2016 Section 5 Green Book

Familial risk of CRSwNP and CRSsNP

reported, we observed that the proportion of non-Whites was higher in the controls than in the case probands. The randomly-selected controls are representative of the distri- bution of race in Utah whereas in the case population, fewer non-Whites may reflect a difference in access to healthcare and we acknowledge this may be a source of bias. However, as the Utah population is racially homogeneous (predom- inantly 86% White, based on the 2010 census) any bias reflected in our estimates is likely to be minimal. Although the racial composition in the state may provide less underly- ing genetic heterogeneity in future planned genetic studies of CRS, findings may not be generalizable to other pop- ulations, and future studies are needed to define CRS in non-White communities. A major challenge in population-wide CRS research us- ing medical records is the accuracy of CRS diagnoses from claims data, which may be questionable. Hsu et al. 24 demonstrated that accuracy of diagnosis in a study population compiled using billing codes generally asso- ciated with CRS can be as poor as 54%. However, ac- curacy was substantially improved when diagnostic crite- ria included otolaryngologic or allergy-immunology spe- cialty evaluation, specific sinus surgery CPT codes, and the exclusion of CF diagnoses. 24 We therefore similarly used strict inclusion and exclusion criteria that portends a higher likelihood of specialty confirmation of diagno- sis. We verified this through a chart review and found a high PPV based on stringent CRS diagnostic parame- ters. We recognize that requiring probands and families to have had surgery for their CRS to be included in the study population likely selects for more severe CRS phe- notypes. By requiring surgery as an inclusion criterion, we may also be selecting for those with greater access to healthcare, although both major healthcare systems in- cluded in this database deliver a significant portion of their care as charity. Notwithstanding these drawbacks, we be- lieve that improving the accuracy of diagnosis in cases and controls was of utmost importance and offsets the limitations. Our sensitivity and specificity analysis demonstrates that in a database study of tens of thousands of patients, the presence or absence of coding for nasal polyposis (ICD- 9-CM 417.x) has some inherent limitations in regards to accuracy. Although still relatively high (71%), diminished accuracy compared to our ability to correctly identify CRS

(regardless of polyp status) may limit the validity of the CRSsNP and CRSwNP comparisons, yet the large sample size appears to have overcome any misclassification error in polyp diagnosis. The gender differences seen between CRSsNP and CRSwNP underscore the validity of our re- sults inasmuch as they confirm previous studies. 25,26 As we learn more about CRS, the differentiation into CRSsNP and CRSwNP may prove to be too simplistic and may even have significant overlap. More sophisticated CRS classifications based on inflammatory patterns or other molecular signatures may help us better differentiate this complex condition. For the years covered in this analy- sis, CRSsNP and CRSwNP were the “state of the art.” We nonetheless recognize that as we move into a more prospec- tive genetic analysis of CRSsNP versus CRSwNP, greater attention will need to be paid to accurately subclassifying CRS. Conclusion Although a clear understanding of the etiology of CRS still eludes us, this study firmly establishes a familial basis. These findings set the stage for future studies, in which high-risk pedigrees will be identified to further elucidate susceptibil- ity genes, in conjunction with investigations of comorbid disease and environmental exposures. A better understand- ing of the genetic susceptibility of CRS could clarify the underlying pathophysiology and lead to the development of more effective, targeted treatments. Acknowledgments We thank the Pedigree and Population Resource, funded by the Huntsman Cancer Foundation, for its role in the ongo- ing collection, maintenance and support of the Utah Pop- ulation Database (UPDB). The UPDB is also supported by Award Number P30CA042014 from the National Cancer Institute. The content of this study is solely the responsi- bility of the authors and does not necessarily represent the official views of the National Cancer Institute or the Na- tional Institutes of Health. No outside funding or material support was used for the design and conduct of this re- search study; for the collection, management, analysis, and interpretation of the data; or for the preparation, approval, or submission of the manuscript.

References 1. Noone PG, Leigh MW, Sannuti A, et al. Primary cil- iary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med . 2004;169:459–467. 2. Wang X, Kim J, McWilliams R, Cutting GR. Increased prevalence of chronic rhinosinusitis in carriers of a cys- tic fibrosis mutation. Arch Otolaryngol Head Neck Surg . 2005;131:237–240. 3. Kim SI, Kim SJ, Shin SY, Lee KH, Kim SW, Cho JS. Comparison analysis of hered- ity aspect on allergic rhinitis . European Rhinol- ogy Society Conference, Amsterdam: The Nether- lands; 2014. http://erscongress.eu/abstract/129/ERS- 0990. Accessed December 6, 2014. 4. Hsu J, Avila PC, Kern RC, Hayes MG, Schleimer RP, Pinto JM. Genetics of chronic rhinosinusitis: state of

the field and directions forward. J Allergy Clin Im- munol . 2013;131:977–993, 993.e1–993.e5. 5. Greisner WA 3rd, Settipane GA. Hereditary factor for nasal polyps. Allergy Asthma Proc . 1996;17:283– 286. 6. Cohen NA, Widelitz JS, Chiu AG, Palmer JN, Kennedy DW. Familial aggregation of sinonasal polyps correlates with severity of disease. Otolaryn- gol Head Neck Surg . 2006;134:601–604. 7. Adappa ND, Howland TJ, Palmer JN, et al. Ge- netics of the taste receptor T2R38 correlates with chronic rhinosinusitis necessitating surgical inter- vention. Int Forum Allergy Rhinol . 2013;3:184– 187.

8. Skolnick M, Bean L, Dintelman S, Mineau G. A com- puterized family history database system. Sociol Social Res . 1979;63:506–523. 9. Castano R, Boss´e Y, Endam LM, Filali-Mouhim A, Desrosiers M. c-MET pathway involvement in chronic rhinosinusitis: a genetic association analysis. Oto- laryngol Head Neck Surg . 2010;142:665–671. 10. Kerber RA, O’Brien E. A cohort study of cancer risk in relation to family histories of cancer in the Utah population database. Cancer . 2005;103:1906–1915. 11. Samadder NJ, Curtin K, Tuohy TM, et al. In- creased risk of colorectal neoplasia among fam- ily members of patients with colorectal cancer: a population-based study in Utah. Gastroenterology . 2014;147:814–821.e5; quiz 821.e15–821.e16.

International Forum of Allergy & Rhinology, Vol. 5, No. 4, April 2015

76