The P4COPD Study: Rationale, Goals and Study Design – Prediction, Prevention, Personalized and Precision Management of COPD in Young Adults

Abstract

Introduction

Chronic obstructive pulmonary disease (COPD) is a major public health problem. Research over the past few years has shown that COPD is the result of dynamic and cumulative gene–environment interactions starting early in life. This opens new opportunities for the Prediction, Prevention, Personalized and Precise management (P4) of COPD in young adults. The P4COPD study sought to: (1) investigate the genomic and environmental/lifestyle determinants of COPD in young adults (18–50 years); (2) contrast them with those determined in children, adolescent and older individuals; and (3) explore the feasibility and cost of implementing a P4 strategy for COPD in young adults in clinical practice.

Materials and methods

The P4COPD study leverages from already existing cohorts (EarlyCOPD, INMA, LEVANTE, Aduheart) of young subjects (18–50 years) and de novo recruitment from primary care centers, in whom we: (1) analyzed demographic, epidemiological, clinical and physiologic information; (2) measured genetic, epigenetic and proteomic markers; (3) used analytical methods to identify endotypes, biomarkers and potential therapeutic targets associated with the presence of COPD, pre-COPD and/or low peak lung function. Results in young individuals: (4) were contrasted with healthy controls from the general population (IMPACT cohort) and COPD cohorts in older patients (BIOMEPOC, CHAIN and ECLIPSE). Besides, we (5) explored how to implement results in clinical practice; and (6) estimated its potential health cost implications.

Results

First results are expected in the third and fourth quarters of 2026.

Conclusions

Identifying young individuals at risk of COPD, in whom to establish a P4 strategy is highly relevant to promote healthy aging.

Resumen

Introducción

La enfermedad pulmonar obstructiva crónica (EPOC) es un problema mayor de salud pública. La investigación de los últimos años ha demostrado que la EPOC es el resultado de interacciones dinámicas y acumulativas entre los genes y el medio ambiente que comienzan en la vida temprana. Esto abre nuevas oportunidades para la predicción, prevención y el manejo personalizado y preciso (P4) de la EPOC en adultos jóvenes. El estudio P4COPD tuvo como objetivos: (1) investigar los determinantes genómicos y ambientales/de estilo de vida de la EPOC en adultos jóvenes (20–50 años); (2) compararlos con los determinados en niños, adolescentes y personas de mayor edad; y (3) explorar la viabilidad y el coste de implementar una estrategia P4 para la EPOC en adultos jóvenes en la práctica clínica.

Material y métodos

El estudio P4COPD aprovecha cohortes ya existentes (EarlyCOPD, INMA, LEVANTE, Aduheart) de sujetos jóvenes (18–50 años), así como un reclutamiento de novo desde centros de atención primaria, en los que: (1) analizaremos información demográfica, epidemiológica, clínica y fisiológica; (2) mediremos marcadores genéticos, epigenéticos y proteómicos; (3) utilizaremos métodos analíticos para identificar endotipos, biomarcadores y posibles dianas terapéuticas asociadas con la presencia de EPOC, pre-EPOC y/o bajo pico de función pulmonar. Los resultados en individuos jóvenes (4) se contrastarán con controles sanos de la población general (cohorte IMPACT) y con cohortes de EPOC en pacientes de mayor edad (BIOMEPOC, CHAIN y ECLIPSE). Además, (5) exploraremos cómo implementar los resultados en la práctica clínica; y (6) estimaremos sus posibles implicaciones en costes sanitarios.

Resultados

Se espera que los primeros resultados estén disponibles en el tercer y cuarto trimestre de 2026.

Conclusión

Identificar a individuos jóvenes en riesgo de EPOC, en quienes establecer una estrategia P4, es altamente relevante para promover un envejecimiento saludable.

Introduction

Chronic obstructive pulmonary disease (COPD) is a major health problem because of its high prevalence (10% in adults), increasing incidence (partly in relation to ageing of the population), associated multi-morbidity and mortality (currently 3rd global cause of death) and associated social and economic cost.¹ According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the diagnosis of COPD requires the demonstration of poorly reversible airflow obstruction, as indicated by a FEV₁/FVC ratio below 0.7, in the appropriate clinical circumstances (symptoms and risk factors).¹ Yet, under-, miss- and late-diagnosis occur very frequently.² Underdiagnosis implies no treatment, misdiagnosis implies wrong treatment and late diagnosis implies less effective treatment because the disease is already advanced.³ More recently a pre-COPD state (with an FEV₁/FVC >0.7 but with respiratory symptoms and/or other physiological alterations) has been identified as a condition of risk for the future development of COPD, although their basic underlying mechanisms are still not well defined.⁴ Furthermore, although COPD has traditionally been considered a disease of old male smokers,⁵ research over the past decade has shown that it is actually the end-result of gene (G)–ENVIRONMENT (E) interactions occurring throughout the lifetime (T); a new GETomic approach (Fig. 1).⁶ The orange shade in Fig. 1 represents examples of environmental factors (the exposome^7,8), from conception to death. The positions of different exposures included in the shaded area are not necessarily related to the time axis (bottom arrow) and may occur multiple times during the lifespan.⁶ At different timepoints, these environmental factors interact with the genetic background of the individual through epigenetic and immune system interactions, which might be identified through various basic omics approaches. These interactions induce differential biological responses/mechanisms (endotypes) that modulate organ structure (development, maintenance and repair, ageing) and function.⁶ Endotypes can be identified by specific biomarkers.⁶ Modulation of organ structure and function, represented here by different lung function trajectories associated with development and ageing,^9,10 determines long-term phenotypes associated with health and disease, which can be explored through clinical omics approaches.⁶

Fig. 1.

A GETomics approach to COPD. The biological effects and clinical outcomes of different gene (G)–environment (E) interactions depend not only on their specific characteristics, but also on a time (T) dimension (i.e., the age of the individual at which the interaction occurs and the cumulative history of the individual's previously encountered GxE interactions). For further explanations see text.

Reproduced with permission from Ref. 6.

According to the novel GETomics approach to COPD,⁶ we hypothesize that it should be possible to investigate endotypes, biomarkers and phenotypes of COPD and pre-COPD in young adults, which in turn can lead to the identification of novel strategies for the Prediction, Prevention, Personalized and Precision management (P4)¹¹ of COPD at a younger age³ thus contributing to promote healthier ageing.^12,13 In this setting, detrimental early life exposures/factors are still not well understood but should be included in the COPD GETomic analysis. Below, we present the goals and methodology of the P4COPD study, a large multicenter prospective, controlled, observational study in young individuals (age range 18–50 years) that sought to explore this hypothesis.

The strategic goal of the P4COPD study is the Prediction, Prevention, Personalized and Precision (P4) management of COPD in young individuals through a better understanding of its genomic and environmental/lifestyle determinants, to facilitate the development of an individual risk calculator and an earlier and more widespread use of forced spirometry in the community as a global health marker.¹⁴

Specific goals of the study were to: (1) fill up the current black box in relation to COPD pathobiology in young adults (18–50 years of age), by describing the genetic, transcriptomic, epigenetic and environmental associated to COPD and pre-COPD; (2) contrast these observations with those determined in other age ranges (infancy, adolescence and elderly), both in the general population (healthy controls) and in older patients with full blown COPD; (3) develop and test risk calculators to predict future risk of developing COPD in young adults; (4) educate both the general population and health-care professionals on the importance of lung health through the life span; (5) foster the widespread use of spirometry as a global health marker in infancy, adolescence and young adults; and (6) explore the feasibility and cost-benefit of the implementation of a P4COPD strategy in clinical practice in young adults.

Materials and methods

The P4COPD study was funded by IMPaCT program, which is the Precision Medicine Infrastructure associated with Science and Technology established by the Carlos III Health Institute to facilitate the effective deployment of Precision Medicine within the National Health System. IMPaCT is structured around three programs that serve as the cornerstone for a coordinated integration of complementary research projects within the field of Precision Medicine: Predictive Medicine (cohorts), Data and Genomic Medicine. The IMPaCT cohort is an ongoing project aiming to set up a population-based cohort with 200,000 participating people, which will allow the psychological, social, environmental and biological determinants of health conditions and diseases of greatest importance in Spain to be explored for 20 years and will serve as a population-based cohort were to contrast the findings of our Project (https://cohorte-impact.es/cohorte-impact/investigacion/diseno-del-estudio/).

Study design and ethics

The P4COPD study was a multi-center, ambispective, controlled, observational study that includes about 1500 young individuals (age range 18–50 years) from different regions of Spain, both in already existing cohorts and with de novo recruitment (including primary care centers) (Table 1). These cohorts were followed up over time throughout the duration of the study. The inclusion criteria were: (1) being part of INMA-Sabadell or INMA-Menorca (general population birth cohort), EarlyCOPD (a young ever smokers cohort), Aduheart (birth cohort of individuals with low birth weight or intrauterine growth restriction matched with normal birth weight controls) or LEVANTE cohorts (medical students); or (2) being between 18 and 50 years of age, from any of the specific regions of Spain where the participating centers are located, able to perform the lung function tests and provide the demographic, biologic and clinical characteristics required. The exclusion criteria were: (a) being older than 50 years of age; (b) suffer any severe organic disease, such as advanced cancer or immune mediated chronic systemic disease; (c) frailty or any condition that difficult the participation in the study; and (d) do not understand any of the Spanish official languages.

Table 1.

Cohorts participating in the P4COPD study.

General population

Discovery

• INMA. (IP: Judith Garcia-Aymerich, ISGlobal). Birth-cohort in Menorca and Sabadell (n = 400–500). Followed up for 18–26 years. Detailed environmental, clinical, lung function information and biological samples available.

• BCN-Natal cohorts: Aduheart (IP. Fatima Crispi). Ambispective, controlled, cohort study whose detailed methodology has been published elsewhere.^29,30 Briefly, from the birth records of Hosp. Clinic Barcelona, we identified individuals born at term (≥37 weeks of gestation) between 1975 and 1995 with either appropriate weight for gestational age (AGA) or SGA (<10th centile for gestational age). CCheart (IP. Fatima Crispi) Prospective cohort, of 80 subjects with Doppler diagnosed Fetal growth Restriction and 120 normally grown fetuses, matched for gender, birth date, and gestational age at birth, of pregnancies cared for from January 2002 to October 2007, followed into adolescence (14 years).^31

Validation

• LEVANTE. (IP: Valle Velasco, Tenerife): About 300 university students in Canary Islands, Zaragoza and Mexico, followed up for 5 years, with anthropometric measurements, spirometry, structured questionnaire (which assessed exposure history, symptoms, family and personal history) and blood test (with biological samples stored). • CADSET (IPs. Rosa Faner, Alvar Agusti, Erik Melen, Wisia Wedzicha), European research network with access to about 250,000 participants of different ages in Europe (www.cadset.org).

• IMPaCT cohort; see information in https://cohorte-impact.es/en.

COPD cohorts

Discovery

• Early COPD. (IP. Borja Cosio, Palma de Mallorca) Cohort of smokers (25–50 years old) with or without COPD, collected by CIBER Enfermedades Respiratorias (CIBERES), with detailed phenotypic characterization. It includes nearly 300 individuals, n = 96 of them with COPD (FEV1/FVC < 0.7), that have 1 follow-up at 3 years.

• CHAIN (IP: Ciro Casanova, Tenerife): ongoing observational study of COPD patients that began enrollment in January 2010 at 24 university hospitals in Spain. About 1000 smokers with COPD and 200 smokers without COPD have been studied (lung function test; blood test in some patients). Currently 300–350 patients remain active in annual recruitment that includes follow-up and new patients.

Validation

• BODE (IP José Mª Marin, Zaragoza) International cohort started in 1998. It is ongoing and include more than 1650 well characterized COPD patients from USA; Venezuela and Spain followed up longitudinally for more than 20 years. • ECLIPSE (IPs Alvar Agusti, Rosa Faner, Barcelona). Multinational cohort of 2164 COPD patients recruited around the globe, carefully phenotyped and followed up for 3 years (8 years in a subsample of about 900 patients, with information and biological samples stored by the coordinating group). • BIOMEPOC (IP. Dr. J. Gea, Barcelona). This cohort includes 269 patients with well-established COPD (mean age 65 years) where sputum microbiome data is available as well as transcriptomic and proteomic determinations. It has been set up by several of the collaborating groups in the CIBERES COPD program.

All participants (or their legal representatives) had already signed their informed consent as per each of the existing cohorts currently available and signed new informed consent for the current project and a follow-up visit, or de novo first visit. A collection consent was also signed to preserve the data and samples for future studies. This project was approved by the ethics committee of the Hospital Clinic de Barcelona (HCB/2022/0087) and in each of the participating centers. The project was conducted in accordance with the Helsinki declaration on the Ethical Principles that should guide Medical Research Involving Human Subjects and current legal requirements (Ley 14/2007 de 3 de julio, de Investigación biomédica). A similar number of males and females were recruited and analyzed in the different age bins studied, and all analyses were stratified to consider the role of biological sex (e.g., hormones) and smoking habits (never, current, former smokers).

Data management plan

A data management plan in agreement with the FAIR data principles was used.¹⁵ Compliance with the EU personal privacy directives were also followed (http://ec.europa.eu/justice/data-protection) in relation to the previously recorded data from the different cohorts where either a data-transfer agreement and/or a federated data analysis based on DataShield was set-up.¹⁶

Data and sample acquisition

Participating centers (Appendix A): (1) recruited and followed-up the assigned number of participants in their area of influence according to the study protocols; (2) used the standard data collection formularies; (3) completed all the data formularies in the web repository promptly and accurately; (4) obtained upper airway swabs and blood samples, at baseline and at the agreed timepoints (2–3 years of follow-up); (5) participated in the analysis and dissemination of results; and (8) participated in the educational activities in their area of influence.

Data harmonization

Data harmonization was performed across cohorts, by selecting a set of variables from the P4COPD study, and mapping them with the variables collected in other cohorts. The variables were recoded, transformed, and derived from available data to target the standard definitions. Adaptation included unit conversions, recoding categorical variables, and defining new variables using pre-existing ones. Missing data was kept as such, no imputation was done. Harmonization was conducted by the central study team in exception of the INMA cohort, which performed local harmonization following shared specifications to ensure compatibility.

Spirometry data was standardized to ensure comparability between cohorts. FEV1, FVC and FEF (when available) were harmonized in liters. From these measurements we calculated FEV1/FVC ratios, percentage predicted values, LLN and z-scores using the GLI 2012 reference equations.

Given the heterogeneity in data availability, we defined a core dataset comprising available variables across cohorts (demographics, smoking, spirometry) and an extended dataset, including variables available in subsets of cohorts.

All data processing and harmonization were performed using standardized scripts in R.

Measurements

Measurements included: (1) Demographics, environmental/lifestyle and clinical variables were collected using validated questionnaires including COPD Assessment Test (CAT),¹⁷ COPD-PS,¹⁸ mMRC dyspnea scale,¹⁹ Murray's sputum color chart,²⁰ PHQ-8 for mental health evaluation,²¹ Mediterranean diet score²² and IPAQ for physical activity,²³ as well as objective measurements and geographic information systems (GIS); (2) Spirometry was recorded following international recommendations, including pre-bronchodilator and, when feasible, post-bronchodilator measurements.²⁴ Reference values were those of the Global Lung Function Initiative (GLI)²⁵; (3) Carbon monoxide lung diffusing capacity (DLCO) and computed tomography (CT) of the chest was offered to young participants with abnormal spirometry (and appropriate controls using a case-control design); (4) exhaled nitric oxide levels (FENO); (5) Genetic background (Infinium Global Screening Array-24 v3.0 K, Illumina, or similar); (6) Epigenetic profile (850k EPIC methylation array, Illumina) and telomere length; (7) Circulating lung injury biomarkers (i.e. CC16, SPD, SPA, CCL19, IL-6 among others); and (10) transcriptomics in a representative subset.

Sample size

A sample size of 1500 young participants (700 from 18 to 35 and 700 from 35 to 50 years) was estimated to be necessary to identify a population prevalence of lung function from 4 to 12%, as previously published (10). Accordingly, we aimed to recruit 1500–2000 individuals across Spain. Of them: (1) 289 individuals aged between 35 and 50 had already been recruited in the early COPD study and were followed up here; (2) n = 300 from the LEVANTE cohort aged 16–26 and n = 500 from the two included INMA cohorts; (3) De novo recruitment of individuals in the 18–50 years age range across Spain was done through primary care centers and volunteers; (4) well established COPD cohorts such as CHAIN and ECLIPSE were used to compare the results; and (5) the IMPACT cohort (https://cohorte-impact.es/) aims to establish a population base reference in Spain for 200,000 individuals. These different sample sizes allow for the investigation of the hypothesis of the study. For biomarker determination, we estimated that 150 subjects per group would allow to identify as statistically significant a difference between each age-bin group of cases and controls.²⁶ For GWAS and methylation analysis, all the young and old individuals to be compared were profiled.²⁷

Analysis plan

Descriptive statics, including n, range, proportion, mean ± standard deviation and median [inter-quartile range] values will be used to describe the population. Continuous variables compared across groups using paired (ANOVA, t-test) or un-paired test (Kruskall–Wallis, Mann–Whitney, Wilcoxon) according to the normality of their distribution (Kolgomorov–Smirnov test). Discrete variables compared using the Chi-square test. A false discovery rate (FDR) correction for multiple comparisons will be used. For the processing of genetic, transcriptomic, and epigenetic data, specific analytical methodologies are applied in R, utilizing tools provided by the Bioconductor ecosystem.²⁸ Briefly across the different respiratory phenotypes: (1) we will explore the association of polygenic risk scores (PRS) for COPD and FEV1 at the different age bins; (2) In the case of methylation, we build upon our previous experience with the EPIC methylation array to determine the whole blood methylation profiles, and determine the biological age (using different epigenetic clocks) in patients with COPD and pre-COPD. And, the methylation and decoupling of biological and chronological age is compared across age bins in relation to lung function indices. (3) Multi-level network analysis and other unbiased analytical approaches will be used to investigate relationships between genetic/epigenetic, demographics, clinical and functional data over time in relation to clinically relevant outcomes (COPD, pre-COPD, presence of symptoms).

Results

Table 2 shows the study timelines until the second visit (approximately 3 years of follow-up per patient). In March 2026 the project had already recruited 1997 individuals, and recruitment will be open until June 2026 when the first assessment finishes. First results are expected in the third and fourth quarters of 2026. Pending the availability of new funding, we plan to ask participants for further follow-up.

Table 2.

Calendar and work plan of the P4COPD study.

	1st year				2nd year				3rd year				4th year
	Q1	Q2	Q3	Q4	Q1	Q2	Q3	Q4	Q1	Q2	Q3	Q4	Q1	Q2	Q3	Q4
Data management plan	x	x
Cohort follow up, and new recruitment		x	x	x	x	x	x	x	x	x	x	x	x	x	x	x
DataShield developments					x	x	x	x	x	x	x	x	x	x	x	x
Biologic determinations					x	x	x	x	x	x	x	x
Multi-level network analysis								x	x	x	x	x	x	x	x
Coordination with IMPaCT (Pillar 1)	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x
Coordination with IMPaCT (Pillar 2)								x	x	x	x	x	x	x	x
Coordination with IMPaCT (Pillar 3)													x	x	x
Design of educational materials for patients and health care professionals		x	x	x	x	x	x	x	x	x	x	x	x
Analysis and design of strategy to align with new clinical practices in the primary health care area			x	x	x	x	x	x	x	x	x	x
Dissemination and publications	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x	x

Discussion

The main findings expected are the description of the clinical and biological characteristics of young individuals with COPD and pre-COPD across Spain, and its comparison with the disease in older age ranges. Since this study includes different pre-existing cohorts and newly-recruited participants, it has some anticipated limitations. Altough all centers follow standardized protocols, and a data harmonization process has been applied, some heterogeneity may persist due to the different projects’ structures. Missing data will not be imputed, which could reduce statistical power; however, given the large sample size, this impact is expected to be minimal. While the integration of multiple cohorts ensures robustness in analysis, the generalizability of the findings may be limited to populations with similar characteristics. However, this will be addressed through external validation in independent international cohorts such those of the CADSET consortium.

Conclusions

The P4COPD study has been set up to investigate the COPD in young adults. Results can provide important clues on novel preventive, early diagnosis and treatment strategies for this devastating disease. These measures can likely have a significant impact on the natural history of COPD by facilitating a healthier ageing of the population.¹⁴

Declaration of generative AI and AI-assisted technologies in the writing process

No AI or AI-assisted technology was used in the writing of this manuscript.

Funding

This work has been supported by “Proyecto PMP21/00090” of Instituto de Salud Carlos III and EU NextGenerationEU/Mecanismo para la Recuperación y la REsilencia (MRR)/PRTR, Fondos Feder una manera de hacer Europa. RF is a Serra Húnter professor, and ICREA-Academia 2024. With the support of the FISTEP predoctoral grants program (2025 STEP 00443) of the Departament de Recerca i Universitats de la Generalitat de Catalunya and co-financing by the European Social Fund Plus.

Authors’ contributions

The study was led by AA, RF, who contributed to the study design and drafting of the manuscript, XCG, LP literature search and drafting of the manuscript. Study design and patient recruitment: AA, XC, CC, BC, FC, AFV, JGA, LGP, JRG, AI, JLI, MMO, JMM, RN, AO, SP, GP, LP, DSR, DSG, MT, MV, VV, MV, RF. All authors revision of the Ms.

Conflicts of interest

Authors do not have a conflict of interest with the submitted work.

Outside the submitted work: Àlvar Agustí reports consulting fees from GSK, AZ, Chiesi Roche and Menarini; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GSK, AZ, Chiesi, Roche, Menarini, Zambon, Glenmark; Support for attending meetings and/or travel from Roche (ERS 2025); Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Chairman of the BoD of GOLD. Rosa Faner reports Grants or contracts from Menarini, GSK, AstraZeneca, Sanofi, Chiesi, ISC-III, Agaur, ICREA, Serra Húnter; Consulting fees from AstraZeneca; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Chiesi. Ciro Casanova has, in the last three years, received honoraria for lectures and/or scientific advisory activities and/or research project funding from AstraZeneca, GlaxoSmithKline, Sanofi/Regeneron and Menarini. Borja Cosio reports Grants or contracts from Menarini, Sanofi, AstraZeneca and Chiesi; Consulting fees from GSK, Sanofi, AstraZeneca and Chiesi; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GSK, Sanofi, AstraZeneca, Menarini and Chiesi. Alberto Fernández-Villar reports Grants or contracts from Grifols and Chiesi; Consulting fees from Chiesi, Sanofi and GSK; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GSK, Chiesi, Zambon, AstraZeneca and Regeneron. Luis González-de Paz reports Grants from Chiesi. Jose Maria Marin reports Grants or contracts from Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain; Consulting fees from Sanofi-Regeneron and GSK; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, GKK and Sanofi-Regeneron. Valle Velasco has, in the last three years, received honoraria for lectures and/or scientific advisory activities and/or research project funding from Sanofi/Regeneron, TEVA and Vertex. Xènia Carrizosa-Guerri, Fatima Crispi, Judith Garcia-Aymerich, Juan R Gonzalez, Amanda Iglesias, Jose Luis Izquierdo, Marta Marin-Oto, Rommy Novoa, Andrea Ocaña, Sergi Pascual, Gabriela Peralta, Lídia Perea, David Sarrat-Gonzalez, David Sanz-Rubio, Maties Torrent, Miguel Vazquez and Marc Vila have nothing to declare.