In this journal, Pellino et al presented survival analysis to assess how deprivation affects prognosis in patients with pulmonary arterial hypertension (PAH)1. Their conclusions were that social deprivation is not a significant referral barrier or prognostic factor for idiopathic (I)PAH or heritable (H)PAH in Scotland. This may appear surprising given the wider context of literature describing outcomes stratified by social deprivation. The authors were thorough on using both the address at time of diagnosis and at time of censoring to assign deprivation scores and compare the two, finding no significant differences between the two approaches. They also compared deprivation assigned to PAH cases to expected deprivation based on Scottish citizenry as a whole and found that PAH patients are more socially deprived than expected. Finally, they used the same survival univariate analysis adjusting for age and sex to assess how several clinical variables are associated with prognosis

Allan, Lawrie

Colin, Church

David, Kiely

Eleni, Sofianopoulou

Gerry, Coghlan

James, Lordan

Luke, Howard

Martin, Johnson

Martin, Wilkins

Morrell, Nicholas

Stephen, Wort

Toshner, Mark

English

Apollo (Cambridge)

Deprivation and prognosis in patientswith pulmonary arterial hypertension:missing the effect of deprivation on arare disease?To the Editor:In this journal, PELLINO et al. [1] presented a survival analysis to assess how deprivation affects prognosisin patients with pulmonary arterial hypertension (PAH). Their conclusions were that social deprivation isnot a significant referral barrier or prognostic factor for idiopathic (I)PAH or heritable (H)PAH inScotland. This may appear surprising, given the wider context of literature describing outcomes stratifiedby social deprivation. The authors were thorough on using both the address at time of diagnosis and attime of censoring to assign deprivation scores and compare the two, finding no significant differencesbetween the two approaches. They also compared deprivation assigned to PAH cases to expecteddeprivation based on Scottish citizenry as a whole, and found that PAH patients are more sociallydeprived than expected. Finally, they used the same survival univariate analysis adjusting for age and sexto assess how several clinical variables are associated with prognosis.The ongoing National Cohort Study of Idiopathic and Heritable PAH collects data from all of the UK andoffers an opportunity to test the relationship between deprivation and outcomes in PAH in a secondpopulation that is geographically distinct but in many other ways highly analogous to that studied byPELLINO et al. [1]. The study collects data from a contemporaneous cohort in all of the specialist PAHcentres in the UK. Therefore, we were able to assess mortality in relation to deprivation in 270 PAHpatients living in England and Wales, residing in the same addresses since diagnosis. Our patients wererecruited in the UK PAH cohort from 1 January, 2014 and followed-up until 28 February, 2019. 36 (13%)participants died and five (2%) were transplanted, resulting in 1-, 3- and 5-year transplant-free survivalestimates of 96%, 86% and 73% for incident patients (n=146) and 100%, 100% and 89% for prevalentpatients (n=124), respectively. PELLINO et al. [1] captured deprivation using the Scottish Index of MultipleDeprivation (IMD), which is a composite index comprising of sub-indices (e.g. income, education,employment, health, access to services, crime). In the UK, IMD is not comparable between England,Scotland and Wales, so for our UK cohort we accessed an adjusted IMD index for use across the UK [2],which consists of the three main domains of IMD: income, employment and educational deprivation. Inaddition to the area level deprivation captured via the UK-IMD, the primary survival model was adjustedfor age at diagnosis and sex, to be in line with the adjustment used by PELLINO et al. [1], fitting Coxproportional hazards regression models. Cox proportional hazards regression models and survival curveswere fitted allowing for left truncation arising from the interval between diagnosis of prevalent cases andenrolment. Prevalent patients were only included in the risk set from the time of study entry and wereexcluded if they entered the study >10 years after diagnosis. We stratified the analysis by centre, due to themulticentre design of our study. In the extended model, we further adjusted for smoking, prevalent/incident status and risk profiles (low/intermediate/high) at the time of diagnosis, calculated using theabbreviated 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) riskstratification strategy [3]. According to data availability, the risk score groups were estimated using theWorld Health Organization functional class, right atrial pressure, cardiac index and mixed venous oxygensaturation, having significant difference (p=0.02) on survival (figure 1), as expected.@ERSpublicationsNo association was found between deprivation and mortality for PAH patients in England and Wales.The association found between risk stratification at baseline and deprivation suggests that the issue ofdeprivation and outcomes in PAH may be more nuanced. https://bit.ly/2y8WgqBCite this article as: Sofianopoulou E, Church C, Coghlan G, et al. Deprivation and prognosis in patientswith pulmonary arterial hypertension: missing the effect of deprivation on a rare disease? Eur Respir J2020; 56: 1902334 [https://doi.org/10.1183/13993003.02334-2019].https://doi.org/10.1183/13993003.02334-2019 Eur Respir J 2020; 56: 1902334| | AGORARESEARCH LETTERThe study participants are more likely to be women (68%) with mean±SD age at diagnosis 51±16 years.The pulmonary haemodynamic characteristics of the study participants were: 1) right atrial pressure9±5 mmHg, 2) mean pulmonary arterial pressure, 53±14 mmHg, 3) cardiac index 2±0.6 L·min−1·m−2,4) cardiac output 4±1.2 L·min−1, 5) pulmonary vascular resistance 12±5 WU and 6) mixed venous oxygensaturation, 64±8%. We found no association between mortality and classes of area deprivation, for boththe primary and adjusted model. As an example, adjusted hazard ratio (HR) was 0.63 (95% CI 0.18–2.16)(p=0.458) for most deprived (quintile 5) areas compared to least deprived (quintile 1) areas. To examinethis further, we investigated area deprivation as predictor of risk profiles, fitting multinomial regressionmodels. We found an association between risk profiles and area deprivation, while adjusting for the samevariables as above. Living within the more deprived areas (quintiles 5, 4 and 3) was associated with higherPAH risk score at baseline, compared to the least deprived areas (quintile 1), therefore increasing thelikelihood of being diagnosed within the ESC/ERS high-risk clinical prediction category. Testing for theoverall effect of deprivation to risk profiles, we found a statistically significant predictor effect (p=0.034,Wald-test). The relative risk ratio changing from least (quintile 1) to most (quintile 5) deprived area is15.01 (95% CI 1.96–114.96) (p=0.009), for being classed as high risk profile versus low risk profile. Thiswas 14.59 (95% CI 2.22–95.9) (p=0.005) and 9.75 (95% CI 1.42–67.06) (p=0.021) for quintiles 4 and 3,respectively. In other words, we found that the expected risk for being in high-risk class is higher forsubjects who live in the most deprived areas. The baseline risk class was also found to be a predictor ofmortality in this survival analysis (adjusted HR 6.71, 95% CI 1.22–36.87) (p=0.028), in line with theliterature [3–5].The notion that deprivation is associated with increased mortality and morbidity for the most deprivedcompared with the most affluent, is confirmed by many studies and, therefore, has been enshrined inhealth studies, theories and policies [6–9]. The main aspects of deprivation are income, employment andeducation that can be collected at area-level and individual level or, preferably, both. The choice for usinga composite index or its subdomains, or individual-level deprivation, is driven by the research questionand availability of deprivation indicators. Studies have faced numerous challenges in terms of using acomposite area-level deprivation index. The data required are based on coverage of routinely collecteddata, which can vary between countries, using also a weighting score that depends on the priorities set byeach country, making these indices not comparable. Usually, though, the highest weights are given toincome, employment and educational deprivation and, therefore, it is possible the composite index issimilar to indices that are based on any of these traditional deprivation markers. Still, we recommend notto assume that any differences would have no impact on the results, especially when using small datasetsas the models can be too sensitive.Even when such an index is used for the intended geographical area it was created for, the geographicaldistributions of sub-indices may have opposing directions, introducing error on the overall measure ofdeprivation. For instance, a high deprivation score should reflect both areas of low income and difficulty1.000.750.500.250.00Probability of surviving to time tTime (t) yearsAt risk n0High risk score105 151610426Low risk scoreIntermediate risk scoreHigh risk score176199303120Intermediate risk scoreLow risk scoreFIGURE 1 Transplant-free survival in relation to risk profile (Kaplan–Meier estimates), at the time of diagnosis(n=270).https://doi.org/10.1183/13993003.02334-2019 2RESEARCH LETTER | E. SOFIANOPOULOU ET AL.in accessing healthcare, with the latter often being measured as distance to primary healthcare centre.Patients who live near city centres, which tend to have higher income deprivation, may not have a longdistance to access a primary care centre, while the opposite holds for wealthier populations that may liveoutside the city centre. Thus, the estimated composite deprivation can be compromised. Even thetraditional indicators of income and education deprivation may vary substantially across areas [10]. Anydifferences can be understood by mapping the individual domains, which is important when consideringhow such data is used in analyses.Composite IMD indices, such as the Scottish IMD used by PELLINO et al. [1], have a health subdomaincalculated based on standardised mortality ratio among other variables, so PAH mortality may be capturedin some degree by this sub-domain. Therefore, ideally, the health sub-domain should not be includedwhen deprivation is examined in relation to mortality. Finally, we would argue that even when prognosis isnot associated with deprivation, this cannot directly lead to the interpretation that prognosis is not affectedby access to care and referrals. Deprivation is linked to several parameters that affect health (i.e. diet, airquality) other than just equity on access to health services.A notable feature of the UK National Health Service specialised commissioning structure for PAH is theequity of access to all licensed treatments to all patients, once they have been referred to the centres. Apossible interpretation of our results and those reported by PELLINO et al. [1] is therefore that deprivationacts as a barrier to referral but once in the specialised system, the equity of treatment availabilitydiminishes the subsequent effect on mortality. We feel it cannot be ignored that, unlike previous work thatshowed a significant effect of deprivation on mortality [11], both UK studies of similar sample sizes havefailed to demonstrate an association with mortality and in health systems with more equal access tolicensed treatment.There are some limitations to this work. It is common for rare disease projects to analyse hundreds ofcases, compared to thousands or millions in common diseases, for the same or similar research questions[12, 13], leading to the need to adopt refined datasets and analytical methods. The introduction ofmeasurement error when using a deprivation index is likely to affect small datasets disproportionately andneeds to be used with caution when conducting sensitivity analysis. Lastly, we are unable to quantify theeffect of patients potentially not surviving to first admission to a tertiary PH care centre, and this drop outis theoretically more significant, specifically because of the association we find with baseline riskstratification.Overall, the study by PELLINO et al. [1] is an important piece in the PAH aetiology puzzle, and the resultsof our study are in line with their lack of association between mortality and social deprivation; althoughwe would caution that both studies are of modest size. At the same time, PELLINO et al. [1] found that PAHpatients are more socially deprived than expected, based on Scottish citizenry as a whole. This alludes thatdeprivation status may have an association with PAH rather than it being a random finding. Our studyadds further to the literature by demonstrating that higher area deprivation is associated with a worse riskprofile at baseline, which in turn is a predictor of worse survival rates, suggesting that the issue of socialdeprivation and outcomes in PAH may be more nuanced. Examining both primary healthcare andhospital data in PAH could provide evidence on whether in deprived areas delays on PAH diagnosis areassociated with the patient taking longer to seek help and the time required for tests related to thediagnosis, compared to least deprived areas.Eleni Sofianopoulou1,11, Colin Church2, Gerry Coghlan3, Luke Howard4, Martin Johnson2, David G. Kiely 5,Allan Lawrie 6, James Lordan7, Martin R. Wilkins 4, Stephen J. Wort4,8, Nicholas W. Morrell9,10 andMark R. Toshner 9,111Dept of Public Health and Primary Care, Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge,UK. 2Golden Jubilee National Hospital, Glasgow, UK. 3Royal Free Hospital, London, UK. 4Imperial College London,London, UK. 5Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK. 6Dept ofInfection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. 7University of Newcastle,Newcastle, UK. 8Royal Brompton Hospital, London, UK. 9Dept of Medicine, University of Cambridge, Cambridge, UK.10NIHR BioResource - Rare Diseases, Cambridge, UK. 11Supervision of this work was shared by E. Sofianopoulou andM.R. Toshner.Correspondence: Eleni Sofianopoulou, University of Cambridge, Dept of Public Health and Primary Care, Wort’sCauseway, Strangeways Research Laboratory, Cambridge CB1 8RN, UK. E-mail: es630@medschl.cam.ac.ukReceived: 5 Dec 2019 | Accepted after revision: 20 March 2020Conflict of interest: E. Sofianopoulou has nothing to disclose. C. Church has nothing to disclose. G. Coghlan reportsgrants and personal fees for conference attendance from Johnson & Johnson, personal fees for lectures fromGlaxoSmithKline, Bayer andMSD, outside the submitted work. L. Howard has nothing to disclose. M. Johnson reportsgrants and personal fees for meeting attendance, lectures and advisory board work from Actelion and MSD, outside thesubmitted work. D.G. Kiely has nothing to disclose. A. Lawrie reports grants from British Heart Foundation andhttps://doi.org/10.1183/13993003.02334-2019 3RESEARCH LETTER | E. SOFIANOPOULOU ET AL.Medical Research Council, grants, personal fees and travel support from Actelion Pharmaceuticals Ltd, grants andpersonal fees from GlaxoSmithKline, outside the submitted work. J. Lordan has nothing to disclose. M.R. Wilkins hasnothing to disclose. S.J. Wort has nothing to disclose. N.W. Morrell has nothing to disclose. M.R. Toshner reportspersonal fees from GSK, grants and personal fees from J&J/Actelion, grants from Merck and Bayer, outside thesubmitted work.Support statement: This work was supported by the Medical Research Council (grant: RG67444), the British HeartFoundation (grant: RG68204) and the NIHR Cambridge Biomedical Research Centre. Funding information for thisarticle has been deposited with the Crossref Funder Registry.References1 Pellino K, Kerridge S, Church C, et al. Social deprivation and prognosis in Scottish patients with pulmonaryarterial hypertension. Eur Respir J 2018; 51: 1700444.2 Abel GA, Barclay ME, Payne RA. Adjusted indices of multiple deprivation to enable comparisons within andbetween constituent countries of the UK including an illustration using mortality rates. BMJ Open 2016; 6:e012750.3 Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015European pulmonary hypertension guidelines risk stratification model. Eur Respir J 2017; 50: 1700740.4 Sofianopoulou E, Kaptoge S, Gräf S, et al. Traffic exposures, air pollution and outcomes in pulmonary arterialhypertension: a UK cohort study analysis. Eur Respir J 2019; 53: 1801429.5 Kylhammar D, Kjellström B, Hjalmarsson C, et al. A comprehensive risk stratification at early follow-updetermines prognosis in pulmonary arterial hypertension. Eur Heart J 2018; 39: 4175–4181.6 Stafford M, Marmot M. Neighbourhood deprivation and health: does it affect us all equally? Int J Epidemiol 2003;32: 357–366.7 Carstairs V, Morris R. Deprivation and Health in Scotland. Edinburgh, Mercat Press, 1991.8 Barnett K, Mercer SW, Norbury M, et al. Epidemiology of multimorbidity and implications for health care,research, and medical education: a cross-sectional study. Lancet 2012; 380: 37–43.9 Office of National Statistics. Statistical Bulletin: Health State Life Expectancies by National Deprivation Deciles,England: 2016 to 2018. www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthinequalities/bulletins/healthstatelifeexpectanciesbyindexofmultipledeprivationimd/2016to2018 Date last updated: 27 March2020.10 Sofianopoulou E, Rushton SP, Diggle PJ, et al. Association between respiratory prescribing, air pollution anddeprivation, in primary health care. J Public Health 2013; 35: 502–509.11 Wu WH, Yang L, Peng FH, et al. Lower socioeconomic status is associated with worse outcomes in pulmonaryarterial hypertension. Am J Respir Crit Care Med 2013; 187: 303–310.12 Woodward M, Brindle P, Tunstall-Pedoe H. Adding social deprivation and family history to cardiovascular riskassessment: the ASSIGN score from the Scottish Heart Health Extended Cohort (SHHEC). Heart 2007; 93:172–176.13 Foster HME, Celis-Morales CA, Nicholl BI, et al. The effect of socioeconomic deprivation on the associationbetween an extended measurement of unhealthy lifestyle factors and health outcomes: a prospective analysis of theUK Biobank cohort. Lancet Public Health 2018; 3: e576–e585.Copyright ©ERS 2020.This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.https://doi.org/10.1183/13993003.02334-2019 4RESEARCH LETTER | E. SOFIANOPOULOU ET AL.

Deprivation and prognosis in patients with Pulmonary Arterial Hypertension: missing the effect of deprivation on a rare disease?

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Deprivation and prognosis in patients with Pulmonary Arterial Hypertension: missing the effect of deprivation on a rare disease?

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