Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort

Magda Gasull, José Pumarega, Hannu Kiviranta, Panu Rantakokko, Ole Raaschou-Nielsen, Ingvar A Bergdahl, Torkjel Manning Sandanger, Fernando Goñi, Lluís Cirera, Carolina Donat-Vargas, Juan Alguacil, Mar Iglesias, Anne Tjønneland, Kim Overvad, Francesca Romana Mancini, Marie-Christine Boutron-Ruault, Gianluca Severi, Theron Johnson, Tilman Kühn, Antonia TrichopoulouAnna Karakatsani, Eleni Peppa, Domenico Palli, Valeria Pala, Rosario Tumino, Alessio Naccarati, Salvatore Panico, Monique Verschuren, Roel Vermeulen, Charlotta Rylander, Therese Haugdahl Nøst, Miguel Rodríguez-Barranco, Amaia Molinuevo, María-Dolores Chirlaque, Eva Ardanaz, Malin Sund, Tim Key, Weimin Ye, Mazda Jenab, Dominique Michaud, Giuseppe Matullo, Federico Canzian, Rudolf Kaaks, Alexandra Nieters, Ute Nöthlings, Suzanne Jeurnink, Veronique Chajes, Marco Matejcic, Marc Gunter, Dagfinn Aune, Elio Riboli, Antoni Agudo, Carlos Alberto Gonzalez, Elisabete Weiderpass, Bas Bueno-de-Mesquita, Eric J Duell, Paolo Vineis, Miquel Porta

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BACKGROUND: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases.

OBJECTIVES: First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles.

METHODS: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models.

RESULTS: There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB.

CONCLUSIONS: The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects' characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.

Original languageEnglish
Pages (from-to)417-433
Number of pages17
JournalEnvironmental Research
Early online date23 Nov 2018
Publication statusPublished - Feb 2019

Bibliographical note

Copyright © 2018 Elsevier Inc. All rights reserved.


  • Case-Control Studies
  • Environmental Exposure/statistics & numerical data
  • Environmental Pollutants
  • Gas Chromatography-Mass Spectrometry
  • Humans
  • Pancreatic Neoplasms/epidemiology
  • Plasma
  • Polychlorinated Biphenyls
  • Prospective Studies
  • Tandem Mass Spectrometry


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