*University of Helsinki. A Population-based Study of Bronchial Asthma in Adult Twin Pairs

Transcription

1 A Population-based Study of Bronchial Asthma in Adult Twin Pairs Markku M. Nieminen, M.D.;t jaakko Kaprio, M.D.;t and Markku Koskenouo, M.D. Aggregation of cases of bronchial asthma in adult twin pairs was studied in the nationwide Finnish twin cohort consisting of 13,888 adult monozygotic (MZ) and same-sex dizygotic (DZ) pairs. Cases of asthma were ascertained by recordlinkage from three sources of data: death certi6cates from the Central Statistical Office; hospital discharges from the nationwide hospital registry; and the nationwide registry for fuuy reimbursed medications of the Social Insurance Institution. A diagnosis of bronchial asthma in one or more of these registers was obtained for 525 (236 men and 289 women) out of 27,776 twin individuals. Among MZ pairs, ten concordant and 138 discordant pairs were identi6ed, while among DZ pairs, 12 concordant and 343 discordant pairs were found. In the whole sample the observed- expected ratio for the number of pairs concordant for bronchial asthma was 4.30 (95 percent con6dence interval [Cll, 2.06 to 7.90) in MZ pairs and 2.61 (95 percent CI, 1.35 to 4.56) in DZ pairs. Using a multifactorial threshold model, we estimated the correlation in liability to asthma as (SE=0.07) in MZ twins and (SE=O.06) in DZ twins, and we obtained a heritability estimate of 35.6 percent. The data also showed a gender difference in asthma heredity, which may, however, be due to chance events affecting the distribution ofconcordant pairs. (Chat 1991; 100:70-5) CI =coafideoce interval; DZ =dizygotic; ICD=Internatiooal Classi8cation of Diseases; MZ = monozygotic; OlE ratio=observed-expected ratio The prevalence of asthma has been reported to be 1.2 to 6.2 percent in adults in the western world. 1-3 Environmental factors, including air pollution, respiratory infections, smoking, and allergens, have an important impact in the development of the disease. Furthermore, genetic factors are believed to playa contributing role in the pathogenesis of asthma, but the genetics of the disease has not been established. There are several previous studies indicating familial aggregation of asthmar':" however, this phenomenon may also be caused by a common environmental factor. In addition, the comparison of the results from different countries is hampered by divergent definitions of asthma used and differences in case finding. There are only a few previous studies on asthma in twins. In 1971, Edfors-Lubs? published the data collected by means of a questionnaire on 7,000 twin pairs in the Swedish Twin Register. She found that the concordance of asthma in monozygotic (MZ) twins, although significantly greater than that in dizygotic (DZ) twins, was only 19 percent, suggesting that the contribution of environmental factors is much higher than had previously been supposed. Hopp and coworkers" investigated by questionnaire 107 pairs of twins and found that MZ twin pairs were not statistically more likely to be positively concordant in having *From the Departmentof Pulmonary Diseases, 'Iampere University Central Hospital, Pikonlinna; the Department of Public Health, University of Helsinki; and the Department of Public Health, Clinical Institute, University ofturku, Turku, Finland. This study was supported by a grant from the Foundation of Ida Montin. ttampere University Central Hospital. *University of Helsinki. University ofturku. Manuscript received August 28; revision accepted November 29. Reprint requests: Dr. Nieminen, Pulmonary Diseases, Tampere University Central Hospital, Pikonlinna, Finland asthma when compared to DZ twins. Redline and colleagues" studied by questionnaire the history of asthma in 207 twin pairs and found the concordance rate to be significantly higher among the MZ twins than in the DZ twins. A recent report by Hopper and co-workers'?from a postal questionnaire studyin3,808 pairs of adult twins in Australia also suggested that genetic factors are implicated in both hay fever and asthma and that some of these genetic factors are common to both traits. The purpose of the present study was to estimate the hereditary liability to bronchial asthma on the basis of the population-based Finnish Twin Cohort. Cases of asthma (diagnosis based on a clinical evaluation) were ascertained by record-linkage to the nationwide registers of death certificates, hospital admissions, and free medications. TheFinnish 1Win Cohort MATERIALS AND METHODS The Finnish Twin Cohort consists of all Finnish twin pairs of the same gender born before 1958and with both twins alive in The twin pairs were selected from the Central Population Registry of Finland in In August to October 1975, a questionnaire was mailed to all pairs then alive. The overall response rate was 89 percent. Twin zygosity was determined by examining the responses of both members of each twin pair to two questions on the similarity of appearance at school age. A set of decision rules was used to classify the twin pairs as MZ, DZ, or of undetermined zygosity.the items on the questionnaire used to assign zygosity are similar to those employed in other large twin samples Their validity in the Finnish cohort was confirmed by blood-typing a subsample of 104 twin pairs living in the Helsinki area. 1I Some 93 percent of all respondent pairs could be classified as MZ or DZ, with only slight probability of misclassification (1.7 percent). A total of 13,888 (4,307 MZ and 9,581 DZ) pairs, aged 18 to 70+ years at baseline testing, were identified. The roughly 2:1 ratio of D7JMZ found for older 70 Bronchial Asthmain AduiltTwinPaIrs (Nieminen, Kaprio,Koskenvuo)

2 twins in the Finnish Cohort reflects the elevated rate of DZ twinning typical in the Scandinavian countries in the first halfof this century, as we have discussed in detail elsewhere." The total number of twin pairs included in the present study ~ a s. 1 3, Table I-Cumulative IncidBrace ofbronchitjl ABthmtJin Twin IndividaalB by Age, Sa, and Zygoaity Incidence, % Definition ofcases Hospitalization Data. The National Board of Health in Finland has kept a registry of hospital admission records since It covers all admissions (ie, all patients treated at a hospital for 15 hours or more) from the hospitals in Finland. The diagnoses at admission are assigned by physicians treating the patient using the ICD.1f Up to four different diagnoses can be used per patient at each admission. Registry data for the years of 1972 to 1985 were linked (with permission from the National Board of Health) with the twin cohort using the unique identi6cation number assigned to each Finnish citizen. For the present study the individual was considered to have bronchial asthma if the admission diagnostic code of any of the four diagnoses in the registry was 493 (bronchial asthma, ICD-8). The reliability of the diagnostic codes of the admission registry of Finland has been found to be satisfactory for epidemiologic purposes. li5 Registry for Reimbursement of Free Medication of the Social Insurance Institution. Patients with chronic bronchial asthma have been provided with medications that are free of charge in Finland from 1970 onwards. The prerequisite for such a reimbursement of costs of medication directly to the pharmacy by the Social Insurance Institution is that the patient's application, which is based on a detailed medical certi6cate about his disease, is approved by the Social Insurance Institution. Thisregistry is virtually complete with regard to working-aged patients with permanent medications due to bronchial asthma. For the present study, data on free medication with a starting date for the reimbursement of medication costs for bronchial asthma during the years of 1970 to 1987 were linked to the twin cohort. Mortality Data. Data on cause of death were available for 1975 to 1985 from the Central Statistical Office Cause-of-Death Bureau. Statistical Analy.ris The age of all pairs at the end of the follow-up period (1985)was used in the analyses. The individual and pairwise cumulative incidences were calculated separately for both MZ and DZ men and women in groups aged 28 to 39, 40 to 49, 50 to 59, 60 to 69, 70 to 79, and 80 years and over. The expected numbers of concordant pairs were calculated in these age groups using the corresponding cumulative incidences of individuals for MZ male, MZ female, DZ male, and DZ female twins. Age-adjustment was made using the direct method. The results were also computed for wider dichotomized categories: 28 to 59 years and 60 years and over. A 95 percent Men \\Omen Age in MZ DZ MZ DZ \mabie 1985, yr (0=4,100) (0=9,810) (0=4,514) (0=9,352) Incidence, percent ~ and before 80t Age-adjusted No. ofcases confidence interval (CI) for the observed-expected (OlE) ratio was calculated according to Fisher. ~ To permit comparison to earlier studies, in which the number of unaffected pairs was unknown, probandwise (the proportion of all probands that belonged to concordant pairs) and pairwise (the proportion of pairs that were concordant for disease) concordance rates were computed.- ~used a multifactorial model to estimate the genetic contribution to the predisposition to disease. Weassume that there is a normally distributed liability to disease with a disease threshold. Tetrachoric correlations were computed to obtain the correlation in liability between twins of MZ and DZ pairs from the 2 x 2 tables of disease occurrence in pairs. Then, estimates of the proportion of phenotypic variance due to genetic effects (heritability) were calculated as twice the difference of MZ and DZ correlations. 28 RESULTS Among the 27,776 twin individuals of the Finnish Twin Cohort, bronchial asthma was diagnosed among 525 persons during the study period: 348 had been di hospitalized, 407 had fully reimbursed me ications, and 230were found in both registers. Bronchial asthma was the underlying cause of death in ten twins during the period of 1975 to 1985, nine of whom were found also in the other registers. The cumulative incidence of bronchial asthma was 1.8 percent in MZ and 1.7 percent in DZ male Table i-number ofconcordant lbinfor Bronchial A8thmtJ and OlE Ratio afconcordant Twin lbirsfor Cumulative IncidBrace OlE Ratio (No. of Concordant Pairs) Men Women Ratio of OlE (MZ) to OlE (DZ) Age in Birth Year 1985, yr MZ DZ MZ DZ Men Women (1) o (0) o (0) 2.58 (1) (1) 7.58 (2) 8.20 (1) 3.01 (1) o (0) 3.57 (2) (1) (0) (1) 2.21 (2) 5.05 (4) 3.82 (2) o (0) 6.06 (1) 4.75 (1) 1.66 (1) and before 80+ o (0) o (0) o (0) o (0) (2) 4.44 (4) 7.84 (2) 1.44 (2) and before (1) 2.72 (3) 4.46 (5) 2.49 (3) Total 3.15 (3) 3.49 (7) 5.08 (7) 1.93 (5) CHEST I 100 I 1 I J U 1991 L ~ 71

3 Table 3-NumberofConcordant and Discordant lbi,., and ProbandwiBe Concordance Bate. by Age, Gender, and Zygosity Gender and Age in Concordant Discordant Zygosity 1985, yr Pairs Pairs Men MZ All 3 67 DZ All Women MZ All 7 71 DZ All Total MZ All DZ All individuals and was 1.9 percent in MZ and 2.2 percent in DZ female individuals (Table 1). The highest cumulative incidence was found among persons aged 60 to 69 years at the end of follow-up. In younger adults, there was an increase in incidence by ten-year age groups. The age trends were similar in all gender and zygosity groups. In the whole sample the OlE ratio for the number of pairs concordant for bronchial asthma was greater for MZ pairs (ratio =4.30; 95 percent CI, 2.06 to 7.90) than for DZ pairs (ratio = 2.61; 95 percent CI, 1.35 to 4.56). This was true for all four age (28 to 59 years vs 60 years and over) and gender groups except for men aged 60 years and over (Table 2). The OlE ratio was 3.15 (95 percent CI, 0.65 to 9.22) in MZ and 3.49 (95 percent CI, 1.40 to 7.19) in DZ male pairs. The corresponding figures for female pairs were 5.08 (95 percent CI, 2.04 to 10.5) and 1.93 (95 percent CI, 0.63 to 4.51). While there were small numbers of concordant pairs in ten-year age classes, there was an overall trend of higher OlE ratios among younger subjects compared with older subjects. Table 4-Tetrachoric Correlations in Liability for MZ and DZ Twins and Heritability Estimate. for Bronchial Asthma in Finnish Adult Population Correlation (SE) Sex and Age, yr MZ DZ Heritability* Men (0.16) (0.11) (0.24) (0.15) Total (0.13) (0.09) Women (0.16) (0.13) (0.22) (0.14) Total (0.13) (0.09) Men and women (0.08) (0.06) *h ll = 2(rwz- roj 72 Unaffected Concordance Total Persons Pairs Rate Cases at Risk 1, , , ,100 3, , ,800 4, ,810 1, , ,008 2, ,514 3, , ,108 4, ,352 4, ,614 9, ,162 In total, 22 pairs were concordant for bronchial asthma (10 MZ and 12 DZ pairs), while 481 pairs were discordant for the disease (138 MZ and 343 DZ pairs) (Table 3). Probandwise concordance rates varied from 0.03 in young (28 to 59 years old) DZ women to over 0.20 in old (60 years and over) MZ women. Based on the data in Table 3, correlations in liability for MZ and DZ pairs were computed (Table 4). In the whole study sample the heritability estimate was 35.6 percent. Marked gender differences were found, with highest correlations in MZ women and lowest in DZ women, yielding a heritability estimate of 67.8 percent in women. Among men the MZ and DZ correlations were significantly increased but were similar in magnitude to each other, thus giving rise to a heritability estimate of zero in men. DISCUSSION The significance of this study rests on two matters: (1) the quality of the studied population; and (2) the methods used to identify subjects with bronchial asthma. The Finnish Twin Cohort was compiled from the Central Population Registry of Finland and so represents the whole population very well. The possible selective effect of twinshipll has a minor effect on epidemiologic variables concerning the population data. An unlimited representative sample like this is the most reliable type of twin study'? to investigate the genetic component in the etiology of diseases. With a large nationwide twin panel like ours, two sources of error can be avoided. First, this study was based on a cohort compiled from the entire population. This decreases the risk of sampling error in clinicbased recruitment, which can lead to an increased ascertainment of disease in concordant compared to discordant twin pairs.31 Secondly, our twin cohort is large enough to reduce the chance of random error in BronchialAsthmain AduiltTwinPairs(Nieminen, Kaprio,Koskenvuo)

4 our findings. Most other twin studies in the field of bronchial asthma have been based on relatively small numbers. The follow-up of hospitalizations because of bronchial asthma (code 493, ICD-8) covered in principle all admissions to hospitals over a period of 14 years. The actual coverage evidently is good using this method, as demonstrated by another study with a similar recordlinkage procedure.p but patients with mild bronchial asthma have not been listed in the hospital admission data if hospitalization is not needed. The representativeness of our combined follow-up data (including the national medication registry) is probably good, because the cumulative incidence of individuals in our sample is similar to the results of Finnish population studies, which will be discussed subsequently. The cumulative incidence and the sex distribution of asthma found in this study agree with the previous epidemiologic reports from Scandinavia in 1960 to 1980s. From Finland, Huhtf" reported in 1965 a cumulative incidence of asthma in adults (age range, 40 to 64 years) of 1.1 percent, and Alanko'? in 1970 reported a value of 1.4 percent (age range, 10 to 59 years) with an M/F ratio of 0.8. In 1980, Haahtela and colleagues" found a' prevalence incidence as high as 4.2 percent, with an M/F ratio of 1.9; however, their material consisted of adolescents with an age range of 15 to 17 years, and most surveys in children in Western countries have reported the prevalence of asthma to be higher in boys, with some MIF ratios exceeding In 1971, the questionnaire analysis of the Swedish Twin Register's material including 14,000 patients, with an age range of 46 to 85 years, showed that the cumulative incidence of asthma was 3.8 percent," and the MIF ratio was 0.9. In 1974, Kiviloog and coworkers" found in a Swedish study of 24,800 subjects (age range of35 to 54 years) a cumulative incidence of 2.6 percent with an MIF ratio of 1.1. In a recent report from Swedish conscripts' examinations (about 55,000 men 18 years old) in 1981, the prevalence of asthma was 2.8 percent." In comparison, in Finnish conscripts in 1989, the prevalence of asthma was 1.8 percent.37 In the present study the estimated heritability of asthma was 35.6 percent in the whole material. An etiologic influence of heredity in the disease has been assumed in the past by several authors. The first extensive approach to the study of genetic factors in asthma was made by Schwartz38 in In his material the incidence of asthma in the 1,634 relatives of the 191 asthmatic subjects was 6.6 percent, but in the 1,790 relatives of the control group, the incidence was only 1.0 percent. Later studies have confirmed the familial aggregation of asthma.r" especially in highly inbred populations.39,40 In the previous reports on asthma in twins, the results have been partly conhicting. Edfors-Lubs" found in the Swedish twin pairs (born in 1886 to 1925; age range of 46 to 85 years) a concordance of 19 percent in 2,400 pairs of MZ twins and a concordance of 4.8 percent in 4,300 pairs of DZ twins. Hopp and eo-workers" studied the data on 107 pairs of twins and found that the MZ twin pairs were not statistically more likely to be positively concordant to have asthma (20 percent) when compared with the DZ twins (9 percent). Redline and eo-workers" observed in 207 twin pairs that the concordance rate for reporting a history of asthma was significantly higher among the MZ twins (36 percent) than the DZ twins (0 percent). However, in their material" the prevalence of asthma was higher than in other studies (5.8 percent for the MZ twins and 9.6 percent for the DZ twins). In the Finnish Twin Cohort, we found the probandwise concordance rate of asthma to be 12.7 percent among the MZ twins and 6.5 percent in the DZ twins. In a recent study by Hopper and co-workers'? performed with a postal questionnaire to 3,808 pairs (1,799 MZ) of adult Australian twins aged 18 years and over, the prevalence of "ever had asthma" was high (13 percent). For the evaluation of data, a log-linear model for pedigree analysis was used," and the correlations in theoretical liabilities to asthma were 0.33 in MZ female, 0.48 in MZ male, 0.12 in DZ female, and 0.09 in DZ male pairs. Thus, there was a gender difference in MZ pairs but not in DZ pairs, which may, however, be due to the marked underrepresentation of male pairs (1:2 ratio to female pairs) in the material. Furthermore, it was calculated that common genetic factors account for about 50 percent of the correlation between the liabilities to hay fever and asthma. A basic difference in our twin study compared to the previous ones was the mode of diagnosis of asthma. The earlier evaluations of twin materials,":" like most epidemiologic studies of asthma' have been based upon questionnaire sources, in which the de6nition of who is asthmatic has been left either to patients themselves or to their parents. The subjects have been asked to answer the question "Have you ever had asthma?" and in some questionnaires also "Was it confirmed by a doctor?" In the past, there have also been major differences among clinicians and epidemiologists in the de6nition or diagnostic criteria of asthma; and terms of wheezing, bronchial hyperreactivity, and asthma have been used confusingly1 First of all, there are two common situations in which variable airhow obstruction may falsely be termed asthma, namely, episodes of "wheezy bronchitis" in children and acute exacerbations of chronic bronchitis accompanied by wheeze in adults. In our material the diagnosis of asthma is based on a clinical evaluation by the attending doctor. Since the 1960s, the diagnostic measures of bronchial asthma in CHEST I 100 I 1 I JUL'{

5 our country have taken place according to the guidelines defined by the American Thoracic Society42 Required as the cornerstones for this diagnosis have been a typical history with chronic or repeated symptoms and a documented variation in the forced expiratory Howrate in one second or in the peak expiratory How rate ~ 2percent 0 spontaneously or ~ 1percent 5 after medication or, alternatively; a 15 percent decrease in airflow after allergen provocation or in an exercise test. This major difference in case finding compared to the earlier three twin reports on bronchial asthma may partly explain the divergent results. In fact, the poor correspondence between the diagnosis of asthma made by physicians from a clinical evaluation and that obtained by a questionnaire was recently found by Cerveri et al. 43 Their data showed that from the subjects defined as asthmatic on the basis of the questionnaire, only 44.8 percent were later clinically proven to be asthmatic. The mode of inheritance in asthma is unclear. On the basis of previous studies on the incidence of asthma in families 5 38 and in twins," it has been suggested to be dominant with incomplete penetration or polygenic inheritance of the disease. We would support the latter theory, which is also suggested by the heterogeneity of asthma. One genetic component in asthma has been linked with atopy and high IgE levels. These are features especially in the early onset of asthma and may explain the marked sex difference in the prevalence of childhood asthma.fr" There is also a greater degree of concordance in the IgE levels in MZ than in DZ twins, which is highest in infancy and early childhood, diminishing with age. 50 Another genetic factor seems to be related to the predisposition to bronchial hyperresponsiveness.s-p which is a cardinal feature of asthma." Furthermore, there are also racial differences in the prevalence of asthma, which may be partly genetic in origin. That is suggested by the high prevalence ratio found in highly inbred populations. 39,4O In addition to a genetic background, however, the present data stress a major environmental influence in the development of asthma in adults. Allergens probably have a major role in childhood asthma, while other nonallergic factors (ie, air pollution, smoking, and respiratory infections) may have a larger impact on the adult onset of asthma in the activation of an inherited predisposition to the disease. In our material, there was a marked gender difference in asthma heredity, which may be due to chance events affecting the distribution of concordant pairs. Among the pairs (3,036 MZ and 6,319 DZ pairs aged 24 years or more) in this same cohort who replied to the 1981 twin questionnaire and who replied to the 74 question "Have you ever been told by a physician that you have asthma?" concordance for self-reported asthma was the same among men and women (unpublished data). The correlation in liability for MZ pairs was 0.55 in both men and women, while the DZ correlation was 0.30 in men and 0.36 in women. Also, the prevalence of asthma in the questionnaire study was of the same order of magnitude as in the present analyses based on medical records. The two measures are not fully comparable, as the questionnaire data are cross-sectional, while the medical records yield cumulative data on incidence over a long period of time. Nonetheless, it indicates that the two sources of information are yielding comparable estimates of the occurrence of asthma in the Finnish adult population. Theoretically, a minor part of the gender difference may be explained by a finding from previous twin studies, ie, that adult identical female twins live together more often than male pairs of DZ pairs, especially at older age. 13 In these few cases the development of asthma might be due to the sharing of a common environment, rather than the influence of heredity; 1.54,55 however, there seems to be a genetic sex-linkedcomponentor components (otherthanatopy and IgE level at childhood) in the inheritance of asthma, which makes female adults more vulnerable to having the disease. In conclusion, the analysis of Finnish nationwide registers linking the twin cohort to death certificates, hospital discharges, and free medications showed that genetic factors playa significant role in the incidence and in the sex distribution of asthma in adults; however, the results also strongly underline a major impact of environmental factors in the development of this disease. REFERENCES 1 Gregg I. Epidemiological aspects. In: Clark T, Godfrey S, eds. Asthma. 2nd ed. London: Chapman and Hall, 1983; Varonier HS. Prevalence of allergy among children and adolescents in Geneva, Switzerland. Respiration 1970; 27(suppl):II Dodge RR, Burrows B. The prevalence and incidence of asthma and asthma-like symptoms in a general population sample. Am Rev Respir Dis 1980; 122: Davis JB, Bulpitt CJ. Atopy and wheeze in children according to parental atopy and family size. Thorax 1981; 36: Sibbald B, Hom MEC, Grey I. A family study of the genetic basis of asthma and wheezing bronchitis. Arch Dis Child 1980; 35: Van Andel PP Jr, Motulsky AG. Frequency and heritability of asthma and allergic rhinitis in college students. Acta Genet 1959; 9: Edfors-Lubs ML. Allergy in 7000 twin pairs. Acta Allergol (Kbh) 1971; 26: HoppRJ, BewtraAK, WattGD, NairNM, TownleyRG. Genetic analysis of allergic disease in twins. J Allergy Clio Immunol 1984; 73: Redlioe S, TIshler P ~Lewitter FI, Tager IB, Munoz A, Speizer FE. Assessment of genetic and nongenetic inhuences on pulmonaryfunction: a twin study. Am Rev RespirDis 1987; 135: BronchialAsthmain AduiltTwinPairs(Nieminen, KBprlo, Koskenvuo)

6 10 Hopper JL, Hannah MC, Macaskill GT, Mathews JD. Twin concordance for a binary trait: 3. A bivariate analysis of hay fever and asthma. Genet Epidemioll990; 7: Kaprio J, Sarna, Koskenvuo M, Rantasalo I. The Finnish Twin Registry: formation and compilation, questionnairestudg zygosity determination procedures and research program. frog Clio Bioi Res 1978; 24B: Kaprio J, Sarna S, Koskenvuo M, Rantasalo I. Baseline characteristics of the Finnish Twin Registry: section 2. History of symptoms and illnesses, use of drugs, physical characteristics, smoking, alcohol and physical activity Helsinki: Department of Public Health Science Publ M37, Kaprio J, Koskenvuo M, Artimo M, Sarna S, Rantasalo I. Baseline characteristics of the Finnish Twin Registry: section 1. Materials, methods, representativeness and results for variables special to twin studies. Helsinki: Department of Public Health Science, Publ M47, Koskenvuo M, Langinvainio H, Kaprio J, Rantasalo I, Sarna S. The Finnish Twin Registry: baseline characteristics: section 3. Occupational and psychosocial factors. Helsinki: Departmentof Public Health Science Publ M49, CederlofR, Friberg L, Johnsson E, Kaij L. Studies on similarity diagnosis in twins with the aid of mailed questionnaires. Acta Genet Stat Med 1961; 11: Harvald B, Hauge M. Hereditary factors elucidated by twin studies. In: Neel,N Shaw M, Schull WJ, eds. Genetics and the epidemiology of chronic disease (publication 1163). US Department of Health, Education, and Welfare, 1965; Jablon S, Neel,N Gershowitz, Atkinson GF. The NAS-NRC twin panel: methods of construction of the panel, zygosity diagnosis and proposed use. Am J Hum Genet 1967; 19: Kasriel J, Eaves LJ. A comparison of the accuracy of written questionnaires with blood-typing for diagnosing zygosity in twins. J Biosoc Sci 1976; 8: Magnus ~Berg K, Nance WE. Predicting zygosity in Norwegian twin pairs born Clin Genet 1983; 24: Martin NE, Martin PG. The inheritance of scholastic abilities in a sample of twins: 1. Ascertainment of the sample and diagnosis of zygosity Ann Hum Genet 1975; 39: Nichols PC, Bilbro we. The diagnosis of twin zygosity. Acta Genet Stat Med 1966; 16: Sarna S, Kaprio J, Sistonen ~Koskenvuo M. Diagnosis of twin zygosity by mailed questionnaire. Hum Hered 1978; 28: Kaprio J, Koskenvuo M, Langinvainio H, Romanov K, Sarna S, Rose RJ. Genetic influences on use and abuse of alcohol: a study of 5638adult Finnish twin brothers. Alcohol Clin Exp Res 1987; 11: International Classification of Disease, 8th revision: WHO manual of the international statistical classification of diseases. Geneva: World Health Organization, Poikolainen K. Accuracy of hospital discharge data: five alcoholrelated diseases. Drug Alcohol Depend 1983; 12: Hehovaara M, Reunanen A, Aromaa A. Validity of hospital discharge data in a prospective study on stroke and myocardial infarction. Acta Med Scand 1984; 216: Rothman KJ, Boice JD. Epidemiologic analysis with a programmable calculator (publication ). National Institutes of Health, Emery AER. Methodology in medical genetics. 2nd ed. Edinburgh: Churchill-Livingstone, Jensen AR. Estimation. of the limits of heritability of traits by comparison of monozygotic and dizygotic twins. Proc Natl Acad Sci USA 1967; 58: Abo K, Koskenvuo M, Tuominen J, Kaprio J. Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol. 1986; 13: Romanov K, Koskenvuo M, Kaprio J. Selection bias in twin studies of disease concordance. Acta Genet Med Gemellol (Roma) (in press) 32 Huhti E. Prevalence of respiratory systems, chronic bronchitis and pulmonary emphysema in a Finnish rural population. Acta Tuberc Pneumol Scand 1965; 61(suppl): Alanko K. Prevalence of asthma in a Finnish rural population. Scand J Respir Dis 1970; 76(suppl):I Haahtela T, Heiskala M, Suoniemi I. Allergic disorders and immediate skin test reactivity in Finnish adolescents. Allergy 1980; 35: Kiviloog J, Irnell L, Eklund G. The prevalence of bronchial asthma and chronic bronchitis in smokers and non-smokers in a representative local Swedish population. Scand J Respir Dis 1974; 55: Aberg N. Asthma and allergic rhinitis in Swedish conscripts. Clin Exp Allergy 1989; 19: Haahtela T, Lindholm H, Bjorksten F, Koskenvuo K, Laitinen LA. Prevalence of asthma in Finnish young men. Br Med J 1990; 301: Schwartz M. Heredity in bronchial asthma. Acta Allergol (Kbh) 1952; 5(suppI2) Mantle J, Pepys J. Asthma amongst Tristan da Cunha islanders. Clin Allergy 1974; 4: Brown ~Gadjusek DC. Acute and chronic pulmonary airway disease in Paci6c island Micronesians. Am J Epidemiol 1978; 108: HopperJL, Hannah MC, Mathews JD. Genetic analysis workshop 2: pedigree analysis of a binary trait without assuming an underlying liability. Genet Epidemioll984; 1: Meneely GR, Renzetti AD, Steele JD, Wyatt J ~Harris HW Chronic bronchitis, asthma and pulmonary emphysema: de6nition and classi6cation of chronic bronchitis, asthma and pulmonary emphysema. Am Rev Respir Dis 1962; 85: Cerveri I, Brischi C, Ricciardi M, Zocchi L, Zoia MC, Rampulla C. Epidemiological diagnosis of asthma: methodological considerations of prevalence evaluation. EurJ Epidemioll987; 3: Eriksson-Lihr Z. Special features in allergy in children. Acta Allergol (Kbh) 1955; 8: Dawson D, Horobin G, Illsley R, Mitchell R. A survey of childhood asthma in Aberdeen. Lancet 1969; 1: Leeder SR, Woolcock AJ, Blackburn CRB. Prevalence and natural history of lung disease in New South Wales schoolchildren. Int J Epidemiol1974; 3: Buffum W Settipane ~ GA. The prognosis of asthma in childhood. Am J Dis Child 1966; 112: McNicol KN, Williams HB. Spectrum of asthma in children: allergic components. Br Med J 1973; 4: Ogilvie AD. Asthma: a study in prognosis of 1000 patients. Thorax 1962; 17: Bazaral M, Orgel HA, Hamburger RN. Genetics of IgE and allergy: serum IgE levels in twins. J Allergy Clin Immunol1974; 54: Longo G, Strinati R, Poli F, Fumi F. Genetic factors in nonspecific bronchial hyperreactivity: an epidemiologic study. Am J Dis Child 1987; 141: HoppRJ, BewtraAK, BivenR, NairNM, TownleyRG. Bronchial reactivity pattern in nonasthmatic parents of asthmatics. Ann Allergy 1988; 61: Nadel JA, Sheppard D. Mechanisms of bronchial hyperreactivity in asthma. In: Weiss EB, Segal MS, Stein M, eds. Bronchial asthma: mechanisms and therapeutics. 2nd ed. Boston: Little, Brown, 1985; Sibbald S. A family study approach to the genetic basis of asthtna. (thesis). University of London, Smith JM, Knowles LA. Epidemiology of asthma and allergic rhinitis: 2. In a university-centered community. Am Rev Respir Dis 1965; 92:31-38 CHEST I 100 I 1 I JUL'(,