Clinical Phenotyping In Sarcoidosis Using Cluster Analysis

Abstract Background Most phenotyping paradigms in sarcoidosis are based on expert opinion; however, no paradigm has been widely adopted because of the subjectivity in classification. We hypothesized that cluster analysis could be performed on common clinical variables to define more objective sarcoidosis phenotypes. MethodsModel-based clustering was performed using the VarSelLCM R package to identify distinct phenotypes of sarcoidosis based on 29 clinical features. The Integrated Completed Likelihood (ICL) criteria were used to estimate number of clusters. To identify features associated with cluster membership, features were ranked based on variable importance scores from the VarSelLCM model, and additional univariate tests (Fisher’s exact test and one-way ANOVA) were performed using q-values correcting for multiple testing. The Wasfi severity score was also compared between clusters. ResultsCluster analysis resulted in 6 sarcoidosis phenotypes. Salient characteristics for each cluster are as follows: Phenotype 1) supranormal lung function and majority Scadding stage 2/3; phenotype 2) supranormal lung function and majority Scadding stage 0/1; phenotype 3) normal lung function and split Scadding stages between 0/1 and 2/3; phenotype 4) obstructive lung function and majority Scadding stage 2/3; phenotype 5) restrictive lung function and majority Scadding stage 2/3; phenotype 6) mixed obstructive and restrictive lung function and mostly Scadding stage 4. Clusters 4,5,6 were significantly more likely to have ever been on immunosuppressive treatment and had higher Wasfi disease severity scores. ConclusionsCluster analysis produced 6 sarcoidosis phenotypes that demonstrated non-severe and severe phenotypes. Phenotypes 1,2,3 have less lung function abnormalities, a lower percentage on immunosuppressive treatment and lower Wasfi severity scores. Phenotypes 4,5,6 were characterized by lung function abnormalities, more parenchymal abnormalities, an increased percentage on immunosuppressive treatment and higher Wasfi severity scores. These data support using cluster analysis as an objective and clinically useful way to phenotype sarcoidosis subjects.

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Sleep and cardiometabolic risk: a cluster analysis of actigraphy-derived sleep profiles in adults and children

SLEEP ◽

10.1093/sleep/zsab014 ◽

2021 ◽

Author(s):

Lisa Matricciani ◽

Catherine Paquet ◽

François Fraysse ◽

Anneke Grobler ◽

Yichao Wang ◽

...

Keyword(s):

Cluster Analysis ◽

Cardiometabolic Risk ◽

High Efficiency ◽

Cardiometabolic Health ◽

Maturity Stage ◽

Cluster Membership ◽

Geographic Clustering ◽

Adults And Children ◽

Study Participants ◽

Generalised Estimating Equations

Abstract Study objectives Sleep plays an important role in cardiometabolic health. While the importance of considering sleep as a multidimensional construct is widely appreciated, studies have largely focused on individual sleep characteristics. The association between actigraphy-derived sleep profiles and cardiometabolic health in healthy adults and children has not been examined. Methods This study used actigraphy-measured sleep data collected between February 2015 and March 2016 in the Child Health CheckPoint study. Participants wore actigraphy monitors (GENEActiv Original, Cambs, UK) on their non-dominant wrist for seven days and sleep characteristics (period, efficiency, timing and variability) were derived from raw actigraphy data. Actigraphy-derived sleep profiles of 1,043 Australian children aged 11-12 years and 1337 adults were determined using K-means cluster analysis. The association between cluster membership and biomarkers of cardiometabolic health (blood pressure, body mass index, apolipoproteins, glycoprotein acetyls, composite metabolic syndrome severity score) were assessed using Generalised Estimating Equations, adjusting for geographic clustering, with sex, socioeconomic status, maturity stage (age for adults, pubertal status for children) and season of data collection as covariates. Results Four actigraphy-derived sleep profiles were identified in both children and adults: Short sleepers, Late to bed, Long sleepers, and Overall good sleepers. The Overall good sleeper pattern (characterised by adequate sleep period time, high efficiency, early bedtime and low day-to-day variability) was associated with better cardiometabolic health in the majority of comparisons (80%). Conclusion Actigraphy-derived sleep profiles are associated with cardiometabolic health in adults and children. The Overall good sleeper pattern is associated with more favourable cardiometabolic health.

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Poor Cognitive Function Is Associated with Obstructive Lung Diseases in Taiwanese Adults

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18052344 ◽

2021 ◽

Vol 18 (5) ◽

pp. 2344

Author(s):

Sun-Wung Hsieh ◽

Da-Wei Wu ◽

Chih-Wen Wang ◽

Szu-Chia Chen ◽

Chih-Hsing Hung ◽

...

Keyword(s):

Cognitive Function ◽

Lung Function ◽

Lung Diseases ◽

Mmse Score ◽

Multivariable Analysis ◽

Forced Expiratory Volume ◽

Normal Lung ◽

Obstructive Lung Diseases ◽

Normal Lung Function ◽

Function Group

Previous studies have reported an association between the impairment of cognitive performance and lung diseases. However, whether obstructive or restrictive lung diseases have an impact on cognitive function is still inconclusive. We aimed to investigate the association between cognitive function and obstructive or restrictive lung diseases in Taiwanese adults using the Mini-Mental State Examination (MMSE). In this study, we used data from the Taiwan Biobank. Cognitive function was evaluated using the MMSE. Spirometry measurements of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were obtained to assess lung function. Participants were classified into three groups according to lung function, namely, normal, restrictive, and obstructive lung function. In total, 683 patients enrolled, of whom 357 participants had normal lung function (52.3%), 95 had restrictive lung function (13.9%), and 231 had obstructive lung function (33.8%). Compared to the normal lung function group, the obstructive lung function group was associated with a higher percentage of cognitive impairment (MMSE < 24). In multivariable analysis, a low MMSE score was significantly associated with low FVC, low FEV1, and low FEV1/FVC. Furthermore, a low MMSE score was significantly associated with low FEV1 in the participants with FEV1/FVC < 70%, whereas MMSE was not significantly associated with FVC in the participants with FEV1/FVC ≥ 70%. Our results showed that a low MMSE score was associated with low FEV1, low FVC and low FEV1/FVC. Furthermore, a low MMSE score was associated with obstructive lung diseases but not with restrictive lung diseases.

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P157 Potential benefit of intravenous immunoglobulin in connective tissue disease associated interstitial lung diseases

Rheumatology ◽

10.1093/rheumatology/keab247.153 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Vasilis Kouranos ◽

Lauren V Host ◽

Corrado Campochiaro ◽

Athol Wells ◽

Christopher P Denton ◽

...

Keyword(s):

Lung Function ◽

Connective Tissue ◽

Lung Diseases ◽

Immunosuppressive Treatment ◽

Interstitial Lung Diseases ◽

Ivig Treatment ◽

Before And After ◽

Predicted Values ◽

Relative Change ◽

Median Change

Abstract Background/Aims Intravenous immunoglobulin (IVIg) confers significant benefit in range of connective tissue diseases (CTD) including inflammatory myopathy (IM) of which interstitial lung diseases (ILD) are a major complication. This study aimed to assess the efficacy of IVIg on pulmonary involvement in refractory active CTD including systemic sclerosis (SSc). Methods All patients with CTD-ILD confirmed on HRCT either with IM or SSc overlap myositis who did not achieve satisfactory clinical response to standard immunosuppressive agents and subsequently received regular IVIg infusions for IM were retrospectively identified. Serial lung function tests and immunosuppressive treatment regimen 9-12 months prior and 9-12 months after repeat courses of IVIg were recorded. Progressive ILD was considered when, despite immunosuppressive treatment, a relative FVC decline≥10% and/or relative DLco decline ≥15% were identified during the 9-12 months preceding IVIg treatment. The significance of median DLco and FVC percentage relative change to IVIg treatment was assessed by Wilcoxon signed-rank test. Results 22 patients (mean age 50.5±13.1 years old) with IM-ILD treated with IVIg were identified. ILD occurred in association with IM in 10 patients, overlap SSc myositis in another 11 patients, while one had mixed connective tissue disease with myositis. Lung function results were available for 19/22 (86%). Eight patients (42.1%) were found to have progressive ILD(four with IM and four with overlap SSc-myositis). The median change in FVC% predicted and DLco% predicted in the 9-12 months before and after IVIg treatment is presented in Table 1. There was a significant difference in the DLco% predicted rate of relative change before and after IVIg treatment (p = 0.035) for the overall cohort. However, no differences in lung function were observed in the rate of relative change between patients with IM and patients with SSc myositis overlap. Significant improvement in DLco% predicted values was identified in the subgroup analysis of patients with progressive ILD(p = 0.012). P157 Table 1:The median change in FVC and DLco% predicted values prior and after the IVIg treatmentPatients with myositis related ILD9-12 months before IVIg treatment (relative change)9-12 months after IVIg treatment (relative change)p-valueAll (n = 19)FVC % predicted-3.8 (-54.4 - 14.6)2.1 (-33 - 33.7)0.145DLco % predicted-9.2 (-60.7 - 9.2)-2.3 (-26 - 41.9)0.035PM/DM (n = 10)FVC % predicted-1.8 (-20.2 - 14.6)0.8 (-33 - 30.9)0.401DLco % predicted-9.6 (-60.7 - 9.2)-2.4 (-26 - 41.9)0.093SSc-PM/DM overlap (n = 11)FVC % predicted-6 (-54.4 - 10.6)3.4 (-19.9 - 33.7)0.139DLco % predicted-10.8 (-47.1 - 2.5)4.2 (-22.7 - 16.8)0.173Progressive ILD (n = 8)FVC % predicted-14.5 (-54.4 - 14.6)5.7 (-11.9 - 33.7)0.123DLco % predicted-25.3 (-60.6 - -14.1)12 (-2.3 - 41.9)0.012 Conclusion IVIg may be an effective rescue therapy in the prevention of further lung function decline in refractory myositis and SSc overlap in particular in subgroups with progressive ILD. Future studies to determine its role in CTD-ILD are warranted. Disclosure V. Kouranos: None. L.V. Host: None. C. Campochiaro: None. A. Wells: None. C.P. Denton: None. V.H. Ong: None. E. Renzoni: None.

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DNA methylation is associated with airflow obstruction in patients living with HIV

Thorax ◽

10.1136/thoraxjnl-2020-215866 ◽

2020 ◽

pp. thoraxjnl-2020-215866

Author(s):

Ana I Hernandez Cordero ◽

Chen Xi Yang ◽

Maen Obeidat ◽

Julia Yang ◽

Julie MacIsaac ◽

...

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Viral Infections ◽

Airflow Obstruction ◽

Normal Lung ◽

People Living With Hiv ◽

Global Methylation ◽

Age Related ◽

Impaired Lung Function ◽

Living With Hiv

IntroductionPeople living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH.MethodsUsing blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV1, FEV1/FVC ratio and FEV1 decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing.ResultsAirflow obstruction as defined by a FEV1/FVC<0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV1/FVC<lower limit of normal. These DMPs were enriched for biological pathways associated with chronic viral infections. The airflow obstruction group was globally hypomethylated compared with those without airflow obstruction. 103 and 7112 DMPs were associated with FEV1 and FEV1/FVC, respectively. No positions were associated with FEV1 decline.ConclusionA large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.

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Prevalence and burden of chronic bronchitis symptoms: results from the BOLD study

European Respiratory Journal ◽

10.1183/13993003.00621-2017 ◽

2017 ◽

Vol 50 (5) ◽

pp. 1700621 ◽

Cited By ~ 19

Author(s):

Filip Mejza ◽

Louisa Gnatiuc ◽

A. Sonia Buist ◽

William M. Vollmer ◽

Bernd Lamprecht ◽

...

Keyword(s):

Lung Function ◽

Lung Disease ◽

Chronic Bronchitis ◽

Airflow Obstruction ◽

Population Based ◽

Normal Lung ◽

Increased Risk ◽

Potential Risk Factors ◽

Definition Of ◽

Disease Study

We studied the prevalence, burden and potential risk factors for chronic bronchitis symptoms in the Burden of Obstructive Lung Disease study.Representative population-based samples of adults aged ≥40 years were selected in participating sites. Participants completed questionnaires and spirometry. Chronic bronchitis symptoms were defined as chronic cough and phlegm on most days for ≥3 months each year for ≥2 years.Data from 24 855 subjects from 33 sites in 29 countries were analysed. There were significant differences in the prevalence of self-reported symptoms meeting our definition of chronic bronchitis across sites, from 10.8% in Lexington (KY, USA), to 0% in Ile-Ife (Nigeria) and Blantyre (Malawi). Older age, less education, current smoking, occupational exposure to fumes, self-reported diagnosis of asthma or lung cancer and family history of chronic lung disease were all associated with increased risk of chronic bronchitis. Chronic bronchitis symptoms were associated with worse lung function, more dyspnoea, increased risk of respiratory exacerbations and reduced quality of life, independent of the presence of other lung diseases.The prevalence of chronic bronchitis symptoms varied widely across the studied sites. Chronic bronchitis symptoms were associated with significant burden both in individuals with chronic airflow obstruction and those with normal lung function.

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Correlation between Level of Autophagy and Amount of CD8+T Cells in Chronic Obstructive Pulmonary Disease

10.21203/rs.3.rs-36595/v1 ◽

2020 ◽

Author(s):

Songming Zhuo ◽

Hong Zhuang ◽

Na Li ◽

Sida Chen ◽

Wugen Zhan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lung Function ◽

Normal Lung ◽

Stable Phase ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Normal Lung Function ◽

Healthy Control ◽

Function Group

Abstract Background: This study aimed to shed light on the correlation between the amounts of CD8+ T cells and autophagy level in COPD. Results: The objects (n = 90) were divided into three groups: COPD group (patients in the stable phase; n = 30), SN group (healthy control of smoking with normal lung function group; n = 30), and NSN groups (healthy control of non-smoking with normal lung function group; n = 30). The amounts of CD8+ (32.33 ± 4.23%), CD8+ effector (25.63 ± 8.57%) and CD8+memory (11.94 ± 5.77%) T cell in the COPD group were significantly higher those in the other two groups, while the apoptotic rate was lower in the COPD group (P < 0.05). Significant linear correlations were found of P62/GAPDH (‰) with CD8+, CD8+effector, and CD8+ memory- T cell amounts (P<0.001). Conclusions: Autophagy level is positively and linearly associated with the amounts of CD8+ T cells, suggesting that cell autophagy might be involved in COPD pathogenesis.

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Asthma‐chronic obstructive pulmonary disease overlap: A clinical entity?

Journal of Precision Respiratory Medicine ◽

10.2500/jprm.2020.3.200003 ◽

2020 ◽

Vol 3 (1) ◽

pp. 2-8

Author(s):

Robert A. Wise

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Lung Function ◽

Middle Age ◽

Clinical Manifestations ◽

Normal Lung ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Neutrophilic Inflammation ◽

Normal Lung Function

Asthma and COPD are easily recognizable clinical entities in their characteristic presentations. Asthma is an early-onset disorder characterized by Type 2, eosinophil-predominant, inflammation of the airways and is associated with atopy. COPD presents in middle age and is characterized by neutrophilic inflammation of the airways and is associated with cigarette smoking or biomass fuel exposure. Between exacerbations, asthma typically has normal lung function whereas COPD has incompletely reversible lung function. Approximately one in five patients with either of these disorders will show some features of both COPD and Asthma. This overlap is far more common than can be accounted for by chance concurrence of two common diseases. There are likely genetic and environmental susceptibilities to both disorders, but there is no single pathobiological mechanism that identifies all such overlap patients. Most likely there are numerous predispositions that lead to Asthma-COPD overlap that may be grounded in early childhood or even pre-natal events. Thus, Asthma-COPD overlap is best considered a family of diseases with overlapping clinical manifestations. The future elucidation of these different pathways to Asthma-COPD overlap, in conjunction with highly targeted therapies will aid clinicians in treating these patients.

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Predicted Values for Spirometry may Underestimate Long-Standing Asthma Severity

The Open Respiratory Medicine Journal ◽

10.2174/1874306401610010070 ◽

2016 ◽

Vol 10 (1) ◽

pp. 70-78 ◽

Cited By ~ 1

Author(s):

Bruno Sposato

Keyword(s):

Lung Function ◽

Reference Point ◽

Asthma Severity ◽

Normal Lung ◽

Bronchial Obstruction ◽

Z Score ◽

Lung Function Decline ◽

Normal Lung Function ◽

Z Scores ◽

Predicted Values

Background: Asthma may show an accelerated lung function decline. Asthmatics, although having FEV1 and FEV1/VC (and z-scores) higher than the lower limit of normality, may show a significant FEV1 decline when compared to previous measurements. We assessed how many asymptomatic long-standing asthmatics (LSA) with normal lung function showed a significant FEV1 decline when an older FEV1 was taken as reference point. Methods: 46 well-controlled LSA (age: 48.8±12.1; 23 females) with normal FEV1 and FEV1/VC according to GLI2012 references (FEV1: 94.8±10.1%, z-score:-0.38±0.79; FEV1/VC: 79.3±5.2, z-score:-0.15±0.77) were selected. We considered FEV1 decline, calculated by comparing the latest value to one at least five years older or to the highest predicted value measured at 21 years for females and 23 for males. A FEV1 decline >15% or 30 ml/years was regarded as pathological. Results: When comparing the latest FEV1 to an at least 5-year-older one (mean 8.1±1.4 years between 2 measurements), 14 subjects (30.4%) showed a FEV1 decline <5% (mean: -2.2±2.6%), 19 (41.3%) had a FEV1 5-15% change (mean: -9.2±2.5%) and 13 (28.3%) a FEV1 decrease>15% (mean: -18.3±2.4). Subjects with a FEV1 decline>30 ml/year were 28 (60.8%). When using the highest predicted FEV1 as reference point and declines were corrected by subtracting the physiological decrease, 6 (13%) patients showed a FEV1 decline higher than 15%, whereas asthmatics with a FEV1 loss>30 ml/year were 17 (37%). Conclusion: FEV1 decline calculation may show how severe asthma actually is, avoiding a bronchial obstruction underestimation and a possible under-treatment in lots of apparent “well-controlled” LSA with GLI2012-normal-range lung function values.

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Diagnostic usefulness of impulse oscillometry in adult asthmatics with normal lung function

World Allergy Organization Journal ◽

10.1016/j.waojou.2020.100213 ◽

2020 ◽

Vol 13 (8) ◽

pp. 100213

Author(s):

Sung-Ryeol Kim ◽

Kyungchul Kim ◽

Kyung Hee Park ◽

Jung-Won Park ◽

Jae-Hyun Lee

Keyword(s):

Lung Function ◽

Normal Lung ◽

Impulse Oscillometry ◽

Normal Lung Function ◽

Diagnostic Usefulness

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Hierarchical correction of p-values via an ultrametric tree running Ornstein-Uhlenbeck process

Computational Statistics ◽

10.1007/s00180-021-01148-6 ◽

2021 ◽

Author(s):

Antoine Bichat ◽

Christophe Ambroise ◽

Mahendra Mariadassou

Keyword(s):

Multiple Testing ◽

R Package ◽

Statistical Testing ◽

Uhlenbeck Process ◽

Explanatory Variables ◽

New Associations ◽

Penalized Estimation ◽

Ultrametric Tree ◽

Ornstein Uhlenbeck Process ◽

The Mean

AbstractStatistical testing is classically used as an exploratory tool to search for association between a phenotype and many possible explanatory variables. This approach often leads to multiple testing under dependence. We assume a hierarchical structure between tests via an Ornstein-Uhlenbeck process on a tree. The process correlation structure is used for smoothing the p-values. We design a penalized estimation of the mean of the Ornstein-Uhlenbeck process for p-value computation. The performances of the algorithm are assessed via simulations. Its ability to discover new associations is demonstrated on a metagenomic dataset. The corresponding R package is available from https://github.com/abichat/zazou.

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