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Exhaled Breath Condensate Metabolome Clusters for Endotype Discovery in Asthma

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Exhaled Breath Condensate Metabolome Clusters for Endotype Discovery in Asthma Sinha et al. J Transl Med (2017) 15:262 https://doi.org/10.1186/s12967-017-1365-7 Journal of Translational Medicine RESEARCH Open Access Exhaled breath condensate metabolome clusters for endotype discovery in asthma Anirban Sinha5†, Koundinya Desiraju1,2†, Kunal Aggarwal1, Rintu Kutum1,2, Siddhartha Roy7, Rakesh Lodha3, S. K. Kabra3, Balaram Ghosh1, Tavpritesh Sethi3,6* and Anurag Agrawal1,2,4* Abstract Background: Asthma is a complex, heterogeneous disorder with similar presenting symptoms but with varying underlying pathologies. Exhaled breath condensate (EBC) is a relatively unexplored matrix which refects the signa- tures of respiratory epithelium, but is difcult to normalize for dilution. Methods: Here we explored whether internally normalized global NMR spectrum patterns, combined with machine learning, could be useful for diagnostics or endotype discovery. Nuclear magnetic resonance (NMR) spectroscopy of EBC was performed in 89 asthmatic subjects from a prospective cohort and 20 healthy controls. A random forest classifer was built to diferentiate between asthmatics and healthy controls. Clustering of the spectra was done using k-means to identify potential endotypes. Results: NMR spectra of the EBC could diferentiate between asthmatics and healthy controls with 80% sensitiv- ity and 75% specifcity. Unsupervised clustering within the asthma group resulted in three clusters (n 41,11, and 9). Cluster 1 patients had lower long-term exacerbation scores, when compared with other two clusters.= Cluster 3 patients had lower blood eosinophils and higher neutrophils, when compared with other two clusters with a strong family history of asthma. Conclusion: Asthma clusters derived from NMR spectra of EBC show important clinical and chemical diferences, suggesting this as a useful tool in asthma endotype-discovery. Keywords: Asthma, Endotype, Exhaled breath condensate, NMR spectroscopy, Metabolomics Background mechanism [3]—is a critical step towards personalized Te simplest defnition of a disease is based on symp- therapy. Te discovery of such endotypes may pro- toms and the best defnition of a disease is based on ceed top down, from clinical phenotype to molecular cause. Asthma is variously defned as a disorder of signatures, or bottom up—from molecular signatures recurrent breathlessness and wheezing [1] and as a com- to clinical phenotypes. Studies refecting the airway plex chronic infammatory airway disease [2]. It is now milieu, such as exhaled breath condensate (EBC) com- mostly agreed upon that asthma is a heterogeneous clin- position, appear to be a good place to start for a bot- ical syndrome, which lacks singular pathophysiological tom up approach. A problem with EBC is that it is an explanation. Discovery of asthma endotypes—specifc unknown dilution of the airway lining fuid and while disease phenotype clusters, with a specifc biological various suggestions have been made for normalization, none are reliable [4]. We previously reported the pres- *Correspondence: [email protected]; [email protected] ence of a characteristic trident peak signature in nuclear †Anirban Sinha and Koundinya Desiraju contributed equally to this work magnetic resonance (NMR) of EBC found through 1 Centre of Excellence for Translational Research in Asthma & Lung Disease, CSIR-Institute of Genomics and Integrated Biology, Mall Road, visual inspection of the spectra. Tis peak signature Delhi 110007, India at 7 parts per million (ppm), which was shown to be 3 Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), attributed to the concentration of ammonium ions in New Delhi, India Full list of author information is available at the end of the article the airway milieu was absent in a majority of asthmatics © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sinha et al. J Transl Med (2017) 15:262 Page 2 of 9 while being present in healthy controls [5]. Many other without a break after which the caps are placed and the informative patterns may exist in the NMR spectra but tube carefully tapped to collect the condensate without these are not obvious to the naked eye. Here, we con- contamination. Tey were immediately stored at − 80 °C. sidered the possibility that NMR signatures of EBC, taken together as a whole, rather than broken down into Sample preparation for NMR spectroscopy individual metabolites, could serve as a fngerprint for To every 450 μL of EBC sample, 50 μL of D2O was added endotypes of asthma. While there have been initial stud- for proper locking of the samples (Cambridge Isotope ies about the local metabolomic patterns in the airway Laboratories) in fne 6 mm bore NMR tubes (Wilmad, that could refect the disease pathogenesis, these have LabGlass, Wilmad, NJ). 4,4-dimethyl-4-silapentane- been focused on identifying metabolites and comparing 1-sulfonic acid (DSS) was added in the sample as internal them [6–8]. Given the difculties in compensating for standard and D 2O mixed to obtain the standard spectra variable dilutions and the limitations in accurately iden- against which all other spectra were compared to. tifying all metabolites from mixed spectral signatures, we considered the possibility of directly using the global Acquisition of free induction decay signal spectral pattern. Tis has the advantage of internal rela- Te tube containing the samples were used for obtain- tive referencing of all peaks within a single spectrum, ing the one dimensional (1-D) FID signal using a nuclear minimizing the impact of dilution. However, this has spectrometer (Bruker, 600 MHz, Germany) equipped the disadvantage of creating a high-dimension dataset with a triple resonance (TCI, 1H, 13C, 15N) inverse cryo- with likely strong internal correlations, requiring newer probe. Data were acquired at 256 scans per sample with forms of statistical and computational analyses. Here, a relaxation delay D1 of 2 s. 7.5 µs of 90° pulse width we show for the frst time how global spectral signatures was used with each spectral width measuring from 1 to can be used to yield not only classifers between asthma 4.7 (parts per million), ppm thus generating 16,000 data and healthy subjects, but also to discover clinically rel- points in each free induction delay signal fles per sample. evant metabolome clusters within asthma. Te temperature was fxed at 298 K for the sample runs. Water suppression in 1-D experiments was done using Methods excitation sculpting with gradients (zgesgp pulse pro- Study design gram for 1D solvent suppression). 1H-NMR FID of D2O Te study includes asthmatic children who were part of water well shaken in RTube© [http://respiratoryresearch. an ongoing prospective asthma cohort at All India Insti- com/rtube/] collection tubes was frst obtained to defne tute of Medical Sciences (AIIMS), New Delhi, India. Te any signature eluting from the RTube itself. FID signals research proposal was approved by the Ethics Committee from the same subject recorded at multiple times were of the Institute. Informed consent was obtained from the used to check for the reproducibility of the downstream patients of the asthmatic children and from the healthy spectra. subjects before recruiting them in the study. Statistical analysis Selection of subjects Fourier transformation and pre-processing Asthmatic and control subjects were recruited based on FID signals were transformed using Fourier transfor- American Toracic Society/European Respiratory Soci- mation to get the metabolomic spectra. Automated ety guidelines (ATS/ERS) [9] specifcally using patient phasing and baseline correction were performed using history, presenting symptoms and evaluation of spirom- iNMR software [http://www.inmr.net/index.html] for etry. Subjects were children less than 18 years of age Macintosh. (Table 2). Healthy adult subjects were recruited as con- trols and were non-smokers; pregnant women were Total intensity normalization excluded. Since EBC is a matrix of unknown dilution of constitu- ents, normalization of the spectra was performed for Sample collection each sample using the total intensity normalization Exhaled breath condensate was collected using RTubes in which each spectrum is scaled to have a unit sum as (Respiratory Research, Austin, Texas). RTubes are ster- described in [10]. ile tubes of plastic make with mouthpieces and caps and have a cold metal cylinder surrounding the tube. Te sub- Dynamic adaptive binning (DAB) ject is asked to rinse his/her mouth with water prior to Dynamic adaptive binning [11] was performed to take the maneuver. Nostrils are clipped to avoid nasal contam- care of the peak shifts in the data using the DAB toolbox ination. Subjects are asked to breathe tidally for 10 min in Matlab 2011b. Sinha et al. J Transl Med (2017) 15:262 Page 3 of 9 Supervised classifcation using Random Forest algorithm from healthy controls (Fig. 1b). While some of these peaks Te parameters “mtry” (number of variables sampled at corresponded to metabolites (Additional fle 1: Table S1, each node), “ntree” (number
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