Early View

Original article

Trajectory and mortality of Preserved Ratio

Impaired Spirometry: the Rotterdam Study

Sara Renata Alex Wijnant, Emmely De Roos, Maryam Kavousi, Bruno Hugo Stricker, Natalie

Terzikhan, Lies Lahousse, Guy G. Brusselle

Please cite this article as: Wijnant SRA, De Roos E, Kavousi M, et al. Trajectory and mortality

of Preserved Ratio Impaired Spirometry: the Rotterdam Study. Eur Respir J 2019; in press

(https://doi.org/10.1183/13993003.01217-2019).

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is

published here in its accepted form prior to copyediting and typesetting by our production team. After

these production processes are complete and the authors have approved the resulting proofs, the article

will move to the latest issue of the ERJ online.

Copyright ©ERS 2019

Trajectory and mortality of Preserved Ratio Impaired

Spirometry: the Rotterdam Study Sara Renata Alex Wijnant1,2,3, Emmely De Roos1,2, Maryam Kavousi2, Bruno Hugo Stricker2,4, Natalie Terzikhan2, Lies Lahousse2,3*, Guy G. Brusselle1,2,5* 1Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; 2Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; 3Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium; 4Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; 5Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands *These authors supervised the work equally. 16-digit ORCID of the authors: Sara Wijnant: 0000-0003-2995-0491 Emmely de Roos: 0000-0003-1683-7211 Maryam kavousi: Bruno Stricker: 0000-0003-3713-9762 Lies Lahousse: 0000-0002-3494-4363 Guy Brusselle: 0000-0001-7021-8505

Corresponding author:

Guy Brusselle Department of Respiratory medicine, University Hospital Ghent Corneel Heymanslaan 10 9000 Ghent, Belgium guy.brusselle@ugent.be

Take home message:

Preserved Ratio Impaired Spirometry – or previously called restrictive spirometry – is a condition associated

with increased mortality and encompassing distinct clinical subsets.

Abstract

Preserved Ratio Impaired Spirometry (PRISm) is a heterogeneous condition but its course and disease

progression remain to be elucidated. We aimed to examine its prevalence, trajectories and prognosis in the

general population.

In the Rotterdam Study (population-based prospective cohort) we examined prevalence, trajectories and

prognosis of subjects with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80%), PRISm (FEV1/FVC≥0.7,

FEV1<80%), and COPD (FEV1/FVC<0.7) at two study visits. Hazard ratios (HR 95%CI) for mortality (until

30/12/2018) were adjusted for age, sex, BMI, current smoking and pack-years.

Of 5487 subjects (age 69.1±8.9; 7.1% PRISm), 1603 were re-examined after 4.5 years. Of PRISm subjects with

re-examination, 15.7% transitioned to normal spirometry and 49.4% to COPD. Lung function decline (ml/year)

was highest in subjects with incident PRISm (FEV1: -92.8[-131.9,-65.8]; FVC: -93.3[-159.8,-49.1]), but similar in

persistent PRISm (FEV1: -30.2[-67.9,-7.5]; FVC: -20.1[-47.7,+21.7]) and persistent controls (FEV1: -39.6[-64.3,-

12.7]; FVC: -20.0[-55.4,+18.8]). Of 5459 subjects with informed consent for follow-up, 692 (12.7%) died during

9.3 years (maximum) follow-up: 10.3% of controls, 18.7% of PRISm subjects and 20.8% of COPD subjects.

Relative to controls, subjects with PRISm and COPD GOLD2-4 had increased all-cause and cardiovascular

mortality (PRISm: HR 1.6[1.2, 2.0] and 2.8[1.5, 5.1]; COPD GOLD2-4: HR 1.7[1.4, 2.1] and 2.1[1.2, 3.6]).

Mortality <1 year was highest in PRISm, often having cardiovascular comorbidity (heart failure or coronary

heart disease; 70.0%).

PRISm is associated with increased mortality and this population encompasses at least three distinct subsets:

one that develops COPD during follow-up, a second with high cardiovascular burden and early mortality, and a

third with persistent PRISm and normal age-related lung function decline.

Introduction

Proportional decreases in Forced Expiratory Volume during the first second (FEV1) and Forced Vital Capacity

(FVC) result in a normal FEV1/FVC ratio despite underlying impairment of pulmonary function. These subjects

with Preserved Ratio Impaired Spirometry (PRISm) – or previously called restrictive pulmonary function [1, 2],

GOLD-unclassified [3], or the nonspecific pattern [4, 5] – do not meet the criteria for Chronic Obstructive

Pulmonary Disease (COPD), but exhibit increased respiratory symptoms [1, 2, 6], increased cardiovascular

comorbidity [7–15] and increased mortality [6, 7, 16–19]. This neglected subgroup has often been excluded in

research papers, though the existing studies to date estimate the prevalence of PRISm to range between 3.0%

and 20% in adults. [3, 5, 7, 18–23] Only few studies were conducted in the general population and they rarely

performed repeated spirometry measurements. Longitudinal studies of subjects with PRISm are scarce and

were mostly conducted in populations of current or past smokers. Some have suggested PRISm is a fluctuating

state, serving as an intermediate phase between normal spirometry and COPD for a subset of individuals. [2, 3,

5, 18, 20] Others have identified risk factors for PRISm: female sex [3, 18], smoking, advanced age, metabolic

syndrome [24, 25], a history of tuberculosis [26], systemic inflammation [4, 27–29], exposure to fine dust [30]

and exposure to biomass cooking fuels [31] have all been associated with PRISm. Still, despite receiving

increasing attention in pulmonary research, the course and disease progression of PRISm remain to be

elucidated.

The term PRISm correctly grasps the findings of an impaired spirometry (i.e. decreased FEV1 and FVC), whereas

the FEV1/FVC ratio is preserved. However, a restrictive spirometry pattern can only suggest the presence of a

possible pulmonary restriction, but this needs conformation by additional pulmonary function testing which

measures residual volume (RV) and total lung capacity (TLC). Given that body plethysmography or multi-breath

dilution techniques are time-consuming, costly, and need to be completed in a specialized setting, it is

reasonable to conduct spirometry in population-based settings. [2]

In this paper, we aimed to examine 1) the prevalence, 2) longitudinal patterns of trajectories and 3) prognosis

of PRISm in an older general population, including ever and never smokers.

Methods

Study design and study population

This study was conducted within the Rotterdam Study, a population-based cohort study that started in 1989,

comprising almost 15000 participants aged ≥45 years aiming to assess the occurrence of, and risk factors for,

chronic diseases in the elderly. [32] Every 3-4 years, participants undergo a home interview and clinical

examinations at the research center (Figure S1). The medical ethics committee of the Erasmus Medical Centre

(Rotterdam, the Netherlands), and the review board of the Netherlands Ministry of Health, Welfare and Sports

(1068889-159521-PG) approved the study. Participants gave written informed consent. The current study

contains a cross-sectional and a longitudinal part (Figure 1). First, all participants with interpretable spirometry

who visited the research center between 2009 and 2014 (phase 1 [P1]) and between 2014 and 2016 (phase 2

[P2]) were eligible for the cross-sectional analysis. Second, participants with interpretable spirometry at both

P1 and P2 were included in the longitudinal part. Characteristics of subjects with and without re-examination

are represented in Table S1. Third, subjects with interpretable spirometry at P1 and informed consent for

follow-up were included in a survival analysis.

Spirometry and diffusion capacity

Given that body plethysmography or multi-breath dilution techniques were not available in the Rotterdam

Study, we used the term PRISm to suggests the presence of a possible pulmonary restriction. Pre-

bronchodilator spirometry was performed by trained paramedical personnel using a Master Screen PFT Pro

(Care Fusion, Netherlands) according to the ATS/ERS guidelines. [33] For diffusion capacity of the lung, the

transfer factor using carbon monoxide was used corrected for hemoglobin (DLCO [mmol/min/kPA]). [34]

Predicted FEV1 and FVC values were calculated using Global Lung Initiative (GLI) reference equations taking age,

sex, height and ethnicity into account. [35] PRISm (FEV1/FVC≥70% and FEV1<80%), COPD (FEV1/FVC<70%) and

normal spirometry (controls; FEV1/FVC≥70% and an FEV1≥80%) were distinguished. Severity of obstruction was

determined according to the modified Global initiative for Chronic Obstructive Lung Disease (GOLD) criteria:

mild COPD (GOLD1, FEV1≥80%) and moderate to severe COPD (GOLD2-4, FEV1<80%).

Characteristics, comorbidities and adverse health outcomes

Smoking status (never, former, and current), cigarette pack-years (years smoked multiplied by daily number of

smoked cigarettes divided by 20), BMI (weight [kg] divided by height [m] squared), obesity (BMI ≥30 kg/m2),

diabetes mellitus (use of blood glucose-lowering medication), hypertension (use of antihypertensive

medication, systolic blood pressure of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg), heart failure

(typical symptoms/signs confirmed by radiographic evidence of cardiac dysfunction [36]) and coronary heart

disease (myocardial infarction, coronary artery bypass grafting or percutaneous coronary intervention [36])

were compared between cases and controls. Blood samples for determination of levels of serum glucose,

cholesterol and white blood cell count were obtained at the research center. Medication prescription data was

available through automated pharmacy records. Asthma was based on doctors diagnosis. [37]

Information on vital status was obtained from general practitioners and from municipal records up until

30/12/2018. Causes of death during follow-up in the Rotterdam Study were validated up until 01/01/2015 and

were coded according to the International Classification Of Diseases (ICD)-10. ICD-10 codes I00-I99 were

classified as cardiovascular mortality.

Statistical analysis

Prevalence was calculated by dividing the total number of cases by the total number of participants. For direct

standardization of age we used the 2013 Euopean Standard Population. [38] Data are expressed as

mean ± standard deviation (SD) for normally distributed variables or as median (interquartile range [IQR])

for non-normally distributed variables. Comparisons between subjects with and without PRISm were studied

using Student’s T (parametrical), Mann-Whitney U (non-parametrical) and X² tests (categorical). Age, sex, BMI,

current smoking, log-transformed pack-years, height, total cholesterol, LDL-cholesterol, HDL-cholesterol, log-

transformed triglycerides, hemoglobin, hypertension, heart failure, coronary heart disease and diabetes

mellitus were considered as potential confounders in logistic regression analyses. Mortality rates per 1000

person-years (PY) were calculated by dividing the number of deaths after spirometry by the total follow-up

time of subjects at risk. The mortality rate ratio was calculated dividing the mortality rate for subgroups by the

mortality rate of the reference category. Age- and sex-specific mortality rates were obtained by dividing the

number of deaths by the number of PY accumulated in 10-year age intervals of the study population. We

constructed cumulative survival curves using the Kaplan-Meier method. Hazard ratios (HR) from Cox

proportional-hazard models were adjusted for age, sex, BMI, current smoking and pack-years. Proportionality

was checked using Schoenfeld residuals. Spirometry results from P2 were included as a time-varying covariate

in a sensitivity analysis. We did separate sensitivity analyses excluding asthma subjects and using Global Lung

Initiative (GLI) definitions for FEV1 and FVC with Lower Limit of Normal (LLN) thresholds. Statistical analyses

were carried on using R version 3.5.1 (Foundation for Statistical Computing, Vienna, Austria).

Results

Prevalence of Preserved Ratio Impaired Spirometry (PRISm)

Among 14926 participants of the Rotterdam Study, 5487 performed interpretable spirometry tests between

2009 and 2014 (P1; Figure 1). 2857 participants were invited for examination between 2014 and 2016, of

whom 1787 performed interpretable spirometry tests (P2). The crude prevalence of PRISm at P1 (PRISm-P1)

was 7.1% (387/5487). The age-adjusted prevalence of PRISm was 7.6%. Age- and sex-specific prevalence of

PRISm and COPD is shown in Figure S2. Table 1 shows characteristics of subjects with PRISm, COPD and normal

spirometry at both P1 and P2. A subset of 4759 individuals performed diffusion capacity testing at P1. Adjusted

for age, sex, height, log-transformed pack-years, hemoglobin, log-transformed triglycerides, diabetes mellitus

and heart failure, DLCO was lower in subjects with PRISm-P1 and COPD-P1 (PRISm: β -0.4 [-0.6,-0.3], p<0.001;

COPD: β -0.5 [-0.6, -0.4], p<0.001), whereas DLCO/VA was higher in subjects with PRISm but lower in subjects

with COPD (PRISm: β 0.2 [0.1,0.2], p<0.001; COPD: β -0.1 [-0.1, -0.1], p<0.001).

Trajectories of lung function impairment

1603 participants had interpretable spirometry at both phases (P1 and P2; Figure 1). Age- and sex-specific

cumulative incidence of PRISm and COPD is shown in Figure S2. Subjects with PRISm-P1 showed lower average

rates of lung function decline relative to controls and COPD subjects (p<0.001; Table S2). However, subjects

with PRISm-P2 showed higher average rates of lung function decline (p<0.001; Table 2). Within PRISm-P1

subjects, 10.4% improved their lung function (i.e., transitioned to normal spirometry), while 32.6% transitioned

towards COPD (Figure 2). PRISm subjects transitioned more often towards a different lung function category

(43.0%) compared to subjects with normal (23.0%) or obstructive lung function (8.9%). Current smoking

accelerated the FEV1 and FVC decline in subjects with PRISm and COPD (Table 2; Table S2).

Characteristics of subjects with PRISm by different trajectories

Subjects with persistent PRISm (i.e. PRISm-P1 and PRISm-P2) had the highest mean BMI at baseline (30.2±4.1

kg/m2, p<0.001; Table S3). Baseline FVC– but not FEV1 – % predicted was lower in persistent PRISm compared

to subjects who evolved from PRISm-P1 towards COPD at P2 (p=001; Table S3). PRISm-P1 subjects with normal

spirometry at P2 were more often female (p=0.041), had a smaller waist circumference at P1 (p=0.031) and had

smoked less pack-years (p=0.098) than other subjects with PRISm-P1 (Table S3). In a subgroup analysis of 1390

individuals with diffusion capacity testing performed at P1, DLCO and DLCO/VA values did not differ

significantly between subjects with persistent PRISm versus incident COPD (i.e. PRISm-P1 and COPD-P2) or

incident normal spirometry (i.e. PRISm-P1 and normal spirometry at P2; Table S4), even after adjustment for

potential confounders.

Persistent PRISm versus persistent controls and persistent COPD

Both FEV1 and FVC decline rates were similar in subjects with persistent PRISm (FEV1: -31.0 [-69.6,-7.7]

ml/year; FVC: -20.6 [-48.9,+22.2] ml/year) and subjects with persistent normal spirometry (FEV1: -40.6 [-65.9,-

13.0] ml/year; FVC: -20.5 [-56.8,+19.3] ml/year; Table S4). FVC– but not FEV1– decline rates were lower in

subjects with persistent COPD (FEV1: -36.2 [-64.0,-4.1] ml/year; FVC: +7.1 [-39.8,+56.3] ml/year) than in

subjects with persistent PRISm (p<0.001). Persistent PRISm subjects had more features of the metabolic

syndrome (higher BMI, waist circumference, glucose: p<0.05) and more cardiovascular comorbidity (incident

heart failure, p<0.05) compared to subjects with persistent normal spirometry or persistent COPD (Table S3).

DLCO did not differ significantly between these subgroups. DLCO/VA was significantly higher in subjects with

persistent PRISm compared to subjects with persistent normal spirometry (p<0.001) or persistent COPD

(p<0.001; Table S4).

Incident PRISm versus incident COPD

Subjects who developed incident PRISm (i.e. normal spirometry or COPD at P1 and PRISm at P2) were older

(p=0.001), had higher BMI (p=0.010), higher waist circumference (p=0.005), worse pulmonary function

(p<0.001), higher DLCO/AV values (p<0.001), more often gained weight (Δ BMI>1.5 kg/m2; p=0.007), and more

often developed incident heart failure (p<0.001) compared to other subjects (Table 3). Overall, higher DLCO/VA

values were seen in both prevalent and incident PRISm subjects compared to other lung function groups (Table

S4). Increase in BMI by 1.5 kg/m2 and incident heart failure were independently associated with incident PRISm

after adjustment for age, sex, baseline BMI, current smoking and pack-years (Δ BMI: OR 3.0 [1.5,5.7], p<0.001;

incident heart failure: OR 8.0 [2.2,25.4], p<0.001). Subjects with incident PRISm also had highest FEV1 and FVC

decline (FEV1: -95.2 [-135.2,-67.5] ml/year; FVC: -95.7 [-163.9,-50.4] ml/year), even relative to incident COPD

(FEV1: -58.5 [-91.3,-28.6] ml/year; FVC: -11.5 [-47.7,+35.4] ml/year; p<0.001). Subjects with incident COPD were

older at baseline (p<0.001), were more often male (p<0.001), were more often current smokers (p<0.001) and

more often developped incident coronary heart disease (p=0.034) compared to other subjects (Table S3).

Compared to subjects with persistent normal spirometry, mortality rate ratio was highest in subjects with

incident PRISm (3.8), followed by persistent PRISm (3.2), persistent COPD (1.8) and incident COPD (1.4; Table

S5).

Incident PRISm subjects with normal spirometry at P1 (90% of incident PRISm; 47/52; Figure 2) differed from

incident COPD subjects with normal spirometry at P1 by their lower FEV1 % predicted and markedly lower FVC

% predicted at P1 (p<0.001; Table S3). They had higher BMI (incident PRISm: 29.0±4.8 kg/m2; incident COPD:

27.2±3.7 kg/m2; p=0.003), a larger waist circumference (incident PRISm: 97.2±14.5 cm; incident COPD:

92.9±11.7 cm; p=0.025), more often gained weight between P1 and P2 (Δ BMI>1.5 kg/m2; incident PRISm:

25.5%; incident COPD: 10.7%; p=0.010), had lower HDL-cholesterol (incident PRISm: 1.4±0.3; incident COPD:

1.5±0.4 mmol/l; p=0.046), and more often developed comorbid heart failure between P1 and P2 (incident

PRISm: 10.9%; incident COPD: 0.7%; p<0.001; Table S4).

Prognosis of Preserved Ratio Impaired Spirometry (PRISm)

Within 9.8 years (maximum) of follow-up starting from P1, 692 out of 5459 subjects (12.7%) with informed

consent for follow-up (Figure 1) died: 430 subjects with normal spirometry (10.3%), 72 subjects with PRISm

(18.7%) and 190 subjects with COPD (20.8%). Subjects with PRISm had unadjusted mortality rates similar to

COPD (Figure 3A), and intermediate between COPD GOLD1 and GOLD2-4 (Figure 3B). Mortality within one year

after examination was highest in subjects with PRISm (n=10). They had more often cardiovascular comorbidity

(heart failure and/or coronary heart disease; 70.0%) compared to subjects with PRISm who died later (≥ 1 year;

27.4%). Of subjects that died within one year after examination, cardiovascular comorbidity was lower in

subjects with normal spirometry (20.0%) or COPD (44.4%) than in subjects with PRISm. Age- and sex-specific

mortality is shown in figure S2.

Relative to controls, PRISm and COPD GOLD2-4 were significant predictors of all-cause mortality in adjusted

Cox proportional-hazard survival analyses (Table 4). Additional adjustment for cardiovascular comorbidity did

not affect these associations (Table S5). Disease-specific mortality was known in 285 out of 692 deaths (Table

S6; cardiovascular mortality: 40.6% in PRISm, 30.8% in COPD, 25.3% in controls). PRISm and COPD GOLD2-4

were significant predictors of cardiovascular mortality (Table 4). Within subjects with PRISm, stratification by

FVC severity – but not by FEV1 severity – distinguished a subset with and without increased cardiovascular

mortality (Table 4).

Sensitivity analysis

When using LLN thresholds for both FEV1 and FEV1/FVC, the prevalence of PRISm-P1 was lower (5.1% instead

of 7.1%). 19.6% instead of 10.4% of PRISm-P1 subjects transitioned towards normal spirometry, while 20.6%

instead of 32.6% transitioned towards COPD (Figure S3). Relative to controls, PRISm (HR 1.9 [1.5, 2.5] instead of

HR 1.6 [1.2, 2.0) and COPD GOLD2-4 (HR 1.9 [1.5, 2.5] instead of HR 1.7 [1.4, 2.1) were significant predictors of

all-cause mortality in adjusted survival analyses using LLN definitions (Table S5). When excluding asthma

subjects (n=486), the prevalence, progression and prognosis of subjects with PRISm remained unchanged

(Table S5). When including spirometry results from P2 as a time-dependent covariate in the Cox proportional-

hazard survival analysis, all-cause and cardiovascular mortality in subjects with PRISm remained unchanged

(Table 4).

Discussion

Preserved Ratio Impaired Spirometry (PRISm) was prevalent in 7.1% of older participants of the Rotterdam

Study and showed higher all-cause and cardiovascular mortality, as well as frequent transition towards COPD.

Repeated spirometry measurements were available for this study. Previous longitudinal studies

on PRISm included mainly cohorts that had single spirometry measurements at baseline with outcomes of

mortality [6, 7, 16–19] or incident comorbid disease. [8–14, 21, 22] Longitudinal cohort studies with repeated

spirometry measurements investigating trajectories are scarce and were mostly conducted in smoking

populations. [1–3, 5, 18] This study provides added value in elucidating the course and disease progression of

PRISm in a population-based prospective cohort study encompassing not only (former and current) smokers

but also never smokers.

In this study, a third of subjects with PRISm at baseline transitioned towards COPD at follow-up, while half of

subjects with PRISm at follow-up had normal spirometry at baseline. A transition from PRISm to COPD has been

observed in 15-38% of subjects from the COPDgene study, the Lovelace Smoker’s Cohort, the Mayo clinic and

the TESOAD study. [2, 3, 5, 18] Most studies in the United States and Europe have shown prevalences of PRISm

ranging between 3% and 20%. [3, 5, 7, 18–21, 23] Merely poorly executed spirometry as an explanation for a

spirometry suggestive for a restrictive syndrome cannot account for such high prevalences. These findings

support the hypothesis that PRISm represents a distinct entity by itself, and is a transitional stage between

normal spirometry and COPD in a subset of individuals.

Results from our study were similar to those of the COPDgene study; subjects with incident PRISm showed

largest declines in FVC, while subjects who transitioned from PRISm to COPD showed a smaller decline in FVC

but a more severe decline in FEV1. [18] We observed more often a direct transition from normal spirometry to

COPD than to PRISm. It is possible that both situations represent distinct disease courses, whereby FVC decline

in PRISm depends on other factors than in COPD. Literature on the association between smoking and PRISm is

inconclusive; some studies showed a link with PRISm [3, 8, 19, 20], while others did not [2, 5, 16]. We found

that smoking affected FEV1 and FVC decline in subjects with PRISm and COPD. Lung function trajectories were

only determined in subjects who survived until phase 2, therefore the actual decline rates are likely

underestimated. Other than age and smoking, possible risk factors and markers of FVC decline in subjects with

PRISm are presence of respiratory symptoms [1], a positive bronchodilator response [5], impaired slow vital

capacity [5], physical inactivity [27], metabolic syndrome [27] and systemic inflammation [4, 27, 28]. Additional

longitudinal studies with frequent repeated spirometry testing and long-term follow-up are desirable to

capture all phases of pulmonary function decline.

Studies have consistently shown increased mortality in subjects with PRISm. [6, 7, 16–19] Our study confirms

previous findings and shows mortality risks in PRISm similar to those in COPD GOLD2-4. We add to existing

knowledge by investigating mortality in subjects with PRISm in the general population, encompassing smokers

and non-smokers, and by examining cardiovascular mortality, which was higher in PRISm (HR 2.7) than in COPD

(HR 1.9). Previous studies have found similar effect estimates but differed in their definition for PRISm. [2, 19]

Moreover, impairment of FVC in subjects with PRISm appeared to better distinguish a subset with higher

cardiovascular mortality than impairment in FEV1. Interestingly, subjects with PRISm who died within one year

after the spirometric examination had often comorbid heart failure and/or coronary heart disease. Pulmonary

congestion and cardiomegaly are mechanisms by which heart failure could result in pulmonary restriction. [39,

40] Moreover, reduced lung volumes and atelectasis are common after open-heart surgery for coronary heart

disease. [41]

The high prevalence of heart failure and obesity in subjects with PRISm in this study – and in previous studies

[7, 14, 16, 25, 42–44] – likely contribute to the low DLCO values and supranormal DLCO/VA values we

observed. Through pulmonary congestion, heart failure can restrict lung volumes, resulting in a reduced DLCO.

Pulmonary congestion usually increases capillary blood volume, possibly contributing to the higher DLCO/VA

values. [40, 45] We showed that subjects with incident PRISm had a concomitant increase in BMI, independent

of incident heart failure. Abdominal obesity may compromise lung function through mechanical effects of

truncal obesity and/or metabolic effects of adipose tissue. [44] Type 2 diabetes showed clear association with

PRISm as well, but longitudinal studies were inconsistent regarding the direction of this association, and

pathophysiological mechanisms remain unclear. [46]

It is possible that part of subjects with PRISm represent an elderly population with normal age-related decline

in FEV1 and FVC given the lower prevalence and higher effect estimates of mortality using Global Lung function

Initiative (GLI) definitions (Figure S3; Table S4). Compared to GOLD definitions, GLI definitions reduce false-

positive estimates of respiratory diseases in elderly subjects [47]. Small sample sizes in some subgroup analyses

justified our choice for using GOLD definitions.

FEV1 and FVC decline rates were lower in subjects with PRISm-P1 compared to others at P1, similar to previous

findings [18, 22]. One would rather expect an excess in lung function decline to accompany the higher mortality

seen in PRISm. The measurement of lung function decline based on P1 and P2 has limitations. PRISm

individuals with a fast lung function decline are more likely to die prior to re-examination. This in contrast to

PRISm individuals with a slower decline rate who are more likely to participate at P2 of the study, resulting in a

healthy survivor bias. This Informative censoring bias of the most severe cases results in an underestimation of

decline rates in subjects with prevalent PRISm (at P1). Subjects with incident PRISm between P1 and P2 or

subjects with PRISm at P2 showed larger decline rates. Moreover, as loss of lung function is generally more

accelerated in early stages of COPD, subjects with PRISm – characterized by even lower FEV1 and FVC than

COPD GOLD1– remain with less potential to lose as well. [48] Finally, heterogeneity within subjects with PRISm

is large and part of this group had even improved FEV1 and FVC. Some of the changes between P1 and P2 in this

group may be the consequence of regression to the mean. Excessive lung function decline was seen in

disadvantageous transitions (i.e. incident PRISm and incident COPD). Remarkably, subjects with incident PRISm,

showing the most severe decline rates, had the highest mortality rate, followed by subjects with persistent

PRISm despite their normal rates of lung function decline. Part of persistent PRISm may represent individuals

who did not attain maximal lung function in early adulthood and experience typical age-related pulmonary

decline. Lower total lung capacities on computed tomography images in PRISm [18, 21], and increased

cardiopulmonary mortality in individuals with lower FEV1 and FVC values at young adulthood [49] confirm these

findings. Absent emphysema [18, 21] and preserved DLCO/VA in the current study supports the hypothesis of

at least some subjects with PRISm having smaller lung volumes but intact lung parenchyma.

Strengths of our study are its population-based setting, the long-term longitudinal follow-up, the large sample

size and the availability of heart failure and diffusion capacity data. Limitations are the use of pre-

bronchodilator spirometry. Actual restriction of pulmonary volumes – defined as a significant decrease in total

lung capacity – is ideally diagnosed by additional pulmonary function tests encompassing body

plethysmography or multi-breath dilution techniques using Nitrogen or Helium. [50] Further, through drop out

and death of severely ill participants between the study visits, the longitudinal part of this study is susceptible

for a healthy survivor bias. Finally, despite the large sample size of the overall population, some subgroup

analyses included very small numbers (e.g. cause-specific mortality [such as cardiovascular deaths in PRISm:

n=15], and mortality rates in PRISm longitudinal subgroups [such as persistent PRISm: n=31]).

To conclude, we provide evidence that PRISm is associated with impaired outcomes in terms of increased all-

cause and cardiovascular mortality. Moreover, we demonstrated that PRISm consists of a heterogeneous

population encompassing at least three subsets: a first subset who develops COPD during follow-up, a second

subset with high cardiovascular burden and early mortality, and a third subset with persistent PRISm though

normal lung function decline rates. These results emphasize the importance of recognizing PRISm in clinical

settings.

Acknowledgements

The authors thank the study participants, the staff from the Rotterdam Study and the participating general

practitioners.

Financial support statement

This research was funded by the ‘Funds for Scientific Research Flanders (Fonds voor Wetenschappelijk

Onderzoek Vlaanderen)’, grant number 3G037618. The Rotterdam Study is supported by the Erasmus MC and

Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (NWO); the

Netherlands Organisation for Health Research and Development (ZonMW); the Research Institute for Diseases

in the Elderly (RIDE); the Netherlands Genomics Initiative; the Ministry of Education, Culture and Science; the

Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of

Rotterdam. The funding sources had no involvement in the collection, analysis, writing, interpretation, or in the

decision to submit the paper for publication.

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Table 1. Cross-sectional analysis of characteristics at phase 1 and phase 2.

Phase 1 (n=5487) Phase 2 (n=1787)

Normal spirometry-P1 (n=4185)

PRISm-P1 (n=387) COPD-P1 (n=915) Normal spirometry-P2 (n=1089)

PRISm-P2 (n=94) COPD-P2 (n=604)

Age (years) 68.8 (8.7) 69.8 (9.6)* 70.6 (9.1)* 78.1 (4.8) 79.8 (6.2)* 79.2 (5.4)* Female sex 2438 (58.3) 224 (57.9) 407 (44.5)* 666 (61.2) 51 (54.3) 280 (46.4)* Obesity (%) 1007 (21.4) 156 (40.4)* 150 (16.4)* 266 (26.2) 33 (38.4)* 126 (21.8) BMI (kg/m2) 27.6 (4.3) 29.4 (5.1)* 26.5 (4.1)* 27.5 (4.2) 29.1 (4.6)* 26.9 (3.9)* Height (cm) 168.7 (9.4) 168.4 (9.8) 170.9 (9.8)* 165.9 (9.2) 166.3 (8.8) 168.8 (9.5)* Caucasian (%) 4080 (97.5) 378 (97.7) 904 (98.8)* 1010 (98.4) 85 (94.4)* 563 (98.8) Never smoker 1555 (37.2) 119 (30.7)* 175 (19.1)* 417 (38.4) 25 (26.6) 130 (21.5)* Former smoker 2247 (53.7) 214 (55.3)* 504 (55.1)* 627 (57.7) 64 (68.1) 408 (67.5)* Current smoker 383 (9.2) 54 (14.0)* 236 (25.8)* 43 (4.0) 5 (5.3) 66 (10.9)* Pack-years (years) 3.0 (0.0, 18.7) 8.5 (0.0, 27.3)* 21.0 (3.0, 41.1)* 1.3 (0.0, 15.6) 6.0 (0.0, 25.0)* 12.0 (0.1, 33.6)* Asthma (%) 334 (8.0) 45 (11.6)* 107 (11.7)* 65 (6.0) 16 (17.0)* 90 (14.9)* Total cholesterol (mmol/l) 5.5 (1.1) 5.3 (1.2)* 5.3 (1.1)* NP NP NP HDL-cholesterol (mmol/l) 1.5 (0.4) 1.4 (0.4)* 1.5 (0.5) NP NP NP Triglicerides (mmol/l) 1.3 (1.0, 1.7) 1.4 (1.1, 1.9)* 1.2 (1.0, 1.7) NP NP NP Glucose (mmol/l) 5.5 (5.1, 6.0) 5.7 (5.2, 6.4)* 5.0 (5.1, 6.0) NP NP NP White blood cell count 6.9 (1.9) 7.5 (2.0)* 7.6 (2.4)* 6.6 (1.9) 7.3 (2.7)* 6.8 (1.6) Hemoglobin 8.8 (0.7) 8.7 (0.8)* 8.9 (0.8)* 8.7 (0.8) 8.7 (0.9) 8.8 (0.8)* Diabetes mellitus 338 (8.2) 44 (11.7)* 90 (10.0) NP NP NP Hypertension 2992 (71.5) 315 (81.4)* 686 (75.0)* 876 (80.4) 80 (85.1) 485 (80.4) Heart failure 93 (2.2) 29 (7.5)* 57 (6.2)* 34 (3.5) 12 (14.5)* 32 (5.8)* Coronary heart disease 332 (8.0) 49 (12.7)* 117 (12.8)* 132 (12.2) 13 (13.8) 87 (14.4) FEV1 % predicted (%) 104.0 (13.3) 71.7 (7.3)* 76.9 (18.4)* 105.7 (14.1) 71.6 (7.4)* 84.3 (18.2)* FVC % predicted (%) 101.7 (12.9) 71.8 (8.7)* 92.3 (17.6)* 104.8 (14.5) 72.3 (8.6)* 100.3 (17.4)* FEV1/FVC (%) 78.8 (4.7) 76.9 (5.1)* 63.2 (6.7)* 76.6 (4.6) 75.0 (4.1)* 63.0 (7.1)* DLCO (mmol/min/kPA) 7.9 (2.0) 7.5 (1.6)* 7.4 (2.0)* NP NP NP DLCO % predicted (%) 97.0 (14.0) 91.5 (17.6)* 88.6 (18.4)* NP NP NP DLCO/VA (mmol/min/kPA/ml) 1.5 (0.2) 1.7 (0.2)* 1.4 (0.3)* NP NP NP DLCO/VA % predicted (%) 110.0 (16.3) 121.5 (20.5)* 100.7 (20.2)* NP NP NP

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; BMI = body mass index; HDL = high-density cholesterol; FEV1 = Forced

Expiratory Volume in one second; FVC = Forced Vital Capacity; DLCO = Diffusion capacity of the Lungs for Carbon monoxide; DLCO/VA = Diffusion capacity of the Lungs for

Carbon monoxide divided by the Alveolar Volume; NP = not performed. *P<0.05 compared to subjects with normal spirometry. Results are presented as mean (SD), count

(percentage) or median (interquartile range).

Table 2. Lung function values at phase 1 and phase 2 stratified by lung function category and smoking status at phase 2.

Normal spirometry-P2

(n=970)

PRISm-P2 (n=83) COPD GOLD1-4-P2

(n=550)

COPD GOLD1-P2

(n=355)

COPD GOLD2-4-P2

(n=195)

Years between P1 and P2 4.6 (0.5) 4.7 (0.43)* 4.6 (0.4) 4.6 (0.4) 4.6 (0.4)

FEV1% predicted at P1 (%) 106.2 (14.7) 82.8 (12.8)* 88.8 (18.2)* 97.9 (12.6)* 72.1 (14.8)*

FEV1% predicted at P2 (%) 106.0 (14.2) 71.5 (7.6)* 84.6 (18.3)* 95.4 (10.7)* 64.9 (11.4)*

Δ FEV1

(ml/year)

All (n=1603) -39.1 [-65.2, -10.8] -76.7 [-109.9, -35.0]* -49.2 [-82.8, -19.1]* -45.9 [-78.6, -16.9]* -58.6 [-90.2, -23.6]*

Never smoker at P2 (n=502) -42.8 [-72.5, -13.7] -73.6 [-113.5, -41.61]* -45.6 [-76.9, -22.9] -45.9 [-80.0, -23.4] -43.1 [-75.6, -15.5]

Former smoker at P2 (n=1000) -37.5 [-61.0, -8.6] -78.7 [-107.1, -28.01]* -48.0 [-82.8, -15.4]* -44.0 [-78.0, -11.2]* -60.1 [-91.9, -21.9]*

Current smoker at P2 (n=99) -24.6 [-54.9, -4.9] -138.4 [-184.0, -96.1]* -63.0 [-103.1, -40.1]* -60.1 [-78.6, -40.2]* -88.4 [-132.7, -36.0]*

FVC% predicted at P1 (%) 102.4 (13.8) 80.1 (11.8)* 95.7 (15.5)* 102.9 (12.1) 82.6 (12.1)*

FVC% predicted at P2 (%) 105.3 (14.3) 72.1 (8.9)* 100.7 (17.2)* 109.7 (12.3)* 84.4 (12.0)*

Δ FVC

(ml/year)

All (n=1603) -19.8 [-56.8, 20.5] -66.7 [-119.4, -21.5]* -3.2 [-44.7, 43.1]* 9.0 [-33.5, 51.7]* -27.5 [-64.2, 29.6]

Never smoker at P2 (n=502) -27.8 [-65.5, 9.1] -64.9 [-124.8, -26.9]* -11.2 [-39.5, 28.5]* -2.0 [-35.1, 31.6]* -20.5 [-47.0, 22.4]

Former smoker at P2 (n=100) -17.7 [-53.6, 22.8] -65.7 [-102.9, -20.6]* 0.0 [-46.3, 56.9]* 11.9 [-29.7, 63.2]* -27.2 [-66.5, 43.2]

Current smoker at P2 (n=99) 2.4 [-48.3, 34.0] -175.2 [-212.4, -125.3]* -24.0 [-48.1, 17.4] 0.0 [-44.1, 26.0] -43.4 [-68.9, 5.5]*

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; GOLD = Global initiative for Chronic Obstructive Lung Disease; P1 = phase 1;

P2 = phase 2; FEV1 = Forced Expiratory Volume in one second; FVC = Forced Vital Capacity; Δ = delta. *P<0.05 compared to subjects with normal spirometry. Results are

presented as mean (SD) or median (interquartile range).

Table 3. Baseline characteristics at phase 1 of subjects with incident PRISm compared to characteristics of other

subjects (prevalent PRISm and COPD excluded).

Other subjects-P1

(prevalent PRISm and COPD

excluded) (n=1229)

Incident PRISm-P2

(n=52)

Years between P1 and P2 5.5 (1.1) 6.1 (1.4)*

Age (years) 73.6 (4.8) 75.9 (5.9)*

Female sex 702 (57.1) 29 (55.8)

BMI (kg/m2) P1 27.5 (4.1) 29.0 (4.7)*

BMI (kg/m2) P2 27.4 (4.1) 29.1 (5.0)

Δ BMI (kg/m2) -0.14 (1.54) 0.05 (2.49)

Δ BMI > 1.5 kg/m2 (%) 141 (11.5) 13 (25.0)*

Waist circumference (cm) P1 92.9 (11.7) 97.6 (14.7)*

Waist circumference (cm) P2 94.7 (12.2) 101.2 (15.2)*

Δ waist circumference (cm) 1.8 (6.6) 3.5 (7.2)

Δ waist circumference > 5 cm (%) 309 (25.1) 21 (40.4)*

Never smoker 453 (36.9) 16 (30.8)

Former smoker 695 (56.6) 32 (61.5)

Current smoker 81 (6.6) 4 (7.7)

Pack-years 3.2 (0.0, 18.8) 3.0 (0.0, 21.8)

Total cholesterol (mmol/l) 5.5 (1.1) 5.4 (1.2)

HDL-cholesterol (mmol/l) 1.5 (0.4) 1.4 (0.3)*

Triglicerides (mmol/l) 1.3 (1.0, 1.7) 1.3 (1.1, 1.6)

Glucose (mmol/l) 5.5 (5.1, 6.1) 5.7 (5.2, 6.5)*

White blood cell count 6.8 (1.6) 7.0 (2.0)

Diabetes mellitus 91 (7.5) 6 (11.5)

Hypertension 1025 (83.4) 45 (86.5)

Prevalent heart failure 33 (2.7) 1 (1.9)

Incident heart failure 10 (0.8) 5 (9.8)*

Prevalent coronary heart disease 118 (9.6) 5 (9.6)

Incident coronary heart disease 25 (2.3) 1 (2.1)

FEV1% predicted (%) 105.3 (13.7) 89.3 (11.1)*

Δ FEV1 (ml/year) -44.7 (-74.9,-16.8) -95.2 (-135.2,-67.5)*

FVC% predicted (%) 102.5 (13.0) 86.7 (8.5)*

Δ FVC (ml/year) -18.2 (-54.7,+22.6) -95.7 (-163.0,-50.4)*

FEV1/FVC (%) 78.6 (4.7) 78.2 (5.4)

Δ FEV1/FVC (%) -1.0 (1.1) -0.7 (1.3)

DLCO (mmol/min/kPA) 7.5 (1.5) 7.3 (1.3)

DLCO % predicted (%) 97.3 (14.0) 96.6 (17.3)

DLCO/VA (mmol/min/kPA/ml) 1.5 (0.2) 1.6 (0.2)*

DLCO/VA % predicted (%) 111.5 (16.4) 121.5 (17.1)*

PRISm = Preserved Ratio Impaired Spirometry; P1 = phase 1; P2 = phase 2; BMI = body mass index; FEV1 =

Forced Expiratory Volume in one second; FVC = Forced Vital Capacity; Δ = delta; DLCO/VA = Diffusion capacity

of the Lungs for Carbon monoxide divided by the Alveolar Volume. *P<0.05 compared to subjects without

incident PRISm. Results are presented as mean (SD), count (percentage) and median (interquartile range).

Table 4. Estimates of mortality stratified by lung function category at phase 1.

Number at risk

HR [95%CI]1 HR [95%CI]1,* HR [95%CI]2 HR [95%CI]2,*

Normal spirometry-P1 4150 Reference Reference Reference Reference PRISm-P1 384 1.6 (1.2-2.0)* 1.6 (1.2, 2.0)* 2.7 (1.5, 5.0)* 2.6 (1.4, 4.7)*

PRISm by FEV1 severity

FEV1≥74% 194 1.3 (0.9, 1.8) 1.4 (1.0, 1.9) 2.6 (1.1, 5.7)* 2.5 (1.1, 5.5)* FEV1<74% 190 1.9 (1.4, 2.6)* 1.7 (1.3, 2.3)* 2.8 (1.3, 6.0)* 2.6 (1.2, 5.7)*

PRISm by FVC severity

FVC≥73% 191 1.4 (1.0, 2.1) 1.4 (0.9, 2.0) 1.8 (0.7, 5.1) 1.7 (0.6, 4.8) FVC<73% 193 1.7 (1.2, 2.3)* 1.7 (1.3, 2.3)* 3.2 (1.6, 6.4)* 3.1 (1.6, 6.1)*

COPD GOLD1-P1 419 1.0 (0.7, 1.3) 0.7 (0.5, 0.9)* 0.5 (0.2, 1.6) 0.5 (0.1, 1.5) COPD GOLD2-4-P1 493 1.7 (1.4, 2.1)* 1.5 (1.2, 1.8)* 1.9 (1.1, 3.4)* 1.8 (1.0, 3.1)*

HR = Hazard Ratio; PRISm = Preserved Ratio Impaired Spirometry; FEV1 = Forced Expiratory volume in one second; FVC = Forced Vital Capacity; COPD = Chronic Obstructive Pulmonary Disease; GOLD = Global initiative for Chronic Obstructive Lung Disease; 1 = HR for all-cause mortality adjusted for age, sex, BMI, current smoking and pack-years; 2 = HR for cardiovascular mortality adjusted for age, sex, BMI, current smoking and pack-years; * = time-dependent Cox proportional-hazard model with lung function category at phase 2 as time varying covariate. Subjects with missing information for one of the covariates were excluded (n=13, of whom 6 died). *P<0.05 compared to subjects without incident PRISm.

Figure 1. Flowchart of participants

P1 = phase 1; P2 = phase 2. Participants with interpretable spirometry who visited the research center between 2009 and 2014 (phase 1 [P1]) and between 2014 and 2016 (phase 2 [P2]) were eligible for the cross-sectional analysis (part 1). Participants with interpretable spirometry at both P1 and P2 were included in the longitudinal part (part 2). Subjects with interpretable spirometry at P1 and informed consent for follow-up were included in a survival analysis (part 3).

Figure 2. Transitions of lung function categories between phase 1 and phase 2.

NL = normal spirometry; PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary

Disease.

Figure 3. Kaplan Meier curve of mortality for different lung function groups. (colour)

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; GOLD = Global

initiative for Chronic Obstructive Lung Disease.

Figure 3. Kaplan Meier curve of mortality for different lung function groups (black and white)

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; GOLD = Global

initiative for Chronic Obstructive Lung Disease.

Trajectory and mortality of Preserved Ratio Impaired

Spirometry: the Rotterdam Study S. R. A. Wijnant1,2,3, E. De Roos1,2, M. Kabousi2, B. H. Stricker2,4, N. Terzikhan2, L. Lahousse2,3*, G. G. Brusselle1,2,5* 1Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; 2Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; 3Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium; 4Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; 5Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands *These authors supervised the work equally.

Corresponding author:

Guy Brusselle Department of Respiratory medicine, University Hospital Ghent Corneel Heymanslaan 10 9000 Ghent, Belgium guy.brusselle@ugent.be

Supplementary files

Tables

1. Representativeness of the study subjects with follow-up data.

2. Lung function values at phase 1 and phase 2 stratified by lung function category and smoking

status at phase 2.

3. Characteristics at phase 1 by lung function category at phase 1 and phase 2.

4. Lung function values at phase 1 and phase 2 up stratified by lung function category at phase

1 and phase 2.

5. ICD10 classification of cause-specific mortality.

6. Estimates of mortality stratified by lung function categories.

Figures

1. Flowchart of the Rotterdam Study.

2. Age- and sex-specific prevalence, incidence and mortality of PRISm and COPD.

3. Transitions between lung function categories according to LLN definitions for FEV1 and the

FEV1/FVC ratio.

Table S1. Representativeness of the study subjects with follow-up data.

A. Characteristics of subjects from cohort 1 and 2 with and without follow-up spirometry at phase 2.

Characteristics at phase 1 of the subgroup with follow-up at phase 2 (n=1603) Characteristics at phase 1 of the subgroup without follow-up at phase 2 (n=1254)

Normal-P1 (n=1276) PRISm-P1 (n=89) COPD-P1 (n=238) Normal-P1 (n=856) PRISm-P1 (n=121) COPD-P1 (n=277) Age (years) 73.7 (4.9) 74.7 (5.7) 74.3 (5.0) 77.8 (6.1)* 78.2 (6.3)* 78.4 (6.1)* Female sex 729 (57.1) 51 (57.3) 106 (44.5) 523 (61.1) 64 (52.9) 126 (45.5) BMI (kg/m2) 27.6 (4.1) 29.1 (3.8) 26.6 (3.9) 27.7 (4.1) 28.7 (5.0) 26.3 (3.8) Current smoker 85 (6.7) 6 (6.7) 29 (12.2) 55 ( 6.4) 20 (16.5) 77 (27.8)* Pack-years (years) 3.2 (0.0, 18.8) 10.8 (0.0, 29.0) 19.8 (1.7, 40.4) 2.3 [0.0, 21.0] 11.3 [0.0, 30.0] 22.8 [5.2, 42.0] White blood cell count 6.8 (1.7) 7.5 (1.8) 7.2 (1.7) 7.0 (1.8) 7.4 (1.9) 7.9 (3.2) Diabetes mellitus 97 (7.7) 6 (6.8) 21 (9.1) 79 ( 9.7) 10 ( 8.9) 28 (10.3) Hypertension 1065 (83.5) 80 (89.9) 202 (84.9) 757 (88.5)* 115 (95.0) 240 (86.6) Heart failure 34 (2.7) 4 (4.5) 11 (4.6) 47 ( 5.5)* 22 (18.3)* 34 (12.3)* Coronary heart disease 123 (9.7) 12 (13.5) 33 (13.9) 103 (12.1) 21 (17.5) 47 (17.0) FEV1% predicted (%) 104.8 (13.8) 72.6 (6.4) 77.9 (17.8) 104.3 (14.0) 70.4 (8.6)* 72.4 (18.1)* FVC% predicted (%) 101.9 (13.2) 72.7 (7.6) 92.6 (16.7) 100.7 (13.9)* 69.7 (9.9)* 87.0 (17.6)* FEV1/FVC (%) 78.6 (4.7) 76.3 (5.1) 63.5 (6.7) 78.8 (4.9) 76.8 (5.0) 62.4 (7.1) DLCO (mmol/min/kPA) 7.5 (1.5) 7.2 (1.4) 7.2 (1.7) 7.1 (1.4)* 7.1 (1.6) 6.5 (1.5)* DLCO/VA (mmol/min/kPA) 1.5 (0.2) 1.6 (0.2) 1.4 (0.3) 1.5 (0.2)* 1.5 (0.3)* 1.3 (0.3)* Deaths before P2 (%) NA NA NA 223 (26.1) 46 (38.0) 100 (36.1)

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; BMI = body mass index; FEV1 = Forced expiratory volume in

one second; FVC = Forced vital capacity; DLCO = diffusion capacity of the lung for carbon monoxide; DLCO/VA = diffusion capacity of the lung for carbon

monoxide per alveolar volume. *P<0.05 compared to subjects with follow-up. Results are presented as mean (SD), count (percentage) or median

(interquartile range).

B. Characteristics of subjects from cohort 1 and 2 with follow-up and of subjects from cohort 1 and 2 with loss of follow-up at phase 2 (i.e. no follow-up

spirometry at phase 2 and no death before end of phase 2 examinations).

Characteristics at phase 1 of the subgroup with follow-up at phase 2 (n=1603) Characteristics at phase 1 of the subgroup with loss of follow-up at phase 2 (i.e. no follow-up spirometry at phase 2 and no death before end of phase 2) (n=884)

Normal-P1 (n=1276) PRISm-P1 (n=89) COPD-P1 (n=238) Normal-P1 (n=633) PRISm-P1 (n=75) COPD-P1 (n=177) Age (years) 73.7 (4.9) 74.7 (5.7) 74.3 (5.0) 76.9 (5.8)* 76.4 (5.9) 77.3 (5.8)* Female sex 729 (57.1) 51 (57.3) 106 (44.5) 412 (65.1)* 46 (61.3) 92 (52.0) BMI (kg/m2) 27.6 (4.1) 29.1 (3.8) 26.6 (3.9) 28.0 (4.2)* 29.2 (5.2) 26.5 (3.9) Current smoker 85 (6.7) 6 (6.7) 29 (12.2) 34 (5.4) 11 (14.7) 45 (25.4)* Pack-years (years) 3.2 (0.0, 18.8) 10.8 (0.0, 29.0) 19.8 (1.7, 40.4) 1.4 (0.0, 20.0) 8.0 (0.0, 25.0) 19.0 (0.3, 39.0) White blood cell count 6.8 (1.7) 7.5 (1.8) 7.2 (1.7) 6.9 (1.6) 7.1 (1.8) 7.6 (2.1)* Diabetes mellitus 97 (7.7) 6 (6.8) 21 (9.1) 59 (9.8) 4 (5.6) 18 (10.3) Hypertension 1065 (83.5) 80 (89.9) 202 (84.9) 558 (88.2)* 73 (97.3) 148 (83.6) Heart failure 34 (2.7) 4 (4.5) 11 (4.6) 25 (4.0) 9 (12.2) 11 (6.2) Coronary heart disease 123 (9.7) 12 (13.5) 33 (13.9) 61 (9.7) 6 (8.1) 23 (13.0) FEV1% predicted (%) 104.8 (13.8) 72.6 (6.4) 77.9 (17.8) 104.8 (13.7) 70.9 (7.8) 74.4 (18.1) FVC% predicted (%) 101.9 (13.2) 72.7 (7.6) 92.6 (16.7) 101.5 (13.6) 70.6 (9.0) 88.5 (17.2)* FEV1/FVC (%) 78.6 (4.7) 76.3 (5.1) 63.5 (6.7) 78.7 (4.7) 76.7 (5.0) 63.2 (6.4) DLCO (mmol/min/kPA) 7.5 (1.5) 7.2 (1.4) 7.2 (1.7) 7.2 (1.4)* 7.5 (1.4) 6.7 (1.5)* DLCO/VA (mmol/min/kPA) 1.5 (0.2) 1.6 (0.2) 1.4 (0.3) 1.5 (0.2) 1.5 (0.3) 1.3 (0.3)

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; BMI = body mass index; FEV1 = Forced expiratory volume in

one second; FVC = Forced vital capacity; DLCO = diffusion capacity of the lung for carbon monoxide; DLCO/VA = diffusion capacity of the lung for carbon

monoxide per alveolar volume. *P<0.05 compared to subjects with follow-up. Results are presented as mean (SD), count (percentage) or median

(interquartile range).

Table S2. Lung function values at phase 1 and phase 2 stratified by lung function category and smoking status at phase 2.

Normal spirometry-

P1(n=1276)

PRISm-P1 (n=89) COPD GOLD1-4-P1

(n=238)

COPD GOLD1-P1(n=114) COPD GOLD 2-4-P1

(n124)

Years between P1 and P2 4.6 (0.5) 4.6 (0.4) 4.6 (0.4) 4.6 (0.4) 4.6 (0.4)

FEV1% predicted at P1 (%) 104.8 (13.8) 72.6 (6.4)* 77.9 (17.8)* 92.9 (9.8)* 64.1 (11.2)*

FEV1% predicted at P2 (%) 102.0 (15.9) 72.8 (13.6)* 78.3 (19.9)* 91.5 (13.2)* 66.2 (17.2)*

Δ FEV1

(ml/year)

All (n=1603) -45.0 (-75.2, -17.4) -20.4 (-67.0, 1.9)* -31.0 (-60.3, 4.4)* -39.4 (-63.3, -14.1) -21.6 (-46.9, 19.3)*

Never smokers (n=534) -46.0 (-76.4, -20.0) -25.2 (-44.6, -2.2) -29.7 (-56.8, 3.7)* -32.4 (-72.1, -21.3) -8.2 (-39.5, 15.3)*

Former smokers (n=949) -43.5 (-74.5, -15.8) -16.4 (-71.5, 1.0)* -29.9 (-58.6, 5.4)* -37.9 (-61.9, -12.6) -22.0 (-48.2, 25.9)*

Current smokers (n=120) -49.3 (-75.1, -25.3) -19.7 (-28.6, -1.5) -40.8 (-65.1, -15.7) -56.1 (-85.8, -22.0) -29.2 (-44.8, -6.7)

FVC% predicted at P1 (%) 101.9 (13.2) 72.7 (7.6)* 92.6 (16.8)* 105.4 (11.2)* 81.0 (11.8)*

FVC% predicted at P2 (%) 104.4 (15.3) 78.9 (13.5)* 97.7 (18.1)* 108.7 (15.0)* 87.6 (14.5)*

Δ FVC

(ml/year)

All (n=1603) -20.2 (-55.8, 20.4) 5.5 (-38.4, 59.0)* -2.0 (-46.4, 50.2)* -6.7 (-66.1, 34.2) 8.0 (-37.6, 65.5)*

Never smokers (n=534) -25.3 (-63.9, 10.6) -13.4 (-37.0, 48.3) -9.5 (-59.9, 25.1) -16.4 (-72.0, 4.5) -5.6 (-43.8, 29.3)

Former smokers (n=949) -17.6 (-53.5, 22.7) 5.7 (-45.2, 60.1)* 2.4 (-43.3, 65.5)* -4.1 (-48.2, 53.1) 12.0 (-36.8, 81.5)*

Current smokers (n=120) -9.0 (-49.0, 23.8] 39.3 (12.6, 105.8) -23.4 (-57.2, 25.3) -42.1 (-80.3, 8.1) 7.2 (-33.5, 44.2]

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; GOLD = Global initiative for Chronic Obstructive Lung

Disease; P1 = phase 1; P2 = phase 2; FEV1 = Forced Expiratory Volume in one second; FVC = Forced Vital Capacity; Δ = delta. *P<0.05 compared to subjects

with normal spirometry. Results are presented as mean (SD) or median (interquartile range).

Table S3. Characteristics at phase 1 by lung function category at phase 1 and phase 2.

Normal (n=1276) PRISm (n=89) COPD (n=238)

Normal (n=931)

PRISm (n=47) COPD (n=298) Normal (n=14) PRISm (n=31) COPD (n=44) Normal (n=25) PRISm (n=5) COPD (n=208)

Years between P2 and P2 4.7 (0.5) 4.9 (0.5) 4.8 (0.5) 4.6 (0.4) 4.8 (0.4) 4.8 (0.4) 4.7 (0.3) 5.3 (0.4) 4.7 (0.4) Age (years) 73.3 (4.6) 75.5 (5.9) 74.6 (5.2) 72.9 (3.3) 74.9 (6.4) 75.1 (5.7) 73.7 (4.4) 80.3 (3.8) 74.3 (5.1) Female sex 561 (60.3) 27 (57.4) 141 (47.3) 12 (85.7) 15 (48.4) 24 (54.5) 15 (60.0) 2 (40.0) 89 (42.8) BMI (kg/m2) P1 27.7 (4.2) 29.0 (4.7) 27.2 (3.7) 28.3 (3.9) 30.2 (4.1) 28.7 (3.6) 26.0 (4.3) 29.5 (4.8) 26.6 (3.8) BMI (kg/m2) P2 27.5 (4.2) 29.3 (5.0) 27.0 (3.8) 28.2 (4.0) 29.7 (4.4) 28.5 (3.9) 25.9 (4.3) 27.4 (5.4) 26.3 (3.9) Δ BMI (kg/m2) -0.2 (1.6) 0.3 (1.9) -0.1 (1.5) -0.1 (1.1) -0.5 (2.2) -0.2 (1.2) -0.02 (0.2) -0.4 (0.9) -0.1 (0.3) Δ BMI > 1.5 kg/m2 (%) 109 (11.7) 12 (25.5) 32 (10.7) 1 (7.1) 5 (16.1) 3 (6.8) 2 (8.0) 1 (20.0) 25 (12.0) Waist circumference (cm) P1 92.9 (11.7) 97.2 (14.5) 92.9 (11.7) 92.8 (12.4) 101.1 (9.4) 99.1 (12.1) 88.1 (14.0) 101.6 (16.9) 94.1 (12.3) Waist circumference (cm) P2 94.5 (12.3) 101.4 (15.2) 95.2 (12.0) 93.4 (11.5) 101.1 (11.0) 101.1 (12.2) 90.7 (12.5) 99.1 (17.4) 95.4 (12.4) Δ waist circumference (cm) 1.6 (6.9) 4.2 (6.8) 2.3 (5.6) 0.6 (3.7) -0.1 (6.8) 2.0 (6.6) 2.6 (4.8) -2.5 (8.8) 1.3 (5.5) Height (cm) 166.9 (9.0) 167.1 (7.3) 169.1 (9.0) 162.5 (7.7) 167.0 (9.7) 167.9 (9.5) 166.7 (9.7) 173.6 (9.9) 170.5 (9.6) Current smokers 44 (4.7) 4 (8.5) 37 (12.4) 1 (7.1) 1 (3.2) 4 (9.1) 3 (12.0) 0 (0.0) 26 (12.5) Pack-years (years) 1.9 (0.0, 16.0) 3.0 (0.0, 20.5) 8.8 (0.0, 25.4) 0.5 (0.0, 7.1) 16.2 (0.1, 32.5) 11.2 (0.0, 30.8) 6.5 (0.5, 15.8) 16.0 (8.5, 25.0) 21.6 (2.9, 44.3) Total cholesterol (mmol/l) 5.5 (1.1) 5.4 (1.2) 5.3 (1.1) 5.4 (0.9) 5.0 (1.0) 5.2 (1.2) 5.2 (1.1) 5.0 (1.1) 5.4 (1.0) HDL-cholesterol (mmol/l) 1.5 (0.4) 1.4 (0.3) 1.5 (0.4) 1.5 (0.4) 1.4 (0.4) 1.4 (0.4) 1.6 (0.5) 1.3 (0.6) 1.5 (0.4) Tryglicerides (mmol/l) 1.3 (1.0, 1.7) 1.3 (1.1, 1.6) 1.2 (1.0, 1.7) 1.5 (1.1, 1.7) 1.4 (1.1, 1.9) 1.4 (1.0, 1.9) 1.1 (0.9, 1.4) 1.4 (1.1, 1.6) 1.2 (0.9, 1.6) Glucosis (mmol/l) 5.5 (5.1, 6.1) 5.7 (5.2, 6.5) 5.5 (5.2, 6.1) 5.5 (4.9, 5.9) 5.9 (5.5, 6.5) 5.5 (5.1, 6.3) 5.3 (4.9, 5.7) 5.7 (5.4, 6.5) 5.5 (5.1, 6.0) White blood cell count 6.8 (1.7) 7.0 (1.9) 6.9 (1.5) 7.1 (1.1) 7.6 (2.2) 7.5 (1.8) 7.1 (1.7) 7.1 (3.0) 7.2 (1.7) Diabetes mellitus 73 (8.0) 6 (12.8) 18 (6.1) 1 (7.7) 2 (6.5) 3 (6.8) 1 (4.0) 0 (0.0) 20 (9.9) Hypertension 775 (83.2) 40 (85.1) 250 (83.9) 13 (92.9) 29 (93.5) 38 (86.4) 23 (92.0) 5 (100.0) 174 (83.7) Prevalent Heart failure 25 (2.7) 1 (2.1) 8 (2.7) 0 (0.0) 2 (6.5) 2 (4.5) 0 (0.0) 0 (0.0) 11 (5.3) Incident Heart failure 8 (0.9) 5 (10.9) 2 (0.7) 0 (0.0) 4 (13.8) 3 (7.1) 1 (4.0) 0 (0.0) 6 (339) Prevalent coronary heart disease 91 (9.8) 5 (10.6) 27 (9.1) 1 (7.1) 4 (12.9) 7 (15.9) 5 (20.0) 0 (0.0) 28 (13.5) Incident coronary heart diease 14 (1.7) 1 (2.4) 11 (4.1) 0 (0.0) 0 (0.0) 1 (2.7) 2 (10.0) 0 (0.0) 6 (3.3) Deaths after P2 42 (4.5) 7 (14.6) 20 (6.7) 1 (7.1) 4 (12.9) 2 (4.5) 1 (4.0) 2 (40.0) 17 (8.2) Follow-up after P2 (person-years) 3135.4 157.6 1009.0 45.7 96.0 147.2 88.4 17.3 701.7 Mortality rate per 1000 PY after P2 13.4 44.4 19.8 21.9 41.7 13.6 11.3 115.5 24.2 Mortality rate ratio after P2 Ref 3.3 1.5 1.6 3.1 1.0 0.8 8.6 1.8

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; BMI = body mass index; HDL = high-density cholesterol; P1 =

phase 1; P2 = phase 2. Results are presented as mean (SD), count (percentage) or median (interquartile range)

Table S4. Lung function values at phase 1 and phase 2 stratified by lung function category at phase 1 and phase 2.

Normal (1276) PRISm (89) COPD (238)

Normal (931) PRISm (47) COPD (298) Normal (14) PRISm (31) COPD (44) Normal (25) PRISm (5) COPD (208)

FEV1% predicted P1 107.2 (13.9) 91.5 (8.9) 99.5 (11.5) 75.5 (4.0) 72.0 (6.9) 72.1 (6.6) 86.7 (15.8) 68.9 (7.6) 77.0 (17.9)

FEV1% predicted P2 106.3 (14.1) 73.8 (5.6) 92.9 (13.8) 92.5 (12.3) 69.0 (8.9) 69.2 (11.3) 101.5 (13.5) 65.9 (8.9) 75.8 (18.9)

Δ FEV1 (ml/year) -40.6 (-65.9, -

13.0)

-104.9 (-146.6, -

73.1)

-62.2 (-92.8, -

32.1)

43.7 (7.7, 75.7) -31.0 (-69.6, -

7.7)

-36.7 (-74.3, -

10.6)

27.1 (-22.1,

106.7)

-24.9 (-86.9,

0.0)

-36.2 (-64.0, -

4.1)

FVC% predicted P1 102.9 (13.4) 87.8 (8.1) 101.3 (11.9) 72.8 (5.9) 69.1 (7.4) 75.3 (7.3) 101.7 (15.8) 76.5 (6.1) 91.9 (16.6)

FVC% predicted P2 105.6 (14.3) 74.2 (7.6) 105.3 (14.6) 91.8 (11.2) 70.1 (9.9) 81.0 (12.3) 99.2 (12.9) 64.9 (8.3) 98.4 (18.1)

Δ FVC (ml/year) -20.6 (-56.8,

19.3)

-91.3 (-171.6, -

52.7)

-11.9 (-40.1,

51.9)

76.2 (49.5,

119.5)

-20.6 (-48.9,

22.2)

-11.9 (-40.1,

51.9)

-51.3 (-82.6, -

8.7)

-103.3 (-157.7, -

47.7)

7.1 (-39.8, 56.3)

FEV1/FVC P1 79.8 (4.4) 79.4 (3.9) 74.7 (3.6) 80.3 (5.5) 79.7 (4.5) 72.7 (2.1) 65.0 (5.1) 67.1 (4.7) 63.2 (6.9)

FEV1/FVC P2 76.4 (4.4) 75.3 (4.8) 66.4 (2.9) 77.0 (3.5) 74.6 (3.5) 64.3 (4.0) 77.5 (5.9) 75.1 (2.2) 57.7 (8.7)

Δ FEV1/FVC (%) -3.4 (4.5) -4.1 (5.4) -8.3 (4.1) -3.3 (5.9) -5.1 (4.7) -8.4 (4.4) 12.5 (8.9) 8.0 (3.1) -5.5 (5.6)

DLCO (mmol/min/kPA) 7.5 (1.5) 7.2 (1.2) 7.5 (1.5) 6.4 (1.0) 7.2 (1.2) 7.6 (1.6) 7.2 (1.1) 8.4 (1.1) 7.1 (1.8)

DLCO % predicted (%) 97.7 (13.7) 95.3 (17.1) 96.0 (14.9) 89.1 (12.5) 95.7 (22.0) 94.6 (20.0) 96.6 (9.9) 109.9 (15.9) 88.5 (19.4)

DLCO/VA

(mmol/min/kPA)

1.5 (0.2) 1.6 (0.2) 1.4 (0.2) 1.6 (0.2) 1.7 (0.3) 1.6 (0.2) 1.5 (0.2) 1.6 (0.2) 1.3 (0.3)

DLCO/VA % predicted

(%)

112.3 (16.0) 120.7 (17.2) 109.1 (17.4) 116.6 (11.0) 125.8 (21.1) 109.1 (17.4) 110.8 (14.9) 129.6 (16.3) 102.2 (20.2)

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; FEV1 = Forced expiratory volume in one second; FVC =

Forced vital capacity; P1 = phase 1; P2 = P2; Δ = delta; DLCO = diffusion capacity of the lung for carbon monoxide; DLCO/VA = diffusion capacity of the lung

for carbon monoxide per alveolar volume. Results are presented as mean (SD) and median (interquartile range)

Table S5. Estimates of mortality stratified by lung function categories.

Number at risk

All deaths

Follow-up (years)

Mortality rate (per 1000 PY)

Mortality rate ratio

HR [95%CI]1 HR [95%CI]2 HR [95%CI]3 HR [95%CI]4 CV deaths

Follow-up (years)

Mortality rate (per 1000 PY)

Mortality rate ratio

HR [95%CI]1 HR [95%CI]4

Total population

5446 686 35766 19.2 NA NA NA NA NA 82 15771 5.2 NA NA NA

Global initiative for Obstructive Lung Disease (GOLD) definition Normal 4150 425 27517 15.4 Reference Reference Reference Reference Reference 43 11973 3.6 Reference Reference Reference PRISm 384 71 2441 29.1 1.9 1.6 [1.2-2.0] 1.6 [1.3, 2.1] 1.6 [1.2, 2.0] 1.6 [1.2, 2.0] 15 111 13.5 3.8 2.7 [1.5, 5.0] 2.6 [1.4, 4.7]

FEV1≥74% 194 30 1261 23.8 1.5 1.3 [0.9, 1.8] NP NP 1.4 [1.0, 1.9] 7 566 12.4 3.4 2.6 [1.1, 5.7] 2.5 [1.1, 5.5] FEV1<74% 190 41 1180 34.7 2.3 1.9 [1.4, 2.6] NP NP 1.7 [1.3, 2.3] 8 545 14.7 4.1 2.8 [1.3, 6.0] 2.6 [1.2, 5.7] FVC≥73% 191 28 1226 22.8 1.5 1.4 [1.0, 2.1] NP NP 1.4 [0.9, 2.0] 4 536 7.5 2.1 1.8 [0.7, 5.1] 1.7 [0.6, 4.8] FVC<73% 193 43 1215 35.4 2.3 1.7 [1.2, 2.3] NP NP 1.7 [1.3, 2.3] 11 575 19.1 5.3 3.2 [1.6, 6.4] 3.1 [1.6, 6.1]

COPD GOLD1 419 52 2735 19.0 1.2 1.0 [0.7, 1.3] 1.0 [0.7, 1.3] 1.0 [0.7, 1.3] 0.7 [0.5, 0.9] 3 1187 2.5 0.7 0.5 [0.2, 1.6] 0.5 [0.1, 1.5] COPD GOLD2-4 493 138 3073 44.9 2.9 1.7 [1.4, 2.1] 1.8 [1.4, 2.2] 1.7 [1.4, 2.1] 1.5 [1.2, 1.8] 21 1499 14.0 3.9 1.9 [1.1, 3.4] 1.8 [1.0, 3.1] Global Lung Initiative definition (GLI): Lower Limit of Normal (LLN) NL 4791 541 31712 17.1 Reference Reference NP NP Reference 62 13944 4.4 Reference Reference Reference PRISm 279 63 1751 36.0 2.1 1.9 [1.5, 2.5] NP NP 1.8 [1.4, 2.3] 9 816 11.0 2.5 2.2 [1.1, 4.5] 2.1 [1.0, 4.2] FEV1≥66% 139 26 847 30.7 1.8 1.2 [1.4, 2.3] NP NP NP 2 364 5.5 1.3 1.8 [0.8,4.0] NP FEV1<66% 140 37 904 40.9 2.4 1.8 [1.4, 2.4] NP NP NP 7 452 15.5 3.5 2.6 [1.5, 4.5] NP FVC≥69% 141 27 891 30.3 1.8 1.4 [1.0, 1.8] NP NP NP 1 402 2.5 0.6 1.7 [0.8, 3.6] NP FVC<69% 138 36 860 41.9 4.5 1.7 [1.3, 2.2] NP NP NP 8 414 19.3 4.4 3.3 [1.8, 5.9] NP COPD GOLD1 131 17 822 20.7 1.2 1.4 [0.8, 2.2] NP NP 1.1 [0.7, 1.7] 1 335 3.0 0.7 0.7 {0.1, 5.4} NA COPD GOLD2-4 245 65 1480 43.9 2.6 1.9 [1.5, 2.5] NP NP 1.6 [1.3, 2.1] 10 676 14.8 3.4 2.1 [1.0, 4.3] 2.0 [1.0, 4.2] Subgroup with spirometry measurements at both phase 1 and phase 2* Persistent NL 924 42 3135 13.4 Reference Reference NP NP NA 1 NA NA NA NA NA Persistent PRISm

31 4 96 42.7 3.2 2.2 [0.8, 6.1] NP NP NA 0 NA NA NA NA NA

Incident PRISm 52 9 174 51.5 3.8 2.4 [1.1, 4.9] NP NP NA 0 NA NA NA NA NA Persistent COPD

208 17 702 24.2 1.8 1.0 [0.6, 1.9] NP NP NA 0 NA NA NA NA NA

Incident COPD 342 22 1156 19.0 1.4 0.9 [0.5, 1.5] NP NP NA 0 NA NA NA NA NA

HR = Hazard Ratio; CV = cardiovascular; GOLD = Global initiative for Chronic Obstructive Lung Disease; PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; FEV1 = Forced Expiratory volume in one second; FVC = Forced Vital Capacity; PY = person-years; NA = not applicable; NP = Not Performed; 1 = HR adjusted for age, sex, BMI, current smoking and pack-years; 2 = HR adjusted for age, sex, BMI, current smoking and pack-years and subjects with physician-diagnosed asthma excluded; 3 = HR adjusted for age, sex, BMI, current smoking, pack-years and cardiovascular comorbidity (heart failure and/or coronary heart disease); 4 = time-dependent HR adjusted for age, sex, BMI, current smoking and pack-years with lung function category at phase 2 as time varying covariate; * follow-up time start after spirometry at phase 2. Subjects with missing information for one of the covariates were excluded (n=13, of whom 6 died).

Table S6. ICD10 classification of cause-specific mortality.

ICD10 code Normal PRISm COPD

C00-D48 Neoplasms 81 (47.6%) 11 (29.7%) 38 (48.7%) I00–I99 Diseases of the circulatory system 43 (25.3%) 15 (40.6%) 24 (30.8%) F00–F99 Mental and behavioural disorders 12 (7.1%) 3 (8.1%) 6 (7.7%) R00–R99 Symptoms, signs and abnormal clinical and laboratory findings not

elsewhere classified 15 (8.8%) 3 (8.1%) 2 (2.6%)

J00–J99 Diseases of the respiratory system 4 (2.3%) 4 (10.8%) 6 (7.7%) G00–G99 Diseases of the nervous system 4 (2.3%) 1 (2.7%) 0 (0.0%) K00–K93 Diseases of the digestive system 4 (2.3%) 0 (0.0%) 0 (0.0%) V01–Y98 External causes of morbidity and mortality 3 (1.8%) 0 (0.0%) 1 (1.3%) S00–T98 Injury, poisoning and certain other consequences of external

causes 2 (1.2%) 0 (0.0%) 1 (1.3%)

A00-B99 Certain infectious and parasitic diseases 1 (0.6%) 0 (0.0%) 0 (0.0%) M00–M99 Diseases of the musculoskeletal system and connective tissue 1 (0.6%) 0 (0.0%) 0 (0.0%) Total deaths with ICD10 code registration (until 01/01/2015) 170 (39.5%) 37 (51.4%) 78 (41.1%) Total deaths (until 30/06/2018) 430 72 190

ICD = International Classification Of Diseases; PRISm = Preserved Ratio Impaired Spirometry; COPD =

Chronic Obstructive Pulmonary Disease.

Figure S1. Flowchart of the Rotterdam Study

Diagram of examination cycles of the Rotterdam Study (RS). RS-I-1 refers to the baseline examination

of the original cohort (pilot phase 07/1989–12/1989; cohort recruitment 01/1990–09/1993). RS-I-2,

RS-I-3, RS-I-4, RS-I-5, and RS-I-6 refer to re-examinations of the original cohort members. RS-II-1

refers to the extension of the cohort with persons in the study district that became 55 years since the

start of the study or those of 55 years or over that migrated into the study district. RS-II-2, RS-II-3,

and RS-II-4 refer to re-examinations of the extension cohort. RS-III-1 refers to the baseline

examination of all persons aged 45 years and over living in the study district that had not been

examined already (i.e., mainly comprising those aged 45–60 years). RS-III-2 refers to the first re-

examination of this third cohort. Examination RS-I-4 and RS-II-2 were conducted as one project and

feature an identical research program. Similarly, examinations RS-I-5, RS-II-3, and RS-III-2 share the

same program items. Also, examinations RS-I-6 and RS-II-4 are conducted as one project. RS-IV-1

refers to the baseline visit of a new cohort, to be established in February 2016.

Figure S2. Age- and sex-specific prevalence, incidence and mortality of PRISm and COPD.

PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive Pulmonary Disease; PY = person-

years. Cumulative incidence of PRISm and COPD was calculated in a subset of individuals with spirometry at

both phase 1 and phase 2, after exlusion for prevalent PRISm and COPD in the case of incident PRISm (n=1278),

and after exclusion of prevalent COPD in the case of incident COPD (n=1365).

Figure S3. Transitions between lung function categories according to GLI definition for FEV1 and the

FEV1/FVC ratio.

NL = normal spirometry; PRISm = Preserved Ratio Impaired Spirometry; COPD = Chronic Obstructive

Pulmonary Disease.