Measuring the corticosteroid responsiveness endophenotype in asthmatic patients - 06/08/15
, Ann Chen Wu, MD, MPH b, c, Bernard Rosner, PhD a, Michael J. McGeachie, PhD a, Augusto A. Litonjua, MD, MPH a, Kelan G. Tantisira, MD a, Scott T. Weiss, MD, MS aAbstract |
Background |
Inhaled corticosteroids are the most commonly used controller therapies for asthma, producing treatment responses in 6 clinical phenotypes: lung function, bronchodilator response, airway responsiveness, symptoms, need for oral steroids and frequency of emergency department visits and hospitalizations. We hypothesize that treatment response in all of these phenotypes is modulated by a single quantitative corticosteroid responsiveness endophenotype.
Objective |
We sought to develop a composite phenotype that combines multiple clinical phenotypes to measure corticosteroid responsiveness with high accuracy, stability across populations, and robustness to missing data.
Methods |
We used principal component analysis to determine a composite corticosteroid responsiveness phenotype that we tested in 4 replication populations. We evaluated the relative accuracy with which the composite and clinical phenotypes measure the endophenotype using treatment effect area under the receiver operating characteristic curve (AUC).
Results |
In the study population the composite phenotype measured the endophenotype with an AUC of 0.74, significantly exceeding the AUCs of the 6 individual clinical phenotypes, which ranged from 0.56 (P < .001) to 0.67 (P = .015). In 4 replication populations with a total of 22 clinical phenotypes available, the composite phenotype AUC ranged from 0.69 to 0.73, significantly exceeded the AUCs of 14 phenotypes, and was not significantly exceeded by any single phenotype.
Conclusion |
The composite phenotype measured the endophenotype with higher accuracy, higher stability across populations, and higher robustness to missing data than any clinical phenotype. This should provide the capability to model corticosteroid pharmacologic response and resistance with increased accuracy and reproducibility.
Le texte complet de cet article est disponible en PDF.Key words : Asthma, corticosteroids, drug therapy, endophenotype, pharmacogenetics, pharmacologic response
Abbreviations used : AMSYM, AUC, BDRABPCT, BURSTS, CAMP, EDHOS, ICS, IMPACT, LNPC20, PACT, PC, PCA, PREFEV, ROC, SHARP, SOCS
Plan
| Supported by the National Heart, Lung, and Blood Institute through K08 HL088046 (primary investigator: A. C. Wu), and U01 HL065899 and R01 NR013391 (primary investigator: S. T. Weiss and K. G. Tantisira). |
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| Disclosure of potential conflict of interest: G. L. Clemmer and A. C. Wu have received research support from the National Heart, Lung, and Blood Institute (NHLBI). B. Rosner has received research support from the National Institutes of Health (NIH) and royalties from Cengage Publishing. M. J. McGeachie has received research support from the NHLBI and the Parker B Francis Foundation. A. A. Litonjua has received research support from the NHLBI and royalties from UpToDate and Springer Humana Press. K. G. Tantisira has received research support from the NIH. S. T. Weiss has received research support from the Channing Division of Network Medicine at Brigham and Women's Hospital. |
Vol 136 - N° 2
P. 274 - août 2015 Retour au numéro
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