Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program

• Type of Material: Article
• Authors: Hilary A Robbins, International Agency for Research on Cancer; Karine Alcala, International Agency for Research on Cancer; Elham Khodayari Moez, Sinai Health; Florence Guida, International Agency for Research on Cancer; Sera Thomas, Sinai Health; Hana Zahed, International Agency for Research on Cancer; Matthew T Warkentin, Sinai Health; Karl Smith-Byrne, University of Oxford Medical Sciences Division; Yonathan Brhane, Sinai Health; David Muller, Imperial College London; Xiaoshuang Feng, International Agency for Research on Cancer; Demetrius Albanes, National Cancer Institute (NCI); Melinda C Aldrich, Vanderbilt University Medical Center; Alan A Arslan, NYU Grossman School of Medicine; Julie Bassett, Cancer Council Victoria; Christine D Berg, Retired; Qiuyin Cai, Vanderbilt University Medical Center; Chu Chen, Fred Hutchinson Cancer Research Center; Michael PA Davies, University of Liverpool; Brenda Diergaarde, University of Pittsburgh Graduate School of Public Health; John K Field, University of Liverpool; Neal D Freedman, National Cancer Institute (NCI); Wen-Yi Huang, National Cancer Institute (NCI); Mikael Johansson, Umeå Universitet; Michael Jones, The Institute of Cancer Research; Woon-Puay Koh, NUS Yong Loo Lin School of Medicine; Stephen Lam, British Columbia Cancer Agency; Qing Lan, National Cancer Institute (NCI); Arnulf Langhammer, Norges Teknisk-Naturvitenskapelige Universitet; Linda M Liao, National Cancer Institute (NCI); Geoffrey Liu, Ontario Cancer Institute University of Toronto; Reza Malekzadeh, Digestive Diseases Research Institute; Roger L Milne, Cancer Council Victoria; Luis M Montuenga, Universidad de Navarra; Thomas Rohan, Albert Einstein College of Medicine of Yeshiva University; Howard D Sesso, Harvard Medical School; Gianluca Severi, Université Paris-Saclay; Mahdi Sheikh, International Agency for Research on Cancer; Rashmi Sinha, National Cancer Institute (NCI); Xiao-Ou Shu, Vanderbilt University Medical Center; Victoria L Stevens, Rollins School of Public Health; Martin C Tammemägi, Brock University; Lesley F Tinker, Fred Hutchinson Cancer Research Center; Kala Visvanathan, Johns Hopkins Bloomberg School of Public Health; Ying Wang, Emory University; Stephanie J Weinstein, National Cancer Institute (NCI); Emily White, Fred Hutchinson Cancer Research Center; David Wilson, University of Pittsburgh School of Medicine; Jian-Min Yuan, UPMC Hillman Cancer Center; Xuehong Zhang, Harvard Medical School; Wei Zheng, Vanderbilt University Medical Center; Christopher I Amos, Baylor College of Medicine; Paul Brennan, International Agency for Research on Cancer; Mattias Johansson, International Agency for Research on Cancer; Rayjean J Hung, Sinai Health, Canada
• Language: English
• Date: 2023-01-01
• Publisher: Elsevier Inc.
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.annepidem.2022.10.014
• Title of Journal or Parent Work: Annals of Epidemiology
• Volume: 77
• Start Page: 1
• End Page: 12
• Keywords: Lung; Tomography, X-Ray Computed; nodule malignancy; Biomarkers; Lung cancer screening; risk prediction; Prospective Studies; study design; Early Detection of Cancer; Humans; biomarker discovery and validation; Case-Control Studies; early detection; Lung Neoplasms; Cohort Studies; biomarkers
• Research Categories: Health Sciences, Epidemiology

Abstract

The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.