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.

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.

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.

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