Development and Validation of a Prostate Biopsy Risk Calculator in Black Men.

PURPOSE: We sought to develop and validate a prostate biopsy risk calculator for Black men and compare it with the Prostate Cancer Prevention Trial version 2.0, Prostate Biopsy Collaborative Group, and Kaiser Permanente Prostate Cancer Risk Calculators for the detection of Gleason Grade Group (GG) ≥ 2 prostate cancer (PCa). MATERIALS AND METHODS: We prospectively recruited 2 cohorts of men undergoing prostate biopsy from 5 facilities in Chicago. The first cohort was split into development (70%) and internal validation (30%) groups. The second was used for external validation. Iterative logistic regression was used to develop 3 models for predicting GG ≥ 2 PCa. Models were compared for discrimination using the C statistics, calibration curves, and net benefit curves. The frequency of unnecessary biopsies and missed PCas was compared at 10% and 30% risk thresholds. RESULTS: The 2 cohorts included 393 and 292 Black men, respectively. Our first model, Mistry-Sun 1, used serum PSA and prior negative biopsy. Mistry-Sun 2 added abnormal digital rectal exam (DRE) and an interaction term with abnormal DRE and PSA to Mistry-Sun 1. Mistry-Sun 3 added prostate volume, abnormal DRE, and age to Mistry-Sun 1. The C statistics were 0.74, 0.74, and 0.78, respectively, and were similar to or higher than established calculators. At the 10% and 30% risk thresholds our models had the fewest unnecessary biopsies and an appropriate proportion of missed GG ≥ 2 PCas. CONCLUSIONS: Tailoring a risk calculator to detect clinically significant PCa in Black men may improve biopsy decision-making and outcomes compared to tools developed in non-Black populations.

Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency.

A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D variation, we performed a GWAS for skin pigmentation with 395 AAs and a replication study with 681 AAs. Then, we tested if the identified variants are associated with serum 25(OH) D concentrations in a subset of AAs (n = 591). Skin pigmentation, Melanin Index (M-Index), was measured using a narrow-band reflectometer. Multiple regression analysis was performed to identify variants associated with M-Index and to assess their role in serum 25(OH)D variation adjusting for population stratification and relevant confounding variables. A variant near the SLC24A5 gene (rs2675345) showed the strongest signal of association with M-Index (P = 4.0 x 10-30 in the pooled dataset). Variants in SLC24A5, SLC45A2 and OCA2 together account for a large proportion of skin pigmentation variance (11%). The effects of these variants on M-Index was modified by sex (P for interaction = 0.009). However, West African Ancestry (WAA) also accounts for a large proportion of M-Index variance (23%). M-Index also varies among AAs with high WAA and high Genetic Score calculated from top variants associated with M-Index, suggesting that other unknown genomic factors related to WAA are likely contributing to skin pigmentation variation. M-Index was not associated with serum 25(OH)D concentrations, but the Genetic Score was significantly associated with vitamin D deficiency (serum 25(OH)D levels less than 12 ng/mL) (OR, 1.30; 95% CI, 1.04-1.64). The findings support the hypothesis suggesting that skin pigmentation evolved responding to increased demand for subcutaneous vitamin D synthesis in high latitude environments.

Vitamin D and genetic ancestry are associated with apoptosis rates in benign and malignant prostatic epithelium.

PURPOSE: Vitamin D metabolites may be protective against prostate cancer (PCa). We conducted a cross-sectional analysis to evaluate associations between in vivo vitamin D status, genetic ancestry, and degree of apoptosis using prostatic epithelial terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. EXPERIMENTAL DESIGN: Benign and tumor epithelial punch biopsies of participants with clinically localized PCa underwent indirect TUNEL staining. Serum levels of 25 hydroxyvitamin D [25(OH)D] and 1,25 dihydroxyvitamin D were assessed immediately before radical prostatectomy; levels of prostatic 25(OH)D were obtained from the specimen once the prostate was extracted. Ancestry informative markers were used to estimate the percentage of genetic West African, Native American, and European ancestry. RESULTS: One hundred twenty-one newly diagnosed men, age 40-79, were enrolled between 2013 and 2018. Serum 25(OH)D correlated positively with both tumor (ρ = 0.17, p = 0.03), and benign (ρ = 0.16, p = 0.04) prostatic epithelial TUNEL staining. Similarly, prostatic 25(OH)D correlated positively with both tumor (ρ = 0.31, p < 0.001) and benign (ρ = 0.20, p = 0.03) epithelial TUNEL staining. Only Native American ancestry was positively correlated with tumor (ρ = 0.22, p = 0.05) and benign (ρ = 0.27, p = 0.02) TUNEL staining. In multivariate regression models, increasing quartiles of prostatic 25(OH)D (ß = 0.25, p = 0.04) and Native American ancestry (ß = 0.327, p = 0.004) were independently associated with tumor TUNEL staining. CONCLUSIONS: Physiologic serum and prostatic 25(OH)D levels and Native American ancestry are positively associated with the degree of apoptosis in tumor and benign prostatic epithelium in clinically localized PCa. Vitamin D may have secondary chemoprevention benefits in preventing PCa progression in localized disease.

IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias.

Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

BACKGROUND: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. METHODS: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg-1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. RESULTS: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). CONCLUSION: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.

BACKGROUND: Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. METHODS: This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients. RESULTS: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men. CONCLUSIONS: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes.

Undercutting efforts of precision medicine: roadblocks to minority representation in breast cancer clinical trials.

Precision (or personalized) medicine holds great promise in the treatment of breast cancer. The success of personalized medicine is contingent upon inclusivity and representation for minority groups in clinical trials. In this article, we focus on the roadblocks for the African American demographic, including the barriers to access and enrollment in breast oncology trials, the prevailing classification of race and ethnicity, and the need to refine monolithic categorization by employing genetic ancestry mapping tools for a more accurate determination of race or ethnicity.

Performance of Prostate Health Index in Biopsy Naïve Black Men.

PURPOSE: The Prostate Health Index is validated for prostate cancer detection but has not been well validated for Gleason grade group 2-5 prostate cancer detection in Black men. We hypothesize that the Prostate Health Index has greater accuracy than prostate specific antigen for detection of Gleason grade group 2-5 prostate cancer. We estimated probability of overall and Gleason grade group 2-5 prostate cancer across previously established Prostate Health Index ranges and identified Prostate Health Index cutoffs that maximize specificity for Gleason grade group 2-5 prostate cancer with sensitivity >90%. MATERIALS AND METHODS: We recruited a "cancer-free" Black control cohort (135 patients) and a cohort of biopsy naïve Black men (158) biopsied for elevated prostate specific antigen. Descriptive statistics compared the prostate cancer cases and controls and the frequency of Gleason grade group 2-5 prostate cancer across Prostate Health Index scores. Receiver operating characteristics compared the discrimination of prostate specific antigen, Prostate Health Index and other prostate specific antigen related biomarkers. Sensitivity and specificity for Gleason grade group 2-5 prostate cancer detection were assessed at prostate specific antigen and Prostate Health Index thresholds alone and in series. RESULTS: Of biopsied subjects 32.9% had Gleason grade group 2-5 prostate cancer. In Blacks with prostate specific antigen from 4.0-10.0 ng/ml, Prostate Health Index and prostate specific antigen had similar discrimination for Gleason grade group 2-5 prostate cancer (0.63 vs 0.57, p=0.27). In Blacks with prostate specific antigen ≤10.0, a threshold of prostate specific antigen ≥4.0 had 90.4% sensitivity for Gleason grade group 2-5 prostate cancer; a threshold of prostate specific antigen ≥4.0 with Prostate Health Index ≥35.0 in series avoided unnecessary biopsy in 33.0% of men but missed 17.3% of Gleason grade group 2-5 prostate cancer. Prostate specific antigen ≥4.0 with Prostate Health Index ≥28.0 in series spared biopsy in 17.9%, while maintaining 90.4% sensitivity of Gleason grade group 2-5 prostate cancer. CONCLUSIONS: The Prostate Health Index has moderate accuracy in detecting Gleason grade group 2-5 prostate cancer in Blacks, but Prostate Health Index ≥28.0 can be safely used to avoid some unnecessary biopsies in Blacks.

Leveraging genetic ancestry to study health disparities.

Research to understand human genomic variation and its implications in health has great potential to contribute in the reduction of health disparities. Biological anthropology can play important roles in genomics and health disparities research using a biocultural approach. This paper argues that racial/ethnic categories should not be used as a surrogate for sociocultural factors or global genomic clusters in biomedical research or clinical settings, because of the high genetic heterogeneity that exists within traditional racial/ethnic groups. Genetic ancestry is used to show variation in ancestral genomic contributions to recently admixed populations in the United States, such as African Americans and Hispanic/Latino Americans. Genetic ancestry estimates are also used to examine the relationship between ancestry-related biological and sociocultural factors affecting health disparities. To localize areas of genomes that contribute to health disparities, admixture mapping and genome-wide association studies (GWAS) are often used. Recent GWAS have identified many genetic variants that are highly differentiated among human populations that are associated with disease risk. Some of these are population-specific variants. Many of these variants may impact disease risk and help explain a portion of the difference in disease burden among racial/ethnic groups. Genetic ancestry is also of particular interest in precision medicine and disparities in drug efficacy and outcomes. By using genetic ancestry, we can learn about potential biological differences that may contribute to the heterogeneity observed across self-reported racial groups.

Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension.

Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.

Association of genetic ancestry with colorectal tumor location in Puerto Rican Latinos.

BACKGROUND: Colorectal cancer (CRC) is the first cause of cancer deaths among Puerto Ricans. The incidence and mortality of CRC in Puerto Rico continue to be on the rise. The burden of CRC in Puerto Rico is higher than among US Hispanics and is second only to African Americans, thus supporting the importance of studying this CRC health disparity. The genetic background of the Puerto Rican population is a mix of European, African, and Amerindian races, which may account, in part, for the differences observed in the CRC mortality rates among Puerto Ricans. The objective of the study was to assess the role of genetic ancestry in CRC risk and its association with clinicopathological features of CRC tumors in Puerto Ricans. RESULTS: We used a validated panel of 105 ancestry informative markers (AIMs) to estimate genetic ancestry in 406 Puerto Rican CRC cases and 425 Puerto Rican controls. We examined the association of genetic ancestry with CRC risk and tumor clinicopathological characteristics. CONCLUSIONS: The mean ancestry proportions in the study population were 61% European, 21% African, and 18% Amerindian. No association was observed between genetic ancestry and risk of CRC. However, African ancestry was associated with an increased risk of developing rectal tumors (OR = 1.55, 95% CI 1.04-2.31). Additional studies are needed to fully elucidate the role of African ancestry in CRC carcinogenesis.

Comprehensive molecular profiling of 718 Multiple Myelomas reveals significant differences in mutation frequencies between African and European descent cases.

Multiple Myeloma (MM) is a plasma cell malignancy with significantly greater incidence and mortality rates among African Americans (AA) compared to Caucasians (CA). The overall goal of this study is to elucidate differences in molecular alterations in MM as a function of self-reported race and genetic ancestry. Our study utilized somatic whole exome, RNA-sequencing, and correlated clinical data from 718 MM patients from the Multiple Myeloma Research Foundation CoMMpass study Interim Analysis 9. Somatic mutational analyses based upon self-reported race corrected for ancestry revealed significant differences in mutation frequency between groups. Of interest, BCL7A, BRWD3, and AUTS2 demonstrate significantly higher mutation frequencies among AA cases. These genes are all involved in translocations in B-cell malignancies. Moreover, we detected a significant difference in mutation frequency of TP53 and IRF4 with frequencies higher among CA cases. Our study provides rationale for interrogating diverse tumor cohorts to best understand tumor genomics across populations.

Comparative analysis of p16 expression among African American and European American prostate cancer patients.

BACKGROUND: Expression of p16 is increased in a number of malignancies, including prostate cancer (PCa). Recent studies in a European cohort showed that expression of p16 is correlated with expression of the TMPRSS2/ERG (T/E) fusion protein. The T/E fusion is significantly less common in PCas in African American (AA) men. Thus, it would be predicted that p16 expression should be less common in PCas in AA men. We, therefore, sought to compare the expression of p16 in benign prostate and PCas from AA and European American (EA) men. METHODS: Immunohistochemistry for p16 and ERG was performed on tissue microarrays constructed from radical prostatectomies performed on AA and EA veterans. Staining was scored and the scores compared with demographic, clinical and pathological parameters. Percent of West African ancestry in the AA cohort was assessed using ancestry informative markers. RESULTS: Contrary to our predictions, p16 expression was similar in the cancers in the AA and EA cohorts. Consistent with prior reports, expression of p16 was quite low in benign prostate tissues from EA patients but surprisingly was significantly higher in benign tissues from AA patients. Expression of p16 was significantly associated with a family history of PCa in AA men. In addition, p16 was associated with ERG expression in AA PCa. CONCLUSIONS: While overall expression of p16 is similar in PCas from the two racial groups, the expression of p16 in benign tissues from a subset of AA men and the stronger correlation with ERG expression implies that there are different mechanisms for p16 overexpression in PCas from the two racial groups.

Hereditary Susceptibility for Triple Negative Breast Cancer Associated With Western Sub-Saharan African Ancestry: Results From an International Surgical Breast Cancer Collaborative.

OBJECTIVE: To investigate subtype-specific risk of germline alleles associated with triple negative breast cancer (TNBC) in African ancestry populations. BACKGROUND: Breast cancer (BC) mortality is higher in African American (AA) compared to White American (WA) women; this disparity is partly explained by 2-fold higher TNBC incidence. METHODS: We used a surgically maintained biospecimen cohort of 2884 BC cases. Subsets of the total (760 AA; 962 WA; 910 West African/Ghanaian; 252 East African/Ethiopian) were analyzed for genotypes of candidate alleles. A subset of 417 healthy controls were also genotyped, to measure associations with overall BC risk and TNBC. RESULTS: TNBC frequency was highest in Ghanaian and AA cases (49% and 44% respectively; P < 0.0001) and lowest in Ethiopian and WA cases (17% and 24% respectively; P < 0.0001). TNBC cases had higher West African ancestry than non-TNBC (P < 0.0001). Frequency of the Duffy-null allele (rs2814778; an African ancestral variant adopted under selective pressure as protection against malaria) was associated with TNBC-specific risk (P < 0.0001), quantified West African Ancestry (P < 0.0001) and was more common in AA, Ghanaians, and TNBC cases. Additionally, rs4849887 was significantly associated with overall BC risk, and both rs2363956 and rs13000023 were associated with TNBC-specific risk, although none as strongly as the Duffy-null variant. CONCLUSIONS: West African ancestry is strongly correlated with TNBC status, as well as germline variants related to BC risk. The Duffy-null allele was associated with TNBC risk in our cohort.

Relationship between West African ancestry with lung cancer risk and survival in African Americans.

PURPOSE: African Americans, especially men, have a higher incidence of lung cancer compared with all other racial and ethnic groups in the US. Self-reported race is frequently used in genomic research studies to capture an individual's race or ethnicity. However, it is clear from studies of genetic admixture that human genetic variation does not segregate into the same biologically discrete categories as socially defined categories of race. Previous studies have suggested that the degree of West African ancestry among African Americans can contribute to cancer risk in this population, though few studies have addressed this question in lung cancer. METHODS: Using a genetic ancestry panel of 100 SNPs, we estimated West African, European, and Native American ancestry in 1,407 self-described African Americans and 2,413 European Americans. RESULTS: We found that increasing West African ancestry was associated with increased risk of lung cancer among African American men (ORQ5 vs Q1 = 2.55 (1.45-4.48), p = 0.001), while no association was observed in African American women (ORQ5 vs Q1 = 0.90 (0.51-1.59), p = 0.56). This relationship diminished following adjustment for income and education. CONCLUSIONS: Genetic ancestry is not a major contributor to lung cancer risk or survival disparities.

Physiologic serum 1,25 dihydroxyvitamin D is inversely associated with prostatic Ki67 staining in a diverse sample of radical prostatectomy patients.

PURPOSE: To investigate the correlation between serum 25 hydroxyvitamin D, prostatic 25 hydroxyvitamin D, and serum 1,25 dihydroxyvitamin D, and their respective associations with prostatic tumor proliferation at the time of radical prostatectomy. METHODS: In this cross-sectional analysis of 119 men undergoing radical prostatectomy, serum from whole blood and expressed prostatic fluid was collected on the day of surgery. Tumor proliferation was measured in the dominant tumor on formalin-fixed prostatectomy tissues by immunohistochemical staining for Ki67 and quantified by Aperio imaging analysis. RESULTS: The sample included 88 African Americans (74%) and 31 (26%) European Americans. Serum and prostatic levels of 25 hydroxyvitamin D were correlated with each other (Spearman's rho (ρ) = 0.27, p = 0.004), and there was also a correlation between serum 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D (ρ = 0.34, p < 0.001). Serum and prostatic 25 hydroxyvitamin D levels were not correlated with Ki67 staining in tumor cells. Serum 1,25 dihydroxyvitamin D was inversely correlated with Ki67 staining in tumor cells (ρ = - 0.30, p = 0.002). On linear regression, serum 1,25 dihydroxyvitamin D was negatively associated with Ki67 staining in tumor cells (ß - 0.46, 95% CI - 0.75, - 0.04, p = 0.04). CONCLUSION: The correlation between physiologic serum levels of 25 hydroxyvitamin D with both prostatic 25 hydroxyvitamin D and serum 1,25 dihydroxyvitamin D suggests that serum levels are reasonable biomarkers of vitamin D status. Furthermore, serum 1,25 dihydroxyvitamin D has an inverse association with Ki67 staining in tumor cells at physiologic levels and may protect against tumor progression.

A comparative effectiveness analysis of the PBCG vs. PCPT risks calculators in a multi-ethnic cohort.

BACKGROUND: Predictive models that take race into account like the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPT RC) and the new Prostate Biopsy Collaborative Group (PBCG) RC have been developed to equitably mitigate the overdiagnosis of prostate specific antigen (PSA) screening. Few studies have compared the performance of both calculators across racial groups. METHODS: From 1485 prospectively recruited participants, 954 men were identified undergoing initial prostate biopsy for abnormal PSA or digital rectal examination in five Chicago hospitals between 2009 and 2014. Discrimination, calibration, and frequency of avoided biopsies were calculated to assess the performance of both risk calculators. RESULTS: Of 954 participants, 463 (48.5%) were Black, 355 (37.2%) were White, and 136 (14.2%) identified as Other. Biopsy results were as follows: 310 (32.5%) exhibited no cancer, 323 (33.9%) indolent prostate cancer, and 321 (33.6%) clinically significant prostate cancer (csPCa). Differences in area under the curve (AUC)s for the detection of csPCa between PCPT and PBCG were not statistically different across all racial groups. PBCG did not improve calibration plots in Blacks and Others, as it showed higher levels of overprediction at most risk thresholds. PCPT led to an increased number of avoidable biopsies in minorities compared to PBCG at the 30% threshold (68% vs. 28% of all patients) with roughly similar rates of missed csPCa (23% vs. 20%). CONCLUSION: Significant improvements were noticed in PBCG's calibrations and net benefits in Whites compared to PCPT. Since PBCG's improvements in Blacks are disputable and potentially biases a greater number of low risk Black and Other men towards unnecessary biopsies, PCPT may lead to better biopsy decisions in racial minority groups. Further comparisons of commonly used risk calculators across racial groups is warranted to minimize excessive biopsies and overdiagnosis in ethnic minorities.

Genome-Wide Association Study in African Americans with Acute Respiratory Distress Syndrome Identifies the Selectin P Ligand Gene as a Risk Factor.

RATIONALE: Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches. OBJECTIVES: To identify genetic susceptibility targets for ARDS. METHODS: A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort. MEASUREMENTS AND MAIN RESULTS: Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg-/- mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation. CONCLUSIONS: These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.