1 MRC Institute of Hearing Research, Nottingham, England.
2 Institute of Psychiatry, Social, Genetic, and Developmental Research Center, London, England.
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ABSTRACT |
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otitis media; twin studies; twins, dizygotic; twins, monozygotic
Abbreviations: MEDS, middle-ear disease scale; OME, otitis media with effusion; SD, standard deviation; TEDS, Twin Early Developmental Study
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INTRODUCTION |
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Often replicated environmental determinants of otitis media include number of siblings (36
), upper respiratory tract infections (6
9
), and day care attendance (10
13
). These are examples of "shared environment" factors because they are largely shared by children growing up in the same family (14
). In principle, prevention might reduce exposure to such environmental risk factors, although successful prevention seems doubtful when parents would have to forego lifestyle options or work time (15
). Less attention has been paid to the possible genetic component, probably because in a largely benign and eventually resolving condition, genetically based interventions would not be considered. However, in infectious disease more generally, heredity gives people differing susceptibilities to infection. Knowledge of the link between this heritability and particular risk factors could lead in future to the rational targeting of environmental interventions or treatment, for example, by using a biomarker to predict likely persistence as justification for surgical intervention. Such progress could help reduce current international differences in thinking on management. In the United States, surgical intervention is often early and is preceded by antibiotics, but there are issues of possible overintervention and bacterial resistance. In much of Europe, surgical intervention is typically later and is more usually preceded by watchful waiting. In the conservative policy more characteristic of Europe, surgical intervention is largely restricted to those cases with persistent otitis media, which time must elapse to document. However, interventions could come too late to be maximally effective in assisting the child's development. For effective case finding, especially in OME, there is a need for affordable biomarkers, for example, DNA tests of polymorphisms that predict the persistence or recurrence of the condition in advance. For a multifactorial condition, high heritability and understanding the timing of expression in the phenotype helps to prioritize further genetic research from which predictive markers may emerge.
Epidemiologic studies of otitis media have long suggested a familial component in the disease (16, 17
). Two recent twin studies have suggested that otitis media runs in families for genetic reasons rather than for reasons of shared family environment (18
, 19
). In a retrospective self-report study of 2,750 Norwegian adult twin pairs, Kvaerner et al. (18
), using a continuous model-fitting approach, estimated the heritability of ear infections at 0.74 in females but only 0.45 in males. The remainder of the variability in females was explained by nonshared environmental factors. In males, the remaining higher variance was explained by both shared environment (29 percent) and nonshared environment (26 percent) effects. Casselbrant et al. (19
) used a clinical sample of 140 twin pairs, measuring time with middle-ear effusion at ages 1 and 2 years. With the statistical model proposed by DeFries and Fulker (20
), the estimated heritability of time with effusion was 0.73 (p < 0.001). A slight and nonsignificant trend to lower heritability in boys (0.64 vs. 0.79 for girls) was again found.
For more insight into pathogenesis, the heritabilities for the disease at different stages or in its different manifestations need to be studied. We had the opportunity to do this in a large, longitudinal United Kingdom twin study, the Twin Early Development Study (TEDS), coordinated from the Institute of Psychiatry, King's College, London, England. In TEDS, a large community sample of twins has been studied prospectively at ages 2, 3, and 4 years. Including a set of ear infection and airway questions in TEDS enabled us to study trends in heritability and shared environment over time for total symptoms as well as for separate symptoms of acute infection from chronic airway symptoms. The airway questions were included because they are readily answerable and are strongly predictive of persistent OME (21).
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MATERIALS AND METHODS |
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Measures
At age 2 years, seven otitis media questions were available, and at age 3 and 4 years, six items were available. Principal component analysis on all available data at each age yielded a first principal component accounting for 22, 22, and 23 percent of the total variance at years 2, 3, and 4, respectively. All items loaded above 0.45 on this principal component, reflecting high interrelation and the appropriateness of using a total score.
Statistical analyses are reported on the longitudinal twin sample at each age. All twin pairs with unknown zygosity (0.12 percent) as well as twins with missing data on the item scores (18.6 percent) were excluded. We made cross-sectional comparisons to study whether the sample of twins whose parents completed all three questionnaires is representative of the sample of twins available at each age.
Analyses
The twin method is a quasi-experimental design that compares phenotype concordance between monozygotic twins, who are genetically identical, and dizygotic twins, who share, on average, 50 percent of their genes. The heritability coefficient quantifies the genetic effect by expressing the proportion of phenotypic (observed) variance attributable to genetic variation; it approximates a doubling of the difference between the correlations for monozygotic and dizygotic twins. The remaining phenotypic variance can be attributed to two types of environmental influence: shared environment, which makes family members similar, and nonshared environment, which makes them different. Twin within-pair similarity for the phenotype is assumed to be due to genetic factors plus shared environment factors. Nonshared or unique environment is a residual term that includes those environmental factors that make members of a family different from one another, plus error of measurement. Comparison of the within-pair correlations for monozygotic twins with those of dizygotic twins gives estimates for the contribution to phenotype variance from genes additive in their effect, from shared environment, and from unique environment.
In practice, structural equation models are fitted to the variance/covariance matrices rather than to simple comparisons of twin correlations. This gives estimates of genetic and environmental parameters plus confidence intervals (25). The ACE model estimates parameters for additive genetic variance (A), common or shared environment (C), and environmental influences that are not shared (E); it assumes that genetic effects are additive and that monozygotic and dizygotic twins experience equally similar environments (14
).
Two major variants of this model were considered. It is possible that disease transmission plays a role in otitis media, that is, affected status in one child can cause affected status in the other, but conceivably more so for monozygotic than for dizygotic twins. We therefore compared the ACE model with a PACE model, which quantifies the portion of the variance-covariance structure (P) accountable by adding a path from the phenotype of a twin to that of the cotwin. As a second variant, we examined concordance with respect to the most extreme symptoms rather than for the entire distribution; here, people with high total scores (above the 95 percent percentile of the distribution) were selected and compared with their cotwin (20). In addition, comparisons were made between boys and girls, and heritabilities on individual items were analyzed.
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RESULTS |
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The results for the individual items in tables 2 and 3 indicate that, as hypothesized a priori, the four acute infection items (earache, ears leaking pus or mucus, pulling or scratching ears, and red or sore ears) show lower heritability on average (0.57) and greater shared environment (0.18) than do the two chronic airway items (breathing through the mouth and snoring or snorting in sleep). The latter have an estimated heritability of 0.72 and a shared environment estimate of 0.10. Hearing/ignoring lie in a third domain not further discussed here.
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DISCUSSION |
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The overall results are consistent with those in a retrospective report study (16) and a prospective, instrument-based study (17
) in finding a large genetic effect, suggesting that differences in method have limited influence on heritability estimates. However, in contrast to the paper by Kvaerner et al. (18
), we did not find higher heritability in females in our prospective study, and the difference in heritability was not significant in the instrument-based study (17
). The discrepancy between the two large, report-based studies could possibly be explained by differences between populations in the distribution of risk factor genes (with different sex-linkage). However, there are few genetic precedents for such a difference in heritability between the sexes being found in some populations but not in others, so there also may be some memory bias in the data on adults in the paper by Kvaerner et al. on retrospective report related to the closer bonding in girls coupled with a higher awareness of health issues.
Effects of age and symptom domain on heritability
For the total symptom score, genetic influence increased from 2 to 4 years, while the estimates for the shared environment declined. Once maternally conferred immunity wanes by 6 months, the environmental influence of exposure to pathogens becomes strong, and acute otitis media (infection) becomes most prevalent from this age to age 2 years. It is of interest that the heritabilities of the items in both domains (acute infections and airway/anatomic problems) increase with time. This may be due to the necessity of an infection to reveal the airway problem, and it remains consistent with the difference in heritability between the symptom areas.
Symptoms indicative of airway blockage showed higher heritability than did those associated with an acute infection. A possible explanation is that the occurrence of airway blockage reflects a second pathogenetic stage with an additional intrinsic component involving genes expressed in the anatomy of the head or the immunologic response of the mucosa. For this blockage to occur, it still needs to be driven by events in the first stage of the common, environmentally determined, respiratory infections. Acute infection must be directly related to an environmental exposure, although the initial immunoglobulin A and immunoglobulin G response (27, 28
) can display genetic susceptibility. The initial ability of the immune system to counter pathogens could be expected to have low heritability and moderate, shared environmental influence. This is because development of the immune system is partly determined by experiences shared by two children growing up in the same family, including similarity of exposure to viruses and bacteria. However, the genes seem to assert their influence on the response to the environmental exposure increasingly as the immune system matures. The environment, in the original sense of what is outside the organism, is closer to the first pathogenetic stage, so the first stage should display lower heritability and greater shared environment than the second stage, as we indeed find.
The two-domain account of symptoms advanced here (acute ear infection and chronic airway blockage) justifies more detailed genetic analyses in which specific risk factors are also documented. Our results, replicated at ages 2, 3, and 4 years, show greater heritability for chronic airway blockage than for acute ear infection. This suggests that the candidate gene approach to susceptibility in otitis media would do well to consider both of these domains rather than undifferentiated otitis media. Meanwhile, the findings can be used clinically by including questions about family history and chronic airway blockage as well as about acute ear symptoms, especially in the older (3 years) child suspect for acute otitis media or OME. In children aged 2 years and less, it is more worthwhile to establishand subsequently minimizea history of exposure.
With richer questionnaire data (five or more items per domain), it would be possible to extract several domain factors and rotate them for maximum independence. Rotated factors usually permit easier interpretation than second and third principal components do because principal components often approximate rather abstract differences or ratios between the factors when the latter are considered as absolute construct scores. Here, however, we simply required a rational basis for valid and reliable reduction of six to seven items to a weighted total score representing all aspects of otitis media. For this, the first principal component is an accepted approach making few assumptions and applicable with relatively few items. The two or three per domain are too few for such reduction. The higher heritability for airway problems is consistent across items within domain; at this point, such consistency is more impressive than greater precision from a total domain score.
Use of report data
The strength of otitis media history measured in this study is based on parental report, which might introduce various types of bias. From the literature, we know that, because of low parental alertness to the clues and fluctuations in hearing, reports of recent hearing difficulties by unselected parents predict current actual hearing in audiometry and other disability-related performance measures with only rather low sensitivity (29). However, parental reports of physical symptoms, consultation, and treatment are sufficiently valid to put together a good cumulative picture of an otitis media history (30
, 31
). Alternatively, symptoms reported by parents can be seen as a style of data complementary to objective tests of hearing loss. The major advantages of parental reports are convenience and cost: It becomes possible to assess symptoms in a large community sample and feasible and affordable to follow the children longitudinally at reasonable expense by comparison with frequent testing or physical examinations. In particular, middle-ear status and hearing loss can fluctuate over a period of days, thus limiting the reliability of single, objective measures. The ability of parental responses to integrate information over time offsets their lower precision and reliability and confers enhanced relevance to the clinical condition of concern, that is, longer-term persistent disease. Previous risk factor studies of otitis media confirm the broader validity of parental symptom history reports in large samples (32
). The similarity of the present overall heritabilities to those of Casselbrant et al. similarly calibrate the relevance of the report data to be a more detailed demonstration of the age and domain effects. These would have been much less practical to establish in an instrument-based study.
Do concordances refer to facts about the children or ideas of the parents? For example, it could be argued that parents of monozygotic twins are more likely to report concordant results than are parents of dizygotic twins. However, in another TEDS study on body weight (33), parental reports of children's weight had an 0.77 correlation with actual measures of the twins' weight taken in their homes by testers (216 families in total), and no difference was found between monozygotic and dizygotic twins.
Interpretation and implications
This study was not designed to identify specific environmental influences, such as the influence of caretaking (day care vs. care at home) and having older siblings. If we had been able to control for these factors explicitly, the residual variation might have been reduced. On the other hand, these factors are mostly shared by twins in a family and therefore contribute to the shared environmental influence. In our results, only 20 percent of the variance was explained by such shared environmental factors.
This study has four main strengths: the prospective data acquisition, the large number of subjects, the a priori distinction between two symptom domains in otitis media that turn out to have different heritabilities, and the longitudinal description of the trajectory of heritability and shared environment during the first years of life. A possible limitation of the study is that we do not have medical data on all twins, so we do not know at precisely what incidence and with what accuracy the children with reported symptoms that yielded a particular score would have resulted in clinical cases with recurrent or persistent otitis media, much less a precise diagnosis. However, given the geographic and social biases in health care uptake, omission of this further source of variability could be seen as a virtue.
In conclusion, the results support a strong genetic influence on the chronic airway blockage that is manifest with respiratory infection and is a risk factor for persistent otitis media with effusion. There is less, but still substantial, genetic influence on acute ear infection. Genetic studies distinguishing these related domains are more likely to be informative than univariate studies of otitis media. Heritability increases over time in a way consistent with the known immunology and epidemiology.
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ACKNOWLEDGMENTS |
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The authors thank the parents of the twins in TEDS for making the study possible.
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NOTES |
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REFERENCES |
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