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ObjectiveBody mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.SubjectsUsing eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.ResultsWe replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P

Introduction: Spread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established., Methods: To assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI)., Results: STAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses., Conclusions: These data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification., Competing Interests: Disclosure Dr. Donington reports receiving personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Merck & Co., Inc., and Genentech, Inc./F. Hoffmann-La Roche Ltd., outside the submitted work. Dr. Joubert reports grants from AstraZeneca, Roche, Merck and Biomark Signature Inc. and personal fees from AstraZeneca and Merck, outside the submitted work. Dr. Mino-Kenudson reports receiving personal fees from AstraZeneca, Pfizer, Repare, Sanofi, AbbVie, Daiichi Sankyo, Boehringer Ingelheim, and Elsevier, outside the submitted work. Dr. Nishimura reports receiving grants from IASLC, outside the submitted work. Dr. Nicholson reports receiving personal fees from Merck, Boehringer Ingelheim, Novartis, AstraZeneca, Bristol Myers Squibb, Roche, AbbVie, Oncologica, UpToDate, the European Society of Oncology, Liberum, Takeda UK, and Sanofi and grants and personal fees from Pfizer, outside the submitted work. Dr. Papotti reports receiving personal fees from Roche, Eli Lilly, AstraZeneca, and Pfizer, outside the submitted work. Dr. Ugalde Figueroa reports receiving personal fees from AstraZeneca, Bristol, Roche, Medtronic, and Johnson & Johnson, outside the submitted work. Dr. Van Schil reports receiving personal fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, and Janssen, outside the submitted work; and serving as President of International Association for the Study of Lung Cancer and Treasurer of Belgian Association for Cardiothoracic Surgery. Dr. Yang reports being on advisory boards for AstraZeneca and Genentech. He has also received honorarium from AstraZeneca, outside the submitted work. Dr. Lievens reports financing from the EU ImmunoSABR project, personal fees from the UpLung project, Astra-Zeneca, outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The TNM classification of lung cancer is periodically revised. The International Association for the Study of Lung Cancer collected and analyzed a new database to inform the forthcoming ninth edition of the TNM classification. The results are herewith presented., Methods: After exclusions, 76,518 patients from a total of 124,581 registered patients were available for analyses: 58,193 with clinical stage, 39,192 with pathologic stage, and 62,611 with best stage NSCLC. The proposed new N2 subcategories (N2a, involvement of single ipsilateral mediastinal or subcarinal nodal station, and N2b, involvement of multiple ipsilateral mediastinal nodal stations with or without involvement of the subcarinal nodal station) and the new M1c subcategories (M1c1, multiple extrathoracic metastases in one organ system, and M1c2, multiple extrathoracic metastases in multiple organ systems) were considered in the survival analyses. Several potential stage groupings were evaluated, using multiple analyses, including recursive partitioning, assessment of homogeneity within and discrimination between potential groups, clinical and statistical significance of survival differences, multivariable regression, and broad assessment of generalizability., Results: T1N1, T1N2a, and T3N2a subgroups are assigned to IIA, IIB, and IIIA stage groups, respectively. T2aN2b and T2bN2b subgroups are assigned to IIIB. M1c1 and M1c2 remain in stage group IVB. Analyses reveal consistent ordering, discrimination of prognosis, and broad generalizability of the proposed ninth edition stage classification of lung cancer., Conclusions: The proposed stages for the ninth edition TNM improve the granularity of nomenclature about anatomic extent that has benefits as treatment approaches become increasingly differentiated and complex., Competing Interests: Disclosure Dr. Nishimura and Ms. Giroux report that statistical consulting by Cancer Research And Biostatistics (CRAB) employees for data collection, analysis, and manuscript preparation in the Staging Project is funded by the International Association for the Study of Lung Cancer (IASLC). Dr. Fong reports payments made to his institution by Competitive Research Grant, MRFF EPCDR Improving Diagnosis in Cancers Low Survival Rates; Competitive Research Grant, NHMRC Ideas grant: Early lung cancer biomarkers; Competitive Research Grant, MRFF Next Generation Clinical Researchers Program - Practitioner Fellowship; Competitive Research Grant, NHMRC Project: Novel biomarkers for lung cancer; Competitive Research Grant, NHMRC Low dose computed tomography (LDCT) to diagnose lung cancer; payments to himself by UpToDate Reviewer and Cochrane Clinical Answers Reviewer; payment for travel support to WCLC, ATS in 2022 and PCCP in 2023; payments for travel support by the 2023 Asia Pacific Coalition Against Lung Cancer; and payments from the Asia Pacific Society of Respirology former President and EXCO member; support with loan bronchoscopes for the purpose of a research study—no financial funding from Olympus; and software licensing for Computer Aided Diagnosis research in the International Lung Screen Trial (ILST) from Mevis Veolity. Dr. Giuliani reports receiving payments for Advisory Board member from AstraZeneca and Bristol Myers Squibb; and being Section Editor, of the International Journal of Radiation Oncology, Biology and Physics. Dr. Marom reports receiving honorarium for lectures from Boehringer Ingelheim, Merck Sharp & Dohme, and AstraZeneca. Dr. Nicholson reports receiving personal fees from Merck, Boehringer Ingelheim, Novartis, AstraZeneca, Bristol-Myers Squibb, Roche, AbbVie, Oncologica, UpToDate, the European Society of Oncology, and Liberum; and grants and personal fees from Pfizer, outside of the submitted work. Dr. Van Schil reports receiving lecture and consulting institutional fees from AstraZeneca and Janssen and lecture and consulting personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; and having leadership positions in BACTS (Belgian Association for Cardiothoracic Surgery) as treasurer and IASLC (International Association for the Study of Lung Cancer) as president with no fees. Dr. Travis reports receiving a grant from the National Cancer Institute: MSKCC Core Grant: P30 CA008748. Dr. Rusch reports receiving support for the present manuscript from NIH Cancer Support Grant P30-CA008748; institutional funding for a clinical trail from Genentech; and miscellaneous honoraria for lectures of no commercial interest at various universities; funding for meeting preparation and attendance by NIH Thoracic Malignancy Steering Committee (Co-Chair); and reports being a committee member of MARS II and RAMON trials (Cancer Research UK). Dr. Asamura reports receiving funding for analyses of results and manuscript preparation and support from the IASLC for attending meetings. The remaining authors report no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: This study analyzed all metastatic categories of the current TNM classification of NSCLC to propose modifications of the M component in the next edition (ninth) of the classification., Methods: A database of 124,581 patients diagnosed between 2011 and 2019 was established; of these, 14,937 with NSCLC in stages IVA to IVB were available for this analysis. Overall survival was calculated using the Kaplan-Meier method, and prognosis was assessed using multivariable-adjusted Cox proportional hazards regression., Results: The eighth edition M categories revealed good discrimination in the ninth edition data set. Assessments revealed that an increasing number of metastatic lesions were associated with decreasing prognosis; because this seems to be a continuum and adjustment for confounders was not possible, no specific lesion number was deemed appropriate for stage classification. Among tumors involving multiple metastases, decreasing prognosis was found with an increasing number of organ systems involved. Multiple assessments, including after adjustment for potential confounders, revealed that M1c patients who had metastases to a single extrathoracic organ system were prognostically distinct from M1c patients who had involvement of multiple extrathoracic organ systems., Conclusions: These data validate the eighth edition M1a and M1b categories, which are recommended to be maintained. We propose the M1c category be divided into M1c1 (involvement of a single extrathoracic organ system) and M1c2 (involvement of multiple extrathoracic organ systems)., Competing Interests: Disclosure Dr. Fong reports receiving grants and contracts from MRFF EPCDR, NHMRC Ideas Grant, MRFF Next Generation Clinical Researchers Program, NHMRC; receiving funds from UpToDate as reviewer and Cochrane Clinical Answers as reviewer; and receiving equipment support from Olympus and Mevis Veolity. Mr. Rosenthal reports receiving fees for service from IASLC to complete work associated with publication. Ms. Giroux reports receiving fees for service from IASLC to complete work associated with publication. Dr. Nishimura reports receiving fees for service from IASLC to complete work associated with publication. Dr. Erasmus reports receiving honoraria from Canadian Association of Radiologists. Dr. Lievens reports receiving grants and contracts for the ImmunoSABR EU Project, HERO-VBHC chair; consulting fees from AstraZeneca; and honoraria from Merck Sharp & Dohme. Dr. Marom reports receiving honoraria from Boehringer Ingelheim, Merck, and AstraZeneca. Dr. Putora reports receiving grants or contracts from Bayer, Takeda, and AstraZeneca. Dr. Suárez reports receiving consulting fees from AstraZeneca and Roche; honoraria from AstraZeneca. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: An international database was created by the International Association for the Study of Lung Cancer to inform on the ninth edition of the TNM classification of lung cancer. The present analyses concern its T component., Methods: Data on 124,581 patients diagnosed with lung cancer from January 1, 2011 to December 31, 2019 were submitted to the International Association for the Study of Lung Cancer database. Of these, 33,982 met the inclusion criteria for the clinical T analysis, and 30,715 met the inclusion criteria for the pathologic postsurgical analysis. Survival was measured from the date of diagnosis or operation for clinically and pathologically staged tumors, respectively. T descriptors were evaluated in univariate analysis and multivariable Cox regression analysis adjusted for age, sex, pathologic type, and geographic region., Results: Comprehensive survival analysis revealed that the existing eighth edition T component criteria performed adequately in the ninth edition data set. Although pathologic chest wall or parietal pleura involvement (PL 3) yielded a worse survival compared with the other T3 descriptors, with a similar survival as T4 tumors, this difference was not observed for clinical chest wall or PL 3 tumors. Because of these inconsistent findings, no reallocation of chest wall or PL 3 tumors is advised., Conclusions: The T subcommittee members proposed not to implement any changes and keep the current eighth-edition T descriptors for the ninth edition., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The accurate assessment of nodal (N) status is crucial to the management and prognostication of nonmetastatic NSCLC. We sought to determine whether the current N descriptors should be maintained or revised for the upcoming ninth edition of the international TNM lung cancer staging system., Methods: Data were assembled by the International Association for the Study of Lung Cancer on patients with NSCLC, detailing both clinical and pathologic N status, with information about anatomical location and individual station-level identification. Survival was calculated by the Kaplan-Meier method and prognostic groups were assessed by a Cox regression analysis., Results: Data for clinical N and pathologic N status were available in 45,032 and 35,009 patients, respectively. The current N0 to N3 descriptors for both clinical N and pathologic N categories reflect prognostically distinct groups. Furthermore, single-station N2 involvement (N2a) exhibited a better prognosis than multistation N2 involvement (N2b) in both clinical and pathologic classifications, and the differences between all neighboring nodal subcategories were highly significant. The prognostic differences between N2a and N2b were robust and consistent across resection status, histologic type, T category, and geographic region., Conclusions: The current N descriptors should be maintained, with the addition of new subdescriptors to N2 for single-station involvement (N2a) and multiple-station involvement (N2b)., (Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: Currently, tumors with different histopathologic characteristics and oncologic outcomes comprise the T3 category of the eight edition TNM classification for lung cancers. To better understand the T3 category, we evaluated completeness of resection and long-term survival in patients undergoing resection for T3 NSCLC., Methods: The International Association for the Study of Lung Cancer 1999 to 2010 database was queried for patients with pathologic T3N0M0 NSCLC who underwent lobectomy or pneumonectomy. The primary outcome evaluated was overall survival (OS) stratified by T3 descriptors and completeness of resection., Results: Of 1448 patients with T3N0M0 tumors, 1187 (82.0%) had a single descriptor defining them as T3. T3 tumors with chest wall infiltration (CWI) or parietal pleura infiltration (PL3) had the highest rates of incomplete resection (9.8% and 8.4%, respectively), and those classified as T3 by size only had the lowest rate of incomplete resection (2.9%). Individual T3 descriptors were associated with significant differences in OS (p = 0.005). When tumors with similar survival and complete resection rates were grouped, patients with T3 tumors characterized by size or the presence of a separate nodule (SN) in the same lobe had better 5-year OS than patients with tumors characterized by PL3 or CWI (size/SN 60% versus CWI/PL3 53%, p = 0.017) independent of completeness of resection., Conclusions: Significant differences in 5-year OS were associated with size, SN, PL3, or CWI T3 descriptors. Subdividing pathologic T3N0M0 tumors according to the presence or absence of CWI or PL3 may increase the prognostic accuracy of tumor staging., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

In the past 20 years, the International Association for the Study of Lung Cancer (IASLC) has been working on a global project to revise the TNM classification of lung cancer. The first and second phases of the staging projects proposed recommendations for revision of the TNM classification, which were adopted by the Union for International Cancer Control and the American Joint Committee on Cancer as their seventh and eighth editions of the TNM classifications of lung cancer. For the third phase of the IASLC Staging Project, a new database of lung cancer cases diagnosed between January 2011 and December 2019 has been established. The Staging and Prognostic Factors Committee of the IASLC is in charge of the process of proposing new recommendations. The newly established database consisted of 124,581 cases. The data were obtained from Asia and Australia (56.0%), Europe (24.7%), North America (15.7%), South/Central America (3.4%), and Africa and the Middle East (0.1%). After cases with incomplete data are excluded, 87,043 cases were enrolled in the analysis, of which 52,069 (59.8%) were invasive adenocarcinoma and 15,872 (18.2%) were squamous cell carcinoma. Both clinical and pathologic stages were available in 44,831 (51.5%) cases. Analyses of this database are expected to provide proposals for changing the TNM classification toward the ninth edition, which is scheduled to be in use in January 2024. This newly established global database on lung cancer is described to provide fundamental elements for revisions of the TNM rules for staging lung cancer., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The status of lymph node involvement is a major component of the TNM staging system. The N categories for lung cancer have remained unchanged since the fourth edition of the TNM staging system, partly because of differences in nodal mapping nomenclature, partly because of insufficient details to verify possible alternative approaches for staging. In preparation for the rigorous analysis of the International Association for the Study of Lung Cancer database necessary for the ninth edition TNM staging system, members of the N-Descriptors Subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee reviewed the evidence for alternative approaches to categorizing the extent of lymph node involvement with lung cancer, which is currently based solely on the anatomical location of lymph node metastasis. We reviewed the literature focusing on NSCLC to stimulate dialogue and mutual understanding among subcommittee members engaged in developing the ninth edition TNM staging system for lung cancer, which has been proposed for adoption by the American Joint Committee on Cancer and Union for International Cancer Control in 2024. The discussion of the range of possible revision options for the N categories, including the pros and cons of counting lymph nodes, lymph node stations, or lymph node zones, also provides transparency to the process, explaining why certain options may be discarded, others deferred for future consideration. Finally, we provide a preliminary discussion of the future directions that the N-Descriptors Subcommittee might consider for the 10th edition and beyond., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

In the eighth edition TNM staging, the T3N0M0 category represents a heterogeneous group of non-small cell lung cancers (NSCLC). This study aims to compare the oncologic outcomes associated with individual T3 features. We performed a single-institution, retrospective analysis of 280 consecutive patients with pT3N0M0 NSCLC. Multivariate regression models were used to estimate associations of clinical factors with oncologic outcomes. The patients were grouped according to their T3 features into 4 prognostic groups: chest wall infiltration (CWI-PG), largest diameter >5 cm and ≤7 cm (Size-PG), presence of a satellite nodule (SN-PG), and all other T3 features. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier and Cox proportional hazard analyses. Tumors were most often classified as T3N0M0 by size (156 patients, 55.7%), and the highest rate of incomplete resection occurred in patients with CWI (n = 7, 25.9%). In multivariate analysis, CWI (hazard ratio [HR] 2.45, 95% confidence interval [CI] 1.36, 4.44), incomplete resection (HR 3.01, 95% CI 1.29, 7.05), and age >65 (HR 1.6; 95% CI 1.08, 2.38) were independently associated with worse OS, and female sex was associated with better OS (HR 0.6, 95% CI 0.42, 0.87). The CWI-PG had poorer OS when compared with each of the other prognostic groups (P < 0.05), and the Size-PG had inferior OS when compared with the SN-PG (P = 0.039). This single-center study demonstrated significant differences in OS and PFS between patients with different T3 classifying features and suggest that further subdivision of the T3 category should be considered., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: As immune checkpoint inhibitors (ICI) become increasingly used in frontline settings, identifying early indicators of response is needed. Recent studies suggest a role for circulating tumor DNA (ctDNA) in monitoring response to ICI, but uncertainty exists in the generalizability of these studies. Here, the role of ctDNA for monitoring response to ICI is assessed through a standardized approach by assessing clinical trial data from five independent studies., Patients and Methods: Patient-level clinical and ctDNA data were pooled and harmonized from 200 patients across five independent clinical trials investigating the treatment of patients with non-small-cell lung cancer with programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1)-directed monotherapy or in combination with chemotherapy. CtDNA levels were measured using different ctDNA assays across the studies. Maximum variant allele frequencies were calculated using all somatic tumor-derived variants in each unique patient sample to correlate ctDNA changes with overall survival (OS) and progression-free survival (PFS)., Results: We observed strong associations between reductions in ctDNA levels from on-treatment liquid biopsies with improved OS (OS; hazard ratio, 2.28; 95% CI, 1.62 to 3.20; P < .001) and PFS (PFS; hazard ratio 1.76; 95% CI, 1.31 to 2.36; P < .001). Changes in the maximum variant allele frequencies ctDNA values showed strong association across different outcomes., Conclusion: In this pooled analysis of five independent clinical trials, consistent and robust associations between reductions in ctDNA and outcomes were found across multiple end points assessed in patients with non-small-cell lung cancer treated with an ICI. Additional tumor types, stages, and drug classes should be included in future analyses to further validate this. CtDNA may serve as an important tool in clinical development and an early indicator of treatment benefit.

Introduction: Stage classification provides a consistent and concise nomenclature about the anatomic extent of the cancer. This is a fundamental cornerstone in the management of patients; it enables reporting results and facilitates comparing one treatment to another and judging how closely clinical trial results apply to an individual patient. A nomenclature must be relatively static; however, periodical refinement is needed to adjust to a changing landscape of clinical relevance. Changes must be well justified and thoughtfully developed to maintain the ability to communicate clearly and facilitate comparisons across time., Methods: For thoracic malignancies (lung, pleura, thymus, and esophagus), the International Association for the Study of Lung Cancer (IASLC) has leveraged its worldwide multidisciplinary reach, permitting a sophisticated approach to this process. Refinement of stage classification for the ninth edition of TNM is underway; this article describes the approach adopted by the IASLC Staging and Prognostic Factors Committee., Results: Key guiding principles include the ability to maintain communication over time, a classification that discriminates homogeneous cohorts of tumors consistently across the world in multiple settings, treatment approaches, and patient characteristics, including clinical relevance and practical applicability. The IASLC has again assembled a large international database to permit multifaceted analysis. Providing confidence that the classification performs consistently in multiple settings, treatments, and patients requires consistent discrimination in multiple subset analyses. Although observed outcomes of patients in the 2011 to 2019 database are essential, considerations about how the classification will be used are also important to ensure clinical relevance and applicability., Conclusions: The strategy developed by the Staging and Prognostic Factors Committee is carefully designed to provide useful refinements to the stage classification of thoracic malignancies for the ninth edition of TNM classification of cancers., (Copyright © 2022. Published by Elsevier Inc.)

One mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear. We applied PrediXcan to impute GReX in 51,520 ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) participants (35% African American, 45% Hispanic/Latino, 10% Asian, and 7% Hawaiian) across 25 key cardiometabolic traits and relevant tissues to identify 102 novel associations. We then compared associations in PAGE to those in a random subset of 50,000 White British participants from UK Biobank (UKBB 50k ) for height and body mass index (BMI). We identified 517 associations across 47 tissues in PAGE but not UKBB 50k , demonstrating the importance of diverse samples in identifying trait-associated GReX. We observed that variants used in PrediXcan models were either more or less differentiated across continental-level populations than matched-control variants depending on the specific population reflecting sampling bias. Additionally, variants from identified genes specific to either PAGE or UKBB 50k analyses were more ancestrally differentiated than those in genes detected in both analyses, underlining the value of population-specific discoveries. This suggests that while EA-derived transcriptome imputation models can identify new associations in non-EA populations, models derived from closely matched reference panels may yield further insights. Our findings call for more diversity in reference datasets of tissue-specific gene expression., Competing Interests: Declaration of interests E.E.K. has received speaker honoraria from Illumina, 23andMe, and Regeneron Pharmaceuticals and serves as a scientific board member for Galateo Bio., (Copyright © 2022 American Society of Human Genetics. All rights reserved.)

Background: Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented., Results: We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations., Conclusions: Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine., Competing Interests: The authors have declared that no competing interests exist.

As multiple myeloma (MM) treatments evolve, frequent updates are required to monitor the long-term effect of changes in approach. Traditionally, MM is considered an incurable disease, with most patients eventually relapsing. However, improvements in treatments has raised the possibility that MM might be functionally curable. To examine improvements in long-term survival, we followed 4329 patients with newly diagnosed MM treated with autologous stem cell transplantation (ASCT) at the University of Arkansas for Medical Sciences from 1989 through 2018. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier analysis, Cox proportional hazards models, relative survival analysis, and cure modeling among different time periods, risk groups, and demographic traits. Steady improvements in OS were found, with patients treated in 2014 or later having superior OS (hazard ratio, 0.35; 95% confidence interval [CI], 0.27-0.45) and reduced excess risk for MM death (relative excess risk, 0.30; 95% CI, 0.22-0.41) compared with patients treated in 1997 or earlier. Patients treated during intervening time periods often had intermediate survival, but trends in OS, PFS, and landmarked analyses were inconsistent. Cure models support the potential for cure, ranging from 6.3% to 31.3%, depending on the year of treatment, with 10.0% to 18.6% of patients achieving their normal life expectancy across multiple periods. There was some evidence of reductions in early mortality within 3 years of diagnosis, longer complete response (CR) duration, and reductions in relapse after achieving CR. However, results differed depending on age, risk group, and cytogenetic characteristics., (© 2020 by The American Society of Hematology.)

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry 1-3 . In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific 4-10 . Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations 11,12 . Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions 13 -the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

Background: Acute respiratory infections are a major cause of morbidity in children and are often caused by viruses. However, the relative severity of illness associated with different viruses is unclear. The objective of this study was to evaluate the risk of hospitalization from different viruses in children presenting with an influenza-like illness (ILI)., Methods: Data from children 5 years old or younger participating in an ILI natural history study from April 2010 to March 2014 was analyzed. The adjusted odds ratio for hospitalization was estimated in children with infections caused by respiratory syncytial virus (RSV), metapneumovirus, bocavirus, parainfluenza viruses, rhinovirus/enterovirus, coronavirus, adenovirus, and influenza., Results: A total of 1486 children (408 outpatients and 1078 inpatients) were included in this analysis. At least one virus was detected in 1227 (82.6%) patients. The most frequent viruses detected as single pathogens were RSV (n = 286), rhinovirus/enterovirus (n = 251), parainfluenza viruses (n = 104), and influenza A or B (n = 99). After controlling for potential confounders (age, sex, recruitment site, days from symptom onset to enrollment, and underlying illnesses), children with RSV and metapneumovirus infections showed a greater likelihood of hospitalization than those infected by parainfluenza viruses (OR 2.7 and 1.9, respectively), rhinovirus/enterovirus (OR 3.1 and 2.1, respectively), coronaviruses (OR 4.9 and 3.4, respectively), adenovirus (OR 4.6 and 3.2, respectively), and influenza (OR 6.3 and 4.4, respectively)., Conclusions: Children presenting with ILI caused by RSV and metapneumovirus were at greatest risk for hospitalization, while children with rhinovirus/enterovirus, parainfluenza, coronavirus, adenovirus, and influenza were at lower risk of hospitalization., (© 2018 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Objective: In the United States, Puerto Ricans and African Americans have lower prevalence of breastfeeding and worse clinical outcomes for asthma compared with other racial/ethnic groups. We hypothesize that the history of breastfeeding is associated with increased forced expiratory volume in 1 second (FEV 1 ) % predicted and reduced asthma exacerbations in Latino and African American youths with asthma., Methods: As part of the Genes-environments & Admixture in Latino Americans (GALA II) Study and the Study of African Americans, asthma, Genes & Environments (SAGE II), we conducted case-only analyses in children and adolescents aged 8-21 years with asthma from four different racial/ethnic groups: African Americans (n = 426), Mexican Americans (n = 424), mixed/other Latinos (n = 255), and Puerto Ricans (n = 629). We investigated the association between any breastfeeding in infancy and FEV 1 % predicted using multivariable linear regression; Poisson regression was used to determine the association between breastfeeding and asthma exacerbations., Results: Prevalence of breastfeeding was lower in African Americans (59.4%) and Puerto Ricans (54.9%) compared to Mexican Americans (76.2%) and mixed/other Latinos (66.9%; p < 0.001). After adjusting for covariates, breastfeeding was associated with a 3.58% point increase in FEV 1 % predicted (p = 0.01) and a 21% reduction in asthma exacerbations (p = 0.03) in African Americans only., Conclusion: Breastfeeding was associated with higher FEV 1 % predicted in asthma and reduced number of asthma exacerbations in African American youths, calling attention to continued support for breastfeeding.

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m 2 ) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

Rationale: Adverse effects of exposures to ambient air pollution on lung function are well documented, but evidence in racial/ethnic minority children is lacking., Objectives: To assess the relationship between air pollution and lung function in minority children with asthma and possible modification by global genetic ancestry., Methods: The study population consisted of 1,449 Latino and 519 African American children with asthma from five different geographical regions in the mainland United States and Puerto Rico. We examined five pollutants (particulate matter ≤10 μm and ≤2.5 μm in diameter, ozone, nitrogen dioxide, and sulfur dioxide), derived from participant residential history and ambient air monitoring data, and assessed over several time windows. We fit generalized additive models for associations between pollutant exposures and lung function parameters and tested for interaction terms between exposures and genetic ancestry., Measurements and Main Results: A 5 μg/m(3) increase in average lifetime particulate matter less than or equal to 2.5 μm in diameter exposure was associated with a 7.7% decrease in FEV1 (95% confidence interval = -11.8 to -3.5%) in the overall study population. Global genetic ancestry did not appear to significantly modify these associations, but percent African ancestry was a significant predictor of lung function., Conclusions: Early-life particulate exposures were associated with reduced lung function in Latino and African American children with asthma. This is the first study to report an association between exposure to particulates and reduced lung function in minority children in which racial/ethnic status was measured by ancestry-informative markers.

Background: IgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic disorders., Objective: We sought to identify genetic variants associated with IgE levels in Latinos., Methods: We performed a genome-wide association study and admixture mapping of total IgE levels in 3334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1564 European Americans, and 3187 African Americans from independent studies., Results: We confirmed associations of 6 genes identified by means of previous genome-wide association studies and identified a novel genome-wide significant association of a polymorphism in the zinc finger protein 365 gene (ZNF365) with total IgE levels (rs200076616, P = 2.3 × 10(-8)). We next identified 4 admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) at which local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower IgE levels (P = 4.95 × 10(-8)). All but 22q13.1 were replicated in an independent sample of Latinos, and 2 of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified 6 genome-wide significant single nucleotide polymorphisms in Latinos, 2 of which replicated in European Americans. Another single nucleotide polymorphism was peak-wide significant within 14q23.2 in African Americans (rs1741099, P = 3.7 × 10(-6)) and replicated in non-African American samples (P = .011)., Conclusion: We confirmed genetic associations at 6 genes and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse multiethnic populations to uncover novel loci associated with total IgE levels., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest., Objective: To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children., Methods: We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry., Results: Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively)., Conclusion: Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

It has long been accepted that modern reproductive patterns are likely contributors to breast cancer susceptibility because of their influence on hormones such as estrogen and the importance of these hormones in breast cancer. We conducted a meta-analysis to assess whether this 'evolutionary mismatch hypothesis' can explain susceptibility to both estrogen receptor positive (ER-positive) and estrogen receptor negative (ER-negative) cancer. Our meta-analysis includes a total of 33 studies and examines parity, age of first birth and age of menarche broken down by estrogen receptor status. We found that modern reproductive patterns are more closely linked to ER-positive than ER-negative breast cancer. Thus, the evolutionary mismatch hypothesis for breast cancer can account for ER-positive breast cancer susceptibility but not ER-negative breast cancer., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Rationale: Air pollution is a known asthma trigger and has been associated with short-term asthma symptoms, airway inflammation, decreased lung function, and reduced response to asthma rescue medications., Objectives: To assess a causal relationship between air pollution and childhood asthma using data that address temporality by estimating air pollution exposures before the development of asthma and to establish the generalizability of the association by studying diverse racial/ethnic populations in different geographic regions., Methods: This study included Latino (n = 3,343) and African American (n = 977) participants with and without asthma from five urban regions in the mainland United States and Puerto Rico. Residential history and data from local ambient air monitoring stations were used to estimate average annual exposure to five air pollutants: ozone, nitrogen dioxide (NO₂), sulfur dioxide, particulate matter not greater than 10 μm in diameter, and particulate matter not greater than 2.5 μm in diameter. Within each region, we performed logistic regression to determine the relationship between early-life exposure to air pollutants and subsequent asthma diagnosis. A random-effects model was used to combine the region-specific effects and generate summary odds ratios for each pollutant., Measurements and Main Results: After adjustment for confounders, a 5-ppb increase in average NO₂ during the first year of life was associated with an odds ratio of 1.17 for physician-diagnosed asthma (95% confidence interval, 1.04-1.31)., Conclusions: Early-life NO₂ exposure is associated with childhood asthma in Latinos and African Americans. These results add to a growing body of evidence that traffic-related pollutants may be causally related to childhood asthma.

Context: Enlargement of the vestibular aqueduct (EVA) is a commonly detected inner ear anomaly related to hearing loss and often associated with mutations of SLC26A4 encoding pendrin, a transmembrane exchanger of Cl(-), I(-), and HCO(3)(-). Here we describe the phenotypes of 27 Korean EVA subjects and their SLC26A4 genotypes determined by bidirectional nucleotide sequencing., Results: The detected variants include two novel missense substitutions (p.V138L and p.P542R). We characterized the ability of p.V138L and p.P542R pendrin products to traffic to the plasma membrane in COS-7 cells and to transport Cl(-), I(-), and HCO(3)(-) in Xenopus oocytes. The results indicate that p.P542R is a benign polymorphic variant, whereas p.V138L is a pathogenic mutation. Since this and other studies of East Asian EVA cohorts show that the majority of SLC26A4 mutations affect either or both of two amplicons (exons 7-8 and 19), we developed a hierarchical protocol that integrates direct sequencing with denaturing high-performance liquid chromatography analyses for detection of SLC26A4 mutations in these populations. We validated the cost efficiency of the integrated protocol by a simulated screen of published East Asian EVA cohorts with known SLC26A4 genotypes., Conclusions: Our study further defines the spectrum of SLC26A4 mutations among East Asians and demonstrates a rapid and efficient protocol for their detection.