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

Hilary A. Robbins, Karine Alcala, Elham Khodayari Moez, Florence Guida, Sera Thomas, Hana Zahed, Matthew T. Warkentin, Karl Smith-Byrne, Yonathan Brhane, David Muller, Xiaoshuang Feng, Demetrius Albanes, Melinda C. Aldrich, Alan A. Arslan, Julie Bassett, Christine D. Berg, Qiuyin Cai, Chu Chen, Michael P.A. Davies, Brenda DiergaardeJohn K. Field, Neal D. Freedman, Wen Yi Huang, Mikael Johansson, Michael Jones, Woon Puay Koh, Stephen Lam, Qing Lan, Arnulf Langhammer, Linda M. Liao, Geoffrey Liu, Reza Malekzadeh, Roger L. Milne, Luis M. Montuenga, Thomas Rohan, Howard D. Sesso, Gianluca Severi, Mahdi Sheikh, Rashmi Sinha, Xiao Ou Shu, Victoria L. Stevens, Martin C. Tammemägi, Lesley F. Tinker, Kala Visvanathan, Ying Wang, Renwei Wang, Stephanie J. Weinstein, Emily White, David Wilson, Jian Min Yuan, Xuehong Zhang, Wei Zheng, Christopher I. Amos, Paul Brennan, Mattias Johansson, Rayjean J. Hung

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.
Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalAnnals of Epidemiology
StatePublished - Jan 1 2023
Externally publishedYes

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