Family history as a predictor of asthma risk

Family History as a Predictor of Asthma Risk Wylie Burke, MD, PhD, Megan Fesinmeyer, Kate Reed, MPH, Lindsay Hampson, Chris Carlsten, MD Background: Asthma, one of the most important chronic diseases of children, disproportionately affects minority and low-income children. Many environmental risk factors for asthma have been identified, including animal, mite, and other allergens; cigarette smoke; and air pollutants. Genetics also play an important causative role, as indicated by familial aggregation and the identification of candidate genes and chromosomal regions linked to asthma risk. Using a positive family history of asthma to identify children at increased risk could provide a basis for targeted prevention efforts, aimed at reducing exposure to environmental risk factors. Methods:

To assess the predictive value of family history as an indicator of risk for childhood asthma, we reviewed population-based studies that evaluated family history of asthma and atopic disease in children with asthma.

Results:

Our search identified 33 studies from all geographic regions of the world for review. The studies varied in definitions of positive family history and asthma phenotype and used study populations with asthma prevalence ranging from 2% to 26%. Nevertheless, family history of asthma in one or more first-degree relatives was consistently identified as a risk factor for asthma. In ten studies, sensitivity and predictive value of a positive family history of asthma could be calculated: sensitivity ranged from 4% to 43%, positive predictive value from 11% to 37%, and negative predictive value from 86% to 97%.

Conclusion:

Although a positive family history predicts an increased risk of asthma, it identifies a minority of children at risk. Positive family history may have utility in targeting some individual prevention efforts, but the low positive predictive value limits its value as a means to direct environmental remediation efforts. (Am J Prev Med 2003;24(2):160 –169) © 2003 American Journal of Preventive Medicine

Introduction

A

sthma represents an important public health problem in the United States, affecting 14 to 15 million Americans and resulting in 2 million emergency department visits, nearly 500,000 hospitalizations, and more than 5000 deaths each year.1 It is one of the most important chronic diseases of children1– 4 and disproportionately affects minorities. African Americans are more likely than whites to die or be hospitalized because of asthma,1 and asthma morbidity and mortality are particularly high among low-income minority children.5 Further, asthma rates are rising. Between 1980 and 1996, the prevalence rate of asthma increased by 74%.1 These statistics suggest that strategies identifying children at increased risk of asthma might have public health benefit. Risk factors for developing or exacer-

From the Department of Medical History and Ethics (Burke, Hampson), Institute for Public Health Genetics (Burke, Fesinmeyer, Reed, Hampson), Department of Medicine (Carlsten), University of Washington, Seattle, Washington Address correspondence to: Wylie Burke, MD, PhD, Department of Medical History and Ethics, University of Washington, Box 357120, 1959 NE Pacific, Seattle WA 98195. E-mail: wburke@u. washington.edu.

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bating childhood asthma include many environmental exposures, such as cigarette smoke, exposure to cockroaches and mites, other animal allergens, airborne agents including pollens and air pollution, and food allergens.6 – 8 Targeted efforts to address these exposure factors early in life might help to reduce asthma rates. Identification of children at risk either before symptoms occur or at the time of early wheezing episodes might also increase early diagnosis and thus help to optimize care.8,9 Familial aggregation of asthma and atopic disease has frequently been noted,10 suggesting that a positive family history might be used to identify children at risk. Other evidence suggests that genetics plays an important role in asthma etiology. Linkage and association studies have identified numerous candidate genes and chromosomal regions that may contribute to asthma risk.11 It is unlikely that any single gene plays a dominant role in asthma etiology; rather, asthma appears to occur as the result of environmental exposures in individuals with genetic susceptibility that may often be based on variation in many different genes.10,11 The use of asthma family history as a preventive tool would focus on identifying children early in childhood, or even prenatally, to initiate environmental modifica-

Am J Prev Med 2003;24(2) © 2003 American Journal of Preventive Medicine • Published by Elsevier

0749-3797/03/$–see front matter doi:10.1016/S0749-3797(02)00589-5

tions to reduce the risk of asthma or to improve asthma outcomes. The first step in the evaluation of this strategy is an assessment of family history as a risk predictor. In this paper, we examine published data on the magnitude of risk conferred by a positive family history of asthma or atopic disease, its prevalence, and its predictive value to determine the feasibility of this approach to risk stratification.

Methods We used a two-step search process to identify articles in the PubMed database published from 1990 to the present that evaluated family history as a risk factor for childhood asthma. In the first step, we identified articles by using the search term “asthma/genetics, epidemiology, etiology[MeSH] AND family history,” with the search limited to 0 to 18 years, English language, and human. In the second step of the search, we used the search term “asthma[MeSH] AND (family OR families OR familial OR parent OR parental OR parents OR maternal OR paternal) AND risk* AND history,” excluding the articles identified in the first step and using the same search limitations. A total of 298 articles were identified through this search process. We reviewed abstracts and, when necessary, full texts to identify papers for review. We limited our analysis to studies evaluating populations of at least 100 subjects (defined as children aged 5 to 18 years in whom a family history of asthma and an asthma diagnosis were queried) that provided data on the odds ratio or relative risk of childhood onset asthma with and without a family history of asthma. The main reasons for excluding studies were that they did not assess family history as a risk factor for asthma, lacked a control population, or selected cases on the basis of clinical criteria other than asthma. We also excluded studies that evaluated asthma endpoints predominantly or exclusively before age 5 to avoid potential misclassification of childhood wheezing.4,6,7 On the basis of these selection criteria, we identified 41 articles for review, of which 12 were noted to report on a study population also evaluated in another article in the sample. For each study population for which more than one study was available, we limited our analysis to the study that provided the most detailed family history information, leaving a total of 33 studies for review (Table 1).12– 44 However, in two cases, a second study from the same population provided additional data about the potential interaction of family history with other risk factors; these two studies were reviewed for this aspect of family history risk.45,46 An additional 14 studies identified in the search presented data on family history of atopic disease as a predictor of asthma and were reviewed for this parameter.47– 60 We also identified and reviewed two studies that evaluated family history as a risk factor for asthma severity.61,62 Data were extracted on the relationship between family history of asthma or atopic disease and asthma outcome. When more than one definition of asthma phenotype was measured, we based our analysis on definitions that included a physician diagnosis or evidence of persistent wheezing. For each study, the population and case definitions for asthma in subjects and family members were identified (Table 1). When sufficient data were provided in the paper,

study results were used to calculate prevalence and predictive value of positive family history, as standardly defined.8,9,63

Results Characteristics of the studies selected for review are shown in Table 1. The studies represent populations in 20 countries from all geographic regions of the world. Most studies used school-based recruitment or other population-based sampling frames to identify a study population. Three studies recruited subjects from clinical care settings.39,35,43 Definitions of asthma varied, as shown in Table 1; in addition, the asthma diagnosis was based on parental report for all but four studies.18,31,35,43 Family history of asthma was based on self-report or report of a parent or spouse, with the exception of one study in which documentation of maternal asthma history was sought in medical records.35 Studies varied in the detail of family history gathered; multiple measures of parental and other family history were noted in some studies, whereas for others the definition of a “positive family history” was not specified. Questions used to elicit asthma status also varied. Some focused on history of a medical diagnosis and others on symptoms observed by family members (e.g., “Has a doctor ever diagnosed this child with asthma?”; “Has he/she had any periods when there was wheezing with whistling on his/her chest when he/she breathed?”). Several studies required report of both symptoms and a medical diagnosis. In one study, a diagnosis of persistent wheezing was based on measurements at two different time periods.23 The association of a family history of asthma with asthma risk is summarized in Table 2. Odds ratios (ORs) for a first-degree relative with asthma ranged from 1.5 to 9.7, with the exception of one outlying data point: the OR for asthma conferred by a family history of wheeze or asthma in one of three Southeast Asian populations studied by Leung and Ho20 was 96.7 (95% confidence interval [CI]⫽16.2–575.8), an order of magnitude higher than the risk identified in any other study, including the study of two other Southeast Asian populations by the same authors). In all of the studies reviewed, family history of asthma was associated with increased asthma risk. In a few studies, certain measures of family history were significant predictors of risk, whereas others were not. For example, one study reported an OR of 1.5 (95% CI⫽0.7–2.7) for maternal asthma and an OR of 4.4 (95% CI⫽2.5–7.8) for paternal asthma,21 whereas another study had an opposite finding of a significant increase in risk for maternal but not paternal asthma history.22 Overall, the risk associated with maternal, paternal, or sibling history of asthma was similar. Three studies calculated risk when both parents were affected versus one12,19,41; in each Am J Prev Med 2003;24(2)

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Table 1. Study populations and measurements

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Study United States Beckett et al., 199639 (CT)

London et al., 200112 (CA)

Maier et al., 199737 (WA) Martinez et al., 199523 (AZ) Oliveti et al., 199635 (OH)

Sherman et al., 199042 (MA) Central/South America Celedo´ n et al., 200133 (Costa Rica)

Europe Aberg et al., 199319 (Sweden)

Population

Recruitment

5585 children ⬍18 years

Identified through mothers receiving pregnancy care at study hospitals School cohort

5046 children 9–16 years

925 children 5–9 years 825 children assessed at 2 and 6 years 232 children 4–9 years (mean age, 6.7 years)

School-based survey HMO-based birth cohort

Definition of positive family history

Definition of asthma phenotype

Prevalence of asthma

Report of physiciandiagnosed asthma in mother

Report of asthma

12%

Report of parent or sibling with asthma

Report of physiciandiagnosed asthma

14.5% (4.4% early onset persistent asthma, 2.1% early onset transient asthma, 8% late onset asthma)

Report of parent with asthma Report of parent with asthma

Early onset ⫽ symptoms before age 3 years Persistent ⫽ report of ⱖ1 asthma episodes in past 12 months Report of physiciandiagnosed asthma Persistent wheeze, based on report of symptoms at 2 and 6 years Medical record documentation of physician-diagnosed asthma, and wheezing or coughing, resulting in the use of asthma medications in the past 12 months (cases) or lack thereof (controls) Report of physician diagnosis of asthma

11% 14% (persistent wheezing) N/A

African-American children seen for asthma (cases, n ⫽ 131) or well-child care (controls, n ⫽ 131)

Maternal asthma history in medical record

770 children 5–9 years

School cohort

Report of parental asthma

214 children 10–13 years

Cases (n ⫽ 114) and controls (n ⫽ 100) from school-based random sample

Report of asthma in at least one parent

Report of physiciandiagnosed asthma and cough without cold, or wheezing or nocturnal cough or wheezing (cases) or lack thereof (controls)

N/A

19,814 children aged 7, 10, and 14 years

School cohort

Report of parental asthma or atopic disease

Report of one or more episodes of heavy breathing or wheezing that could not be explained by other disease

5%

12%

(continued on next page)

Table 1. (continued) Definition of positive family history

Definition of asthma phenotype

School cohort

Report of biological parent or sibling with “known asthma”

6665 children 9–11 years

School cohort

Frischer et al., 199325 (Germany) Kelly et al., 199629 (United Kingdom)

1812 children 6–8 years 5348 children 5–11 years

School cohort

Report of bronchial asthma, allergic rhinitis, atopic dermatitis Report of parental asthma Report of maternal or paternal asthma

Ronmark et al., 199816 (Sweden)

2149 children 7–8 years

School cohort

Report of “family history of asthma or allergic disease”

Rusconi et al., 199928 (Italy)

16,333 children 6–7 years

Pre-existing population-based cohort

Report of parental asthma or atopic disease

Withers et al., 199822 (United Kingdom)

2289 children 14–16 years

Regionally based birth cohort

Report of asthma or atopy in immediate family members

Report in the last 12 months of wheezy breathing, or emergency or hospital treatment for acute asthma, or regular anti-inflammatory treatment for asthma Report of physiciandiagnosed asthma or of multiple episodes of wheezy bronchitis Report of physiciandiagnosed asthma Report of cough, history of wheezing, and history of unexpected or unusual breathlessness Report of physiciandiagnosed asthma AND current wheeze, or wheezing/use of asthma medication during last 12 months Report of persistent wheezing: wheezing symptoms present at ages 2 and 6–7 years Report of physiciandiagnosed asthma

Africa Ng’ang’a et al., 199831 (Kenya)

1226 children 8–17 years

Two school cohorts (urban and rural)

Report of “family history of asthma symptoms”

ⱖ10% drop in FEV after exercise challenge

23% (urban) 13% (rural)

Middle East Abuekteish et al., 199624 (Jordan) Abdulrazzaq et al., 199436 (United Arab Emirates)

3540 children 6–12 years 729 children 6–14 years

School cohort

Report of “family history of asthma” Report of asthma in mother or father

Report of physiciandiagnosed asthma Report of history of asthmatic attack, diagnosis of asthma or hospitalization for asthma

4%

Study

Population

Recruitment

Csonka et al., 200026 (Finland)

2027 children 6–13 years

Dold et al., 199221 (Germany)

Two school-based surveys

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School-based survey

Prevalence of asthma

7%

4% 7%–8%

5%

4%

22%

12%

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(continued on next page)

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Table 1. (continued)

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Study

Definition of positive family history

Definition of asthma phenotype

School-based survey

Report of asthma in mother or father

2216 children 6–12 years

School cohort

Report of asthma in first-degree relative

Report of history of asthmatic attack, diagnosis of asthma, or hospitalization for asthma Report of physiciandiagnosed asthma

2867 children 4–17 years

School cohort

Report of “family history of asthma”

Karunasekera et al., 200143 (Sri Lanka)

600 children 1–10 years

Report of asthma in father, mother, sibling, or 2nd- or 3rd-degree relative

Leung and Ho., 199420 (SE Asia)

2208 children 12–18 years

Inpatients admitted for asthma (cases) or with no history suggestive of asthma (controls) School cohorts in three SE Asian cities

Matsuoka et al., 199930 (Japan) Takemura et al., 200113 (Japan)

15,234 children 6 and 9 years 27,767 children mean age 10.7 years

School cohort

Wang et al., 200144 (Taiwan)

434 children 11–16 years

Cases and controls derived from school cohort

Report of asthma in grandmother, grandfather, mother, father, brother, or sister

6394 children 8–11 years

School cohort

Report of parental asthma

Bener et al., 199340 (Saudi Arabia)

Ones et al., 199717 (Turkey) Asia Chhabra et al., 199815 (India)

Australia and New Zealand Belousova et al., 199927 (New South Wales)

Population

Recruitment

3041 children 7–12 years

School cohort

Report of asthma or wheeze ever, in parent or sibling Report of physiciandiagnosed asthma Report of parent treated for asthma

Prevalence of asthma 17.9%

10%

Report of wheezing in past year; or current or past history of exerciseor cold-induced wheezing Documentation in medical records of ⱖ2 inpatient admissions for asthma

17%

Report of history of asthma

Hong Kong: 7% Kota Kinbalu: 3% San Bu: 2% 2.9%

Report of asthma in mother or father History of ⱖ2 attacks of wheezing that caused shortness of breath, physician-diagnosed asthma, and shortness of breath with wheezing at time of diagnosis Report of physiciandiagnosed asthma, asthma symptoms in past 12 months (e.g., moderate wheezing at rest), and nocturnal waking with wheezing or whistling Report of recent wheeze: wheeze or wheeze following exercise in the past 12 months

N/A

10%

N/A

26%

(continued on next page)

Table 1. (continued) Definition of positive family history

Definition of asthma phenotype

School cohort

Report of parental asthma

11%

7368 children 7 years

School cohort

Oddy et al., 200232 (Western Australia)

2860 children 6 years

Birth cohort

Report of physiciandiagnosed asthma and wheeze within past year

17%

Sears et al., 199618 (New Zealand)

1037 children 18 years

Birth cohort

Report of asthma attacks or “wheezing like asthma” Report of current maternal asthma, with wheeze in the past year and use of asthma medication Report of parental asthma

Report of wheeze within past 12 months and airway hyperresponsiveness (ⱖ20% fall in FEV1 with histamine challenge) Report of asthma attacks or wheezy breathing

15%

Shaw et al., 199438 (New Zealand)

708 children 8–13 years (61% Maori, 35% European) 474 children 7–9 years

School-based survey

Report of parental asthma

Identification of symptoms consistent with asthma in medical evaluation Report of whistling or wheezing in the chest in the past 12 months

Cases and controls derived from school cohort

Report of asthma or other atopic disease in parents and siblings

Report of wheeze/ whistling in chest in the past 12 months OR past diagnosis of asthma AND use of asthma medications in past 12 months

24% in parent study

Study

Population

Recruitment

Gray et al., 200034 (New South Wales)

1655 children 8–11 years

Jenkins et al., 199341 (Tasmania)

Wickens et al., 200114 (New Zealand)

HMO, health maintenance organization; N/A, not applicable; FEV, force expiratory volume; FEV1, forced expiratory volume in one second.

Prevalence of asthma

16%

24% (same for Maori and European subjects)

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Table 2. Association between childhood asthma and family history of asthma Definition of positive family history Asthma in mother Dold et al., 199221 Karunasekera et al., 200143 Withers et al., 199822 Csonka et al., 200026 Beckett et al., 199639 Jenkins et al., 199341 Kelly et al., 199629 Abdulrazziq et al., 199436 Frischer et al., 199325 Wickens et al., 200114 Oddy et al., 200232 Rusconi et al., 199928 Martinez et al., 199523 London et al., 200112 (all asthma) Wang et al., 200144 Matsuoka et al., 199930 Bener et al., 199340 Oliveti et al., 199635 Asthma in father Withers et al.22 Kelly et al., 199629 Karunasekera et al., 200143 Jenkins et al., 199341 Rusconi et al., 199928 Abdulrazziq et al., 199436 Wickens et al., 200114 Wang et al., 200144 London et al., 200112 (all asthma) Dold et al., 199221 Frischer et al., 199325 Matsuoka et al., 199930 Bener et al., 199340 Either parent Sherman et al., 199042 Shaw et al., 199438 Gray et al., 200034 Belousova et al., 199927 Dold et al., 199221 Celedo´ n et al., 200133 Maier et al., 199737 Takemura et al., 200113 Abdulrazziq et al., 199436 Aberg et al., 199619 Sibling Withers et al., 199822 Karunasekera et al., 200143 Wickens et al., 200114 Wang et al., 200144 (sister) Wang et al., 200144 (brother) Parent or sibling Belousova et al., 199927 Takemura et al., 200113 Leung and Ho, 199420 (Hong Kong) Leung and Ho, 199420 (Kota Kin)

ORa

95% CIa

1.5 1.6 2.0 2.2 2.5 2.6 2.7 2.7 3.2 3.2 3.3 4.1 4.1 4.1

0.7–2.7 1.1–2.2 1.5–2.8 1.3–2.6 2.1–3.0 2.1–3.3 1.9–3.9 1.7–4.4 1.1–9.3 2.1–5.1 —b 3.2–5.2 2.1–7.9 3.0–5.6

4.1 5.3 (RR) 5.5 9.7

1.1–14.7 —b 3.7–8.2 2.6–36.5

1.5 1.7 2.1 2.5 2.7 2.9 3.0 3.6 4.1

NSb 1.1–2.6 1.4–3.2 2.0–3.2 2.1–3.6 1.8–4.5 1.8–5.1 0.4–29.7 3.0–5.8

4.4 4.8 6.2 7.2

2.5–7.8 1.9–12.0 —b 4.9–10.7

2.0 2.1 2.4 2.5 2.6 2.6 2.9 3.0 3.1 4.3

1.3–3.0 1.4–3.1 1.7–3.4 2.2–2.9 1.7–4.0 1.3–5.2 1.8–4.7 2.7–3.4 2.1–4.5 3.7–5.0

1.9 1.9 2.8 6.9 5.7

1.5–2.4 1.3–2.8 1.9–4.1 1.1–44.0 1.3–24.9

2.5 2.5 4.2

1.7–2.7 1.8–3.5 2.2–8.0

5.8

1.7–19.5 (continued)

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Table 2. (continued) Definition of positive family history Leung and Ho, 199420 (San Bu) Both parents Sears et al., 199618 Jenkins et al., 199341 Aberg et al., 199619 London et al., 200112 (all asthma) Two first-degree relatives Dold et al., 199221 Not specified Ng’ang’a et al., 199831 Karunasekera et al., 200143 Abuekteish et al., 199624 Ronmark et al., 199816 Wang et al., 200144 Chhabra et al., 199815

ORa

95% CIa

96.7

16.2–575.8

3.2 7.0 9.6 12.1

1.3–8.1 4.5–11.1 6.7–13.9 7.9–18.7

5.2

2.5–10.8

1.6 2.2 2.5 3.2 3.3 3.7

1.1–2.4 1.6–3.0 1.9–3.3 —b 1.6–6.9 2.8–4.7

a

Rounded to single decimal point. Confidence interval not provided. CI, confidence interval; NS, not significant; OR, odds ratio; RR, relative risk.

b

case, risk was higher when both parents were affected than when one parent was affected. Fourteen studies evaluated a family history of atopic disease using a definition of positive family history that included asthma as well as other atopic diseases, such as allergic rhinitis or atopic dermatitis.47– 60 Those studies found that a positive family history of atopy significantly increased risk of asthma, with OR ranging from 1.7 to 6.8. When atopic diseases other than asthma were considered separately, however, the results were mixed. Four studies found no evidence for risk associated with a family history of atopic diseases other than asthma,22,25,26,41 one study found a risk elevated only if two relatives were affected,21 and seven studies found risk elevated significantly if one or more first-degree relatives were affected, with OR ranging from 1.5 to 4.0 for a single affected relative.12,19,28,30,36,40,44 One study found a significant elevation of risk when the mother had allergic rhinitis (OR⫽2.5, 95% CI⫽1.4 – 4.6) but not when the father did (OR⫽1.6, 95% CI⫽0.9 to 2.9). Ten studies provided sufficient prevalence data to permit the calculation of sensitivity, specificity, and positive and negative predictive value. These data are summarized in Table 3. For definitions of family history that were relatively inclusive (e.g., asthma in either parent, any first-degree relative, or any family member), sensitivity ranged from 16% to 43%; sensitivity was generally lower if family history was limited to maternal or paternal asthma. Positive predictive value ranged from 11% to 37%, and negative predictive value ranged from 86% to 97%. Two studies evaluated family history of asthma as a risk factor for increased severity of disease. One study

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Table 3. Positive and negative predictive value of family history of asthma Definition of ⴙ family history Mother Frischer et al., 199325 Gray et al., 200034 Oddy et al., 200232 Rusconi et al., 199928 Father Frischer et al., 199325 Gray et al., 200034 Rusconi et al., 199928 >1 first-degree relatives Ones et al., 199717 Either parent London et al., 200112 Sherman et al., 199042 Takemura et al., 200113 Not specified Abuekteish et al., 199624 Chhabra et al., 199815 a

Prevalence of ⴙ family history (%)

Prevalence of asthma (%)

Sensitivity (%)

Specificity (%)

Positive predictive value (%)

Negative predictive value (%)

4 4 15 4

3.5 11 17 4

11 4 31 14

97 96 88 97

11 11 35 15

97 89 86 96

4 4 4

3.5 11 4

13 7 10

96 96 97

11 19 11

97 90 96

20

10

16

93

20

91

19 28 10

14.5a 12 10

38 43 23

84 74 91

30 18 22

89 91 92

15 13

12 17

27 29

87 90

23 37

89 86

All asthma.

evaluated risk factors for intubation among a consecutive series of 300 children requiring treatment for asthma in the intensive care unit.61 In that study, a parental history of asthma or allergy was associated with an increased likelihood of intubation (OR⫽3.4, 95% CI⫽1.2–10.0). A second study found that among 322 children hospitalized for asthma, a history of maternal asthma death was associated with an increased likelihood of seasonal admissions for asthma—a pattern that, in turn, was related to reduced likelihood of asthma remission.62 Few studies evaluated interactions between family history and other risk factors. However, two studies found evidence for an interaction between maternal smoking and family history of asthma. One study found evidence of a joint effect of these risk factors that was more than additive.12 The other study had mixed results: Among young children, maternal smoking was associated with greater risk of asthma only among those with a positive family history of asthma; in adolescents, the asthma risk conferred by maternal smoking was limited to those with a negative family history.45 A smaller study did not observe an interaction.35 Yet another study demonstrated a protective effect for asthma in households with indoor dogs; this effect was largely limited to children without a family history of asthma.46

Discussion Most of the studies reviewed here used large population-based samples to assess family history as a risk factor for asthma. Although there were many methodologic differences, the picture that emerges is consistent. A family history of asthma is a strong predictor of

asthma risk, with most ORs falling between 2 and 4 when a first-degree relative has asthma. Family history of atopic disease was also a risk factor when asthma was included, but results were inconsistent when atopic diseases other than asthma were considered separately. Several studies also allowed calculation of the sensitivity and positive predictive value of asthma family history. These calculations demonstrate that the positive predictive value of a family history of asthma is less than 50% (Table 3). Thus, although family history of asthma clearly predicts increased likelihood of developing the disease, it fails to identify the majority of children at risk. Two small studies suggest the possibility that children with a family history of asthma might have a greater likelihood of more severe course,61,62 but this possibility requires further research. Similarly, further study of interactions between family history and other asthma risk factors is needed. A family history of atopy is a less reliable indicator of asthma risk. Most studies were limited by the use of a questionnaire for data collection, with the potential for misreporting of asthma or family history status. In addition, 15 of 33 studies required a report of physician-diagnosed asthma as part of the case definition. Underdiagnosis of asthma has been documented64,65 and could have resulted in misclassification of cases and controls in these studies. This effect may have been minimized by the use of symptoms as a basis for case definition in many studies65 and by the use of validated questionnaires in most.66 Because various definitions of asthma and positive family history were used, the comparability of results from different studies may be limited. Further, these studies involved geographically diverse populations that differed in asthma prevalence. Am J Prev Med 2003;24(2)

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Because of the relatively low positive predictive value of a family history of asthma, it would be difficult to justify its use as the basis for environmental remediation efforts to reduce asthma risk, such as housing improvements or provision of mattress covers, hotwater laundry facilities, or other similar efforts to reduce asthma risk factors. Directing such efforts toward families with asthmatic children (irrespective of family history) or based on demographic risk factors, such as low income housing, would probably target a higher proportion of children likely to benefit from such interventions. However, the asthma risk associated with family history might represent a useful predictor in some preventive health efforts. Knowledge of asthma risk might help to motivate behavioral efforts on the part of parents of children at risk (e.g., increased use of mattress covers, removal of rugs, avoidance of humidifiers, and efforts to spare children exposure to cigarette smoke). Knowledge of the risk associated with a family history of asthma might also help healthcare providers and parents to identify early signs of asthma and to be more proactive about treatment and remediation of nongenetic risk factors. All family members affected by atopic diseases would potentially benefit from these efforts. The use of family history as a predictor of risk might also be enhanced by incorporating it into a predictive tool that included other measures related to a child’s risk of asthma (e.g., transient wheezing episodes in infancy or other allergic disorders).67 In specific populations, family history might prove to have a higher predictive value than we found in this general review. The population of San Bu, in which Leung and Ho20 found a markedly elevated risk of asthma associated with a positive family history, could represent such an example. If this proves to be the case, it will probably reflect population differences in the prevalence of gene variants associated with asthma as well as environmental factors associated with asthma risk. The use of family history for these purposes poses potential risks as well as benefits. Identification of children at risk of asthma could lead to stigmatization, overprotection, or increased use of healthcare resources without compensatory health outcome benefits. A focus on family history as a risk factor could also decrease motivation to address environmental risk factors for asthma when a family history of asthma is absent. Our analysis suggests that a family history of asthma has some potential to identify children at risk, but its use as a prevention tool requires further study. We would like to thank Sherry K. Dodson for her assistance with the medical literature search and Cynthia Fester for her assistance in preparing the manuscript. This work was supported under a cooperative agreement from the Centers for Disease Control and Prevention (CDC) through the Associa-

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tion of Schools of Public Health (ASPH), Grant No. U36/ CCU300430-20, and by the UW NIEHS-sponsored Center for Ecogenetics and Environmental Health, Grant No. NIEHS P3ES07033. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of CDC, ASPH or NIEHS.

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