susceptibility. In addition, we use the sex-ratio change (observed over a 35-year interval), to derive the relationship between MS-probability and an increasing likelihood of a suitable environmental-exposure. RESULTS: We demonstrate that genetic-susceptibitly is restricted to less than 4.7% of populations across Europe and North America. Among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, fewer than 20% are even in the subset-(G). Women are less likely to be susceptible than men although their MS-penetrance is considerably greater. Response-curves for MS-probability increase with an increasing likelihood of a suitable environmental-exposure, especially among women. These environmental response-curves plateau at under 50% for women and at a significantly lower level for men. CONCLUSIONS: MS is fundamentally a genetic disorder. Despite this, a suitable environmental-exposure is also critical for disease-pathogenesis. Genetic-susceptibility requires specific combinations of non-additive genetic risk-factors. For example, the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, by itself, poses no MS-risk. Moreover, the fact that environmental-response-curves plateau below 50%, indicates that disease-pathogenesis is partly stochastic. By extension, other diseases for which monozygotic-twin recurrence-risks greatly exceed disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis.
doi:10.1101/2020.08.13.249920 fatcat:bx5c4svh75cshciy6lesnj2ncu

High-accuracy HLA type inference from whole-genome sequencing data [article]

Alexander Dilthey, Pierre-Antoine Gourraud, Zamin Iqbal, Gil McVean
2015 bioRxiv   pre-print
Extensive hyperpolymorphism and sequence similarity between the HLA genes make HLA type inference from whole-genome sequencing data a challenging problem. We address these by representing sequences from over 10,000 known alleles in a reference graph structure, enabling accurate read mapping. HLA*PRG, our algorithm, outperforms existing methods by a wide margin and for the first time consistently achieves the accuracy of gold-standard reference methods with one error across 158 alleles tested.
doi:10.1101/035253 fatcat:gvqbujqfjvguzmeehlkr7jy3ny

Analytical Methods for Immunogenetic Population Data [chapter]

Steven J. Mack, Pierre-Antoine Gourraud, Richard M. Single, Glenys Thomson, Jill A. Hollenbach
2012 Msphere  
In this chapter, we describe analyses commonly applied to immunogenetic population data, along with software tools that are currently available to perform those analyses. Where possible, we focus on tools that have been developed specifically for the analysis of highly polymorphic immunogenetic data. These analytical methods serve both as a means to examine the appropriateness of a dataset for testing a specific hypothesis, as well as a means of testing hypotheses. Rather than treat this
more » ... as a protocol for analyzing any population dataset, each researcher and analyst should first consider their data, the possible analyses, and any available tools in light of the hypothesis being tested. The extent to which the data and analyses are appropriate to each other should be determined before any analyses are performed.
doi:10.1007/978-1-61779-842-9_13 pmid:22665237 pmcid:PMC4209087 fatcat:bcy2h3zlebeibcym4hvyq5j3v4

Multiple Sclerosis: Exploring the Limits of Genetic and Environmental Susceptibility [article]

Douglas S. Goodin, Pouya Khankanian, Pierre-Antoine Gourraud, Nicolas Vince
2022 medRxiv   pre-print
OBJECTIVE: To explore the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and to define the limits of this nature based on the statistical uncertainties regarding the various epidemiological observations that have been made. BACKGROUND: Certain parameters of MS-epidemiology can be directly observed (e.g., the risk of MS-recurrence in siblings and twins of an MS proband, the proportion of women among MS patients, the population-prevalence of MS, and the
more » ... t changes in the sex-ratio). By contrast, other parameters can only be inferred from the observable parameters (e.g., the proportion of the population that is genetically susceptible, the proportion of women among susceptible individuals, the probability that a susceptible individual will experience an environment sufficient to cause MS given their genotype, and if they do, the probability that they will ultimately develop the disease). DESIGN/METHODS: The "genetically-susceptible" subset (G) of the population (Z) is defined to include everyone with anynon-zero life-time chance of developing MS. For the observed parameters, plausible ranges are assigned values such that they include either the 95% confidence intervals or the estimated parameter-ranges for each observation. By contrast, for the non-observed parameters, the ranges are assigned such that they cover any plausible value for each parameter. Using both a Cross-sectional Model and a Longitudinal Model, together with established parameter relationships, we explore iteratively trillions of potential parameter combinations and determine those combinations (solutions) that are constrained by the observed parameter ranges. RESULTS: Using both Models, under all circumstances, genetic-susceptibitly is limited to to less than 52% of the population. If solutions are excluded, in which susceptible women either comprise less than 18% of susceptible individuals or have a penetrance more than 20 times that in susceptible men, then both Models agree that genetic-susceptibility is limited to less than 12% of the population. Consequently, a large number (and likely the large majority) of individuals have no chance whatsoever of developing MS, regardless of their environmental exposure. Also, although the penetrance of MS in susceptible women is greater than it is in men and, for most solutions, susceptible men outnumber susceptible women. As expected, the probability that susceptible individuals will develop MS increases with an increased likelihood of individuals experiencing a sufficient environmental exposure. Nevertheless, as this probability approaches 1, these response-curves plateau at <64% for women and at <23% for men. Finally, under current environmental conditions are such that more than 68% of susceptible individuals are experiencing an environment sufficient to cause MS given their particular genotype. CONCLUSIONS: The development of clinical MS (in an individual) requires both that they have the appropriate genotype (which is quite rare in the population) and that they have an environmental exposure sufficient to cause MS given their particular genotype (which is currently quite common among susceptible individuals). Nevertheless, even when the necessary genetic and environmental factors, required for MS pathogenesis, co-occur for an individual, this is still insufficient for that person to develop MS. Rather, disease pathogenesis, even in this circumstance, involves an important element of chance.
doi:10.1101/2022.03.09.22272129 fatcat:h4mgyxzk4nhaxf3bpfjuenmilm

Standard Methods for the Management of Immunogenetic Data [chapter]

Pierre-Antoine Gourraud, Jill A. Hollenbach, Thomas Barnetche, Richard M. Single, Steven J. Mack
2012 Msphere  
In this chapter, we outline some basic principles for the consistent management of immunogenetic data. These include the preparation of a single master data file that can serve as the basis for all subsequent analyses, a focus on the quality and homogeneity of the data to be analyzed, the documentation of the coding systems used to represent the data, and the application of nomenclature standards specific for each immunogenetic system being evaluated. The data management principles discussed
more » ... e are intended to provide a foundation for the data analysis methods detailed in Chaps. 13 and 14. The relationship between the data management and analysis methods covered in these three chapters is illustrated in Figure 1 .
doi:10.1007/978-1-61779-842-9_12 pmid:22665236 pmcid:PMC4209945 fatcat:owc36u5d65c45injss24bv73qq

SNP imputation bias reduces effect size determination

Pouya Khankhanian, Lennox Din, Stacy J. Caillier, Pierre-Antoine Gourraud, Sergio E. Baranzini
2015 Frontiers in Genetics  
Baranzini, Pouya Khankhanian, Lennox Din, and Pierre-Antoine Gourraud wrote the paper. All authors read and approved the final manuscript. Table 1 | 1 Discordance of imputation.  ...  Baranzini, Pouya Khankhanian, and Pierre-Antoine Gourraud conceived and designed the study. Pouya Khankhanian and Lennox Din performed the data analysis. Stacy J. Caillier performed the assays.  ... 
doi:10.3389/fgene.2015.00030 pmid:25709616 pmcid:PMC4321633 fatcat:z4rz6xnyinhqza5r4dpjsqw3ci

Tests génétiques en accès libre sur Internet

Pascal Ducournau, Pierre-Antoine Gourraud, Emmanuelle Rial-Sebbag, Alexandre Bulle, Anne Cambon-Thomsen
2011 M S.Médecine Sciences  
doi:10.1051/medsci/201127195 pmid:21299969 fatcat:jhtnpqh5q5gjjdqtyi7svv52yi

Biobanks for Genomics and Genomics for Biobanks

Anne Cambon-Thomsen, Pascal Ducournau, Pierre-Antoine Gourraud, David Pontille
2003 Comparative and Functional Genomics  
Biobanks include biological samples and attached databases. Human biobanks occur in research, technological development and medical activities. Population genomics is highly dependent on the availability of large biobanks. Ethical issues must be considered: protecting the rights of those people whose samples or data are in biobanks (information, autonomy, confidentiality, protection of private life), assuring the non-commercial use of human body elements and the optimal use of samples and data.
more » ... They balance other issues, such as protecting the rights of researchers and companies, allowing long-term use of biobanks while detailed information on future uses is not available. At the level of populations, the traditional form of informed consent is challenged. Other dimensions relate to the rights of a group as such, in addition to individual rights. Conditions of return of results and/or benefit to a population need to be defined. With 'large-scale biobanking' a marked trend in genomics, new societal dimensions appear, regarding communication, debate, regulation, societal control and valorization of such large biobanks. Exploring how genomics can help health sector biobanks to become more rationally constituted and exploited is an interesting perspective. For example, evaluating how genomic approaches can help in optimizing haematopoietic stem cell donor registries using new markers and high-throughput techniques to increase immunogenetic variability in such registries is a challenge currently being addressed. Ethical issues in such contexts are important, as not only individual decisions or projects are concerned, but also national policies in the international arena and organization of democratic debate about science, medicine and society.
doi:10.1002/cfg.333 pmid:18629026 pmcid:PMC2447308 fatcat:v3hsiycr35eufcgcpqbswwfveu

Genetic susceptibility to multiple sclerosis in African Americans

Douglas S. Goodin, Jorge R. Oksenberg, Venceslas Douillard, Pierre-Antoine Gourraud, Nicolas Vince, Courtney G. Montgomery
2021 PLoS ONE  
Objective To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans. Background Recently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB1*15:01~HLA-DQB1*06:02, and HLA-DRB1*03:01~ HLA-DQB1*02:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of
more » ... e newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort. Design/methods The African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational "Be the Match" registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms. Results Of the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB1*15:03~DQB1*06:02~a36 haplotype and three carried the DRB1*15:01~DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)–similar to that observed in the WTCCC (OR = 3.25; p<10−168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)–again, similar to the WTCCC (OR = 2.2; p<10−38). Moreover, four African haplotypes were "protective" relative to a neutral reference, to three European CEHs, and also to the five other African CEHs. Conclusions The common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were "protective"–perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.
doi:10.1371/journal.pone.0254945 pmid:34370753 pmcid:PMC8352072 fatcat:owzx2cyxfjcyfmgnvemehtpjzy

Haplotype-based approach to known MS-associated regions increases the amount of explained risk

Pouya Khankhanian, Pierre-Antoine Gourraud, Antoine Lizee, Douglas S Goodin
2015 Journal of Medical Genetics  
doi:10.1136/jmedgenet-2015-103071 pmid:26185143 pmcid:PMC4552900 fatcat:y6wooxloerbnpdqj6wuxwwq5qq

Genetic contribution to multiple sclerosis risk among Ashkenazi Jews

Pouya Khankhanian, Takuya Matsushita, Lohith Madireddy, Antoine Lizée, Lennox Din, Jayaji M Moré, Pierre-Antoine Gourraud, Stephen L Hauser, Sergio E Baranzini, Jorge R Oksenberg
2015 BMC Medical Genetics  
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, with a strong genetic component. Over 100 genetic loci have been implicated in susceptibility to MS in European populations, the most prominent being the 15:01 allele of the HLA-DRB1 gene. The prevalence of MS is high in European populations including those of Ashkenazi origin, and low in African and Asian populations including those of Jewish origin. Methods: Here we identified and extracted a total of 213
more » ... MS cases and 546 ethnically matched healthy control individuals from two previous genome-wide case-control association analyses, and 72 trios (affected proband and two unaffected parents) from a previous genome-wide transmission disequilibrium association study, using genetic data to define Ashkenazi. We compared the pattern of genetic risk between Ashkenazi and non-Ashkenazi Europeans. We also sought to identify novel Ashkenazi-specific risk loci by performing association tests on the subset of Ashkenazi cases, controls, probands, and parents from each study. Results: The HLA-DRB1*15:01 allele and the non-HLA risk alleles were present at relatively low frequencies among Ashkenazi and explained a smaller fraction of the population-level risk when compared to non-Ashkenazi Europeans. Alternative HLA susceptibility alleles were identified in an Ashkenazi-only association study, including HLA-A*68:02 and one or both genes in the HLA-B*38:01-HLA-C*12:03 haplotype. The genome-wide screen in Ashkenazi did not reveal any loci associated with MS risk. Conclusion: These results suggest that genetic susceptibility to MS in Ashkenazi Jews has not been as well established as that of non-Ashkenazi Europeans. This implies value in studying large well-characterized Ashkenazi populations to accelerate gene discovery in complex genetic diseases.
doi:10.1186/s12881-015-0201-2 pmid:26212423 pmcid:PMC4557862 fatcat:a2thg7ne3bdlvnwgx46pghj2c4

The nature of genetic and environmental susceptibility to multiple sclerosis

Douglas S. Goodin, Pouya Khankhanian, Pierre-Antoine Gourraud, Nicolas Vince, Sreeram V. Ramagopalan
2021 PLoS ONE  
Objective To understand the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and, by extension, susceptibility to other complex genetic diseases. Background Certain basic epidemiological parameters of MS (e.g., population-prevalence of MS, recurrence-risks for MS in siblings and twins, proportion of women among MS patients, and the time-dependent changes in the sex-ratio) are well-established. In addition, more than 233 genetic-loci have now been identified as being
more » ... unequivocally MS-associated, including 32 loci within the major histocompatibility complex (MHC), and one locus on the X chromosome. Despite this recent explosion in genetic associations, however, the association of MS with the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 (H+) haplotype has been known for decades. Design/Methods We define the "genetically-susceptible" subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive "non-susceptible" subset (G–). Using these well-established epidemiological parameters, we analyze, mathematically, the implications that these observations have regarding the genetic-susceptibility to MS. In addition, we use the sex-ratio change (observed over a 35-year interval in Canada), to derive the relationship between MS-probability and an increasing likelihood of a sufficient environmental exposure. Results We demonstrate that genetic-susceptibitly is confined to less than 7.3% of populations throughout Europe and North America. Consequently, more than 92.7% of individuals in these populations have no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, far fewer than 32% can possibly be members the (G) subset. Also, despite the current preponderance of women among MS patients, women are less likely to be in the susceptible (G) subset and have a higher environmental threshold for developing MS compared to men. Nevertheless, the penetrance of MS in susceptible women is considerably greater than it is in men. Moreover, the response-curves for MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these environmental response-curves plateau at under 50% for women and at a significantly lower level for men. Conclusions The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population (< 7.3%) and requires specific combinations of non-additive genetic risk-factors. For example, only a minority of carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype are even in the (G) subset and, thus, genetic-susceptibility to MS in these carriers must result from the combined effect this haplotype together with the effects of certain other (as yet, unidentified) genetic factors. By itself, this haplotype poses no MS-risk. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the fact that environmental response-curves plateau well below 50% (especially in men), indicates that disease pathogenesis is partly stochastic. By extension, other diseases, for which monozygotic-twin recurrence-risks greatly exceed the disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis.
doi:10.1371/journal.pone.0246157 pmid:33750973 fatcat:7hgrlfoimbckxfhb76ldnds4zq

Prevalence of Common Non-Hodgkin Lymphomas and Subtypes of Hodgkin Lymphoma by Nodal Site of Involvement

Camille Laurent, Catherine Do, Pierre-Antoine Gourraud, Geisilene Russano de Paiva, Séverine Valmary, Pierre Brousset
2015 Medicine  
Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) represent a heterogeneous group of malignant lymphoid tumors, which have distinct histological and/or biological characteristics with preferential nodal involvement. However, none of the previous studies have assessed the prevalence of common NHL and HL subtypes at each nodal site of involvement. The aim of our study was to determine the prevalence of HL and NHL subtypes depending on their nodal sites of involvement. We conducted a
more » ... er retrospective study of 938 lymphoma cases diagnosed in the Pathology Department of Toulouse Purpan Hospital in France between 2001 and 2008, taking into account the site that corresponded to the diagnostic biopsy. The most frequent sites were cervical lymph nodes (36.8% of all cases), inguinal lymph nodes (16.4%), axillary lymph nodes (11.9%), and supraclavicular lymph nodes (11%). We found an unexpected association between intraparotid nodes and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and between inguinal nodes and follicular lymphoma. The risk of having classical Hodgkin lymphoma (CHL) was 15 times greater in patients with mediastinal lymphoma compared to those with other sites of involvement. Regarding HL, nodal and extranodal mediastinal sites and supraclavicular nodes were more likely to be involved by nodular sclerosis Hodgkin lymphoma (NSCHL). In addition, intra-abdominal lymph nodes were more frequently involved by lymphocyte depleted Hodgkin lymphoma compared to inguinal nodes where NLPHL predominated. Our study shows that some lymph node sites have a disproportionate prevalence of specific subtypes of lymphoma. Identifying these sites may aid to diagnose and better elucidate the pathogenesis of these tumors. (Medicine 94(25):e987) Abbreviations: aOR = adjusted odds ratio, CHL = classical Hodgkin lymphoma, CLL = chronic lymphocytic leukemia, DLBCL = diffuse large B-cell lymphoma, EBV = Epstein-Barr virus, FL = follicular lymphoma, HL = Hodgkin lymphoma, IC = confidence interval, NHL = non-Hodgkin lymphoma, NLPHL = nodular lymphocyte predominant Hodgkin lymphoma, NSCHL = nodular sclerosis Hodgkin lymphoma, TCL = T-cell lymphoma. Editor: Weimin Guo.
doi:10.1097/md.0000000000000987 pmid:26107683 pmcid:PMC4504656 fatcat:57lcqcgjerhthpg45zy7db4elq

The genetics of multiple sclerosis: an up-to-date review

Pierre-Antoine Gourraud, Hanne F. Harbo, Stephen L. Hauser, Sergio E. Baranzini
2012 Immunological Reviews  
Gourraud Table 2 Population frequencies of genetic variants associated with multiple sclerosis in the MHC region (2) When variant is a SNP, frequencies of the alleles are reproted from HAPMAP relevant  ...  22 rs2283792 1.12 4.70E-09 G 52.7% G/T MAPK1 22 rs140522 1.12 1.70E-08 T 34.5% C/T SCO2 Author Manuscript Author Manuscript Author Manuscript Author Manuscript Gourraud  ... 
doi:10.1111/j.1600-065x.2012.01134.x pmid:22725956 pmcid:PMC5967887 fatcat:a2vzf6ca45e4fdnowvq6x5xs4e

Impact of Relative Change in Temperature and Atmospheric Pressure on Acute Aortic Syndrome Occurrence in France

Guillaume Guimbretière, Simon Nusinovici, Antoine Monnot, Jonathan Sobocinski, Thomas Sénage, Pascal Delsart, Pierre-Antoine Gourraud, Blandine Maurel
2020 Scientific Reports  
Acute aortic syndromes (AAS) have been related to significant circadian and seasonal conditions. We used time series analyses to study the impact of meteorological variations on AAS occurrence. We retrospectively assessed 140 patients presenting with AAS over a 6-year period in a French university hospital. Average daily temperature (T) and atmospheric pressure (AP) at the location of the event were collected within the previous 10 days, and their association with AAS investigated with
more » ... ed additive models. A decrease in temperature of more than 5 °C within the previous seven days was significantly associated with an increased risk of AAS occurrence (OR equal to 1.86 [1.06; 3.44]). Subgroup analysis revealed that the risk was only significant among normotensive individuals (n = 41) free from blood pressure lowering medication (OR equal to 2.3 [1.05; 5.37]), but not among hypertensive individuals under blood pressure lowering medication despite a larger patient number (n = 99). Similarly, only among the subgroup of normotensive individuals a decrease of AP between 2 and 4 kPa within the previous 3 days was associated with an increased risk of AAS (OR equal to 2.93 [1.1; 8.15]) and an increased between 2 and 4 kPa was associated with a decreased risk (OR equal to 0.59 [0.36; 1.00]). Variations of meteorological conditions (temperature and AP) within the previous week seem to have effects on triggering AAS especially among the population free from blood pressure lowering medication.
doi:10.1038/s41598-019-56841-w pmid:31919377 pmcid:PMC6952440 fatcat:4xtl5ihxivd4ddlsc45heg3nn4
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