The Heritability of Otitis Media
A Twin and Triplet Study
Context Anatomical, physiological, and epidemiological data indicate that there may
be a significant genetic component to prolonged time with and recurrent episodes ofotitis media in children.
Objective To determine the genetic component of time with and episodes of middle
ear effusion and acute otitis media (AOM) during the first 2 years of life.
Design Prospective twin and triplet cohort study with enrollment from 1982 through
Setting Otitis Media Research Center in the ear, nose, and throat clinic of Chil-
dren’s Hospital of Pittsburgh, Pittsburgh, Pa.
THEPREDISPOSITIONOFINFANTS PatientsAtotalof168healthysame-sextwinand7tripletsetswererecruitedwithin
the first 2 months of life; zygosity results were available for 140 sets; 138 (99%) of these were followed up for 1 year and 126 (90%) for 2 years.
Main Outcome Measures Proportion of time with middle ear effusion, episodes
of middle ear effusion, and episodes of AOM by zygosity status.
Results At the 2-year end point, the estimate of heritability of time with middle ear
effusion was 0.73 (PϽ.001). The estimates of discordance for 3 or more episodes of middle ear effusion were 0.04 for monozygotic twins and 0.37 for dizygotic twins (P = .01). The estimate of discordance of an episode of AOM in monozygotic twinswas 0.04 compared with 0.49 in dizygotic twins (P = .005).
Conclusions Our study suggests there is a strong genetic component to the amount
tion of genetics to a disease, because the of time with middle ear effusion and episodes of middle ear effusion and AOM in children.
ronmental factors is significantlyreduced. The children in our monozy- Subjects and Enrollment
rolled. A child was ineligible if he or she and throat clinic at Children’s Hospital tions, a medical condition with a predis- cantly higher concordance rate of a trait position for otitis media (OM) (eg, cleft gee-Women’s Hospital in Pittsburgh, Pa, the largest maternity hospital in the area, Author Affiliations: Department of Otolaryngol-
ogy, University of Pittsburgh School of Medicine (Drs Casselbrant, Mandel, and Bluestone); Department of Pediatric Otolaryngology, Children’s Hospital of Pitts-burgh (Drs Casselbrant, Mandel, and Bluestone, and sets of triplets were born. Some sets were Ms Fall); and the Departments of Biostatistics (Dr Rock- ette and Ms Kurs-Lasky) and Human Genetics (Dr Fer-rell), University of Pittsburgh, Pittsburgh, Pa.
Corresponding Author and Reprints: Margaretha L.
Casselbrant, MD, PhD, Children’s Hospital of Pitts- burgh, Department of Pediatric Otolaryngology, 3705Fifth Avenue and DeSoto Street, Pittsburgh, PA 15213 See also p 2167 and Patient Page.
1999 American Medical Association. All rights reserved.
JAMA, December 8, 1999—Vol 282, No. 22 2125
mittee at Children’s Hospital of Pitts- tive medication, such as cefaclor, eryth- Definition of Disease. The diagno-
Entry and Follow-up Evaluation
otalgia, or irritability) and 1 sign (ery- initially for episodes of AOM and OME.
Statistical Methods. The primary
creased mobility or the presence of fluid interval history and pneumatic otoscopy.
either OME or AOM. The term OM rep- tween the dates of 2 successive visits.
Middle ear status for the entire interval Zygosity Testing. During the pilot
ear disease, he or she was treated accord- ear status at the visit within the inter- sessed using a battery of 6 red blood cell Specific Methods of Testing
Acoustic Immittance Measurements.
tis Media Research Center clinic was per- action–based methods.21 Each battery of cause the variable of interest was the pro- Treatment Intervention. In Twin
transformation was applied to the data.
2126 JAMA, December 8, 1999—Vol 282, No. 22
1999 American Medical Association. All rights reserved.
Table 1. Distribution of Twin or Triplet Sets According to Follow-up Time and Zygosity*
Sets With Follow-up, No.
were excluded from the DeFries-Fulker model. This had little effect on Age 1 Year
Age 2 Years
the analysis at later ages, because fewer Sets With
5 sets of triplets, we fit all possible re- ing of 2 members of the triplet set, which lations. For the estimates of the genetic *Numbers in parentheses are number of sets in which Ն1 sib had middle ear effusion by end point. DZ indicates di- zygotic children; MZ, monozygotic children; and NA, not applicable.
component (h2), shared environment(c2), and the corresponding signifi-cance levels, we used a weighted- Table 2. Average Proportion of Time With
Middle Ear Effusion by 3-Month Age Interval
Proportion of Time (n)†
dred twenty-six twin or triplet sets were Interval,
more unbiased estimate of heritability.
*The intervals were defined in terms of nonoverlapping days (eg, 0-91 days, 92-182 days) but for convenience arelisted here in months. Average is weighted by time at insertion was 21.2 months in the DZgroup and 21.4 months in the MZ Proportion of Time With MEE
According to Zygosity Status
Accrual and Follow-up
TABLE 2 summarizes the average pro-
Distribution of Selected
7 triplet sets (33 twin pairs in Twin Study Subject Characteristics
Study II) were recruited within the first (TABLE 1). Only same-sex twin or trip-
at Magee-Women’s Hospital. In the pres- (60% and 45%, respectively, P = .08).
twin or triplet sets in the following sub- (66%) of the 35 twin or triplet sets with family, ear disease in natural family, ear prior to zygosity testing at 1 year of age.
group was 0.21 (P = .99). The average and 0.23 in the MZ group (P = .72).
1999 American Medical Association. All rights reserved.
JAMA, December 8, 1999—Vol 282, No. 22 2127
Differences in MEE
Within a Twin or Triplet Set
Difference in Proportion of Time With
(P = .24). The mean difference in the MEE. No episodes of MEE were ob-
sets (P = .46). In the remaining sets, other at 6 (P = .04), 12 (P = .04), 18 bers of the set in the proportion of time (PϽ.001), and 24 (PϽ.001) months.
(12%) of 76 MZ sets (P = .61) by 2 years Recurrent Episodes of MEE. The oc-
(P = .14). An absolute difference in pro- (13%) MZ sets (P = .20). An absolute sets as defined by Olson et al24 were ob- Figure 1. Correlation of Time With MEE
(6%) MZ sets (P = .03). The mean dif- or triplet sets (P = .01), based on the 126 Recurrent Episodes of AOM. The
Comparison of the Correlation
Within MZ and DZ Sets. The correla-
is shown in FIGURE 1. Estimates of cor-
Correlation of cumulative proportion of time withmiddle ear effusion (MEE) by ages 3, 6, 9, 12, 15, 18, 21, and 24 months for children within a twin or trip- Estimate of Heritability. By 1 year,
let set by zygosity. Restricted to twin or triplet sets inwhich at least 1 child had MEE.
there were 111 twin or triplet sets inwhich at least 1 child had 1 or more epi-sodes of MEE; by 2 years, this was true Figure 2. Proportion of Time With MEE by 24 Months of Age for Sib 1 vs Sib 2 Within a
for 126 twin or triplet sets. FIGURE 2
plots the proportion of time with MEEduring the first 2 years of 1 child (x- axis) vs the proportion of time with MEEfor a second child (y-axis) of a twin or triplet set. The slopes of the lines fitted to the data would be expected to be simi- but if there is a genetic component of dis-ease, one would expect the variability to study, the variability of sibs in DZ sets ability of sibs in MZ sets (P = .007).
Scatterplot of proportion of time with middle ear effusion (MEE) by 24 months of age between children within was 0.76 (P = .02) and the estimate of a twin or triplet set (sib 1 vs sib 2). Restricted to sib pairs in which at least 1 child had MEE. Left, Dizygotic twin or triplet sets; right, monozygotic twin or triplet sets.
cause c2 was not significant, it was elimi- 2128 JAMA, December 8, 1999—Vol 282, No. 22
1999 American Medical Association. All rights reserved.
ant estimate of h2 was 0.73 (PϽ.001).
(PϽ.001) and 0.79 (PϽ.001), respec- blinded to their zygosity status. However, lower heritability estimate, the test for interaction was not statistically signifi- cant (P = .36), indicating that the dif- ference in the heritability estimates be- sive environment.” A retrospective self- single accepted definition of ear disease during the first 2 years of life is an issue in the analysis of the present study. Other proposed that have better statistical prop- (PϽ.001) by age 24 months, and the familiar framework of a linear regression gests that genetics plays a large role in that hereditary factors play a role in the CONCLUSION
toid process, a trait believed to be linked cordance in DZ twins than in MZ twins.
ease state, eliminating dependency on re- Funding/Support: This study was supported by grants
DCO1260 and DC02490 from the National Institute on Deafness and Other Communication Disorders, Na-tional Institutes of Health.
ease. Also, the children were treated for Acknowledgment: We would like to thank our col-
leagues for their help in conducting this study: Gail Barrett, CMA; Dorothy A. Nixon, RN; JenniferKarabin, RN; Darleen Noah, MBA; Marilyn Field, MPM; Lillian Martin, ART; Susan Strelinsky; and REFERENCES
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Let your bookcases and your shelves be your gar-dens and your pleasure-grounds. Pluck the fruit thatgrows therein, gather the roses, the spices and themyrrh.
2130 JAMA, December 8, 1999—Vol 282, No. 22
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