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Dimensions of Respiratory Symptoms in Preschool Children: Population- Based Birth Cohort Study

June 17, 2008

By Smith, Jaclyn A Drake, Richard; Simpson, Angela; Woodcock, Ashley; Pickles, Andrew; Custovic, Adnan

Rationale: A focus on distinctive collections of symptoms may be more informative of the probability of respiratory disease than individual and possibly transient phenotypes. However, such collections or components of overall symptomatology need to be valid, and their relationship established with the known risk factors and physiologic measures. Objectives: To analyze detailed parentally reported respiratory symptoms by principal components analysis and derive symptom components; to examine the relationship of such components with measures of lung physiology and atopy.

Methods: An unselected, population-based birth cohort (n=946).

Measurements and Main Results: Interviewer-administered questionnaires, lung function (specific airway resistance [sRaw]), airway reactivity (dry air challenge), and atopic status were obtained at ages 3 and 5 years; principal components analysis and multivariate analysis of variance were used to analyze the data. The fourcomponent solution (wheeze, cough, colds, chronic symptoms) explained 53.2% of the variance in symptoms at age 3, and the five- component solution (wheeze, wheeze with irritants, wheeze with allergens, cough, chest congestion) explained 49.8% of variance at age 5. The multivariate analysis revealed novel relationships between symptoms, risk factors for asthma, and measures of lung function. At age 3, sRaw and the interaction between maternal asthma and child’s atopy were not only related to wheeze but also independently to the cough component. At age 5, overall wheeze and allergic wheeze were related to lung function and airway reactivity; child’s atopy was only related to symptoms when considered as a continuous trait.

Conclusions: Our analysis supports the need to move beyond the presence or absence of individual symptoms. Syndromes of coexisting symptoms more likely reflect underlying pathophysiologic processes.

Clinical trial registered with http://www.controlled-trials.com (ISRCTN72673620).

Keywords: principal components analysis; wheeze phenotypes; childhood asthma; cough

Childhood asthma is a clinical syndrome in which the diagnosis is often based on a history of wheezing and/or other associated respiratory symptoms (e.g., cough), coupled with the objective measurements of lung function and/or airway inflammation (1). In contrast, in epidemiologic studies, children are often assigned a phenotype based on the response to a single question (e.g., presence/ absence of wheeze or doctor-diagnosed asthma), despite the fact that more detailed information has been collected using extensive questionnaires (2).

Reshaping the wealth of epidemiologic data into a valid but comprehensible form to inform the clinical decision-making process would be of great value. One means to do this, which has been used for over 20 years in other branches of medicine and psychology, is principal components analysis (PCA) (3). PCA is a quantitative method for data reduction to extract simplified patterns from correlated multi-item data, and has relatively established criteria for deciding what may be common underlying components that best explain a dataset. It distills the mass of information from many questionnaire items into a small number of components, which explain the overall variance in item scores, and can generate coherent subsets of items. These components should be more reliable and valid than single items. Subsequent analysis may also reveal relationships between components and objective measures of disease.

On the few occasions that PCA has been used in asthma and allergy research, symptoms formed a single component separate from lung physiology (4), atopy (5), systemic/airway inflammation (6), and quality of life (7), providing evidence of a disjunction between etiologic factors, symptoms, and consequences of symptoms. The fact that most cases of persistent wheezing and asthma begin in early childhood provides an added level of complexity. Our understanding of the nature of childhood wheezing illness has been augmented by the characterization of distinct wheeze phenotypes, based on the temporal patterns of wheezing (early, late onset, persistent) (8). Given this fragmentation of the trajectory and pathophysiology of asthma symptoms, it is not surprising that there have been calls to abandon the concept of asthma as a single disease (9).

We hypothesized that, rather than relying on the presence or absence of an individual symptom (e.g., wheezing) or physician diagnosis (e.g., asthma),more useful information may be obtained by examining syndromes of coexisting symptoms derived fromthe collected data. Such syndromes may better reflect the underlying pathophysiologic processes and predict not only the presence but also the persistence of chronic respiratory disease, and hence be useful in both diagnosis and treatment decision making.

Therefore, in a setting of a population-based birth cohort, we used PCA to analyze detailed parentally reported respiratory symptoms at ages 3 and 5 years and derived representative symptom components. We tested the validity of these components by examining their relations to measures of lung physiology and child’s atopy at each age, and between components from one time point to the other. These data have been presented in abstract form (10).

METHODS

Design

TheManchester Asthma and Allergy Study is an unselected, populationbased birth cohort (11). The study was approved by the South Manchester Local Research Ethics Committee, Manchester, UK. Written, informed consent was obtained from subjects’ parents/ guardians.

We recruited participants during the first trimester of the pregnancy; children were monitored prospectively and reviewed at age 3 and 5 years. For detailed description of the cohort, procedures, and analysis, see the online supplement.

Procedures

Symptoms. Validated respiratory questionnaires were interviewer administered (American Thoracic Society [ATS] [Reference 12], for children age 3; ATS and International Study of Asthma and Allergies in Childhood [ISAAC] [Reference 2], for children age 5).

Lung function. Specific airway resistance (sRaw) was measured using plethysmography (ages 3 and 5 yr) (13, 14). Airway reactivity was assessed by eucapnic voluntary hyperventilation challenge (dry air; age 5) (15, 16).

Atopy. Children were skin tested to common inhalant and food allergens (age 3 and 5). At age 5 years, we also measured specific IgE; sensitization was defined as any value greater than 0.2 kilo- units of allergen per liter. To quantify sensitization, we summed the levels of specific IgE to mite, cat, and dog (17).

Statistical Analysis

All analyses were performed using SPSS version 13.0 (SPSS, Inc., Chicago, IL). PCA is an exploratory technique for investigating patterns within a set of variables (in the current analysis, responses to a series of respiratory symptom questions). The large numbers of responses are reduced to a much smaller number of representative components, based on the covariance among responses. If subsets of symptoms are correlated, this suggests they are measuring aspects of a common underlying process; several components may suggest a series of underlying processes.

We used the same procedures to analyze the symptom items at ages 3 and 5 years. The steps involved in the analyses were as follows:

1. Item selection: Repetitive questions and questions that correlated with partial correlation coefficients greater than 0.4 to other questions were removed (i.e., not all questions were included).

2. Component extraction: PCA generated the component solutions, and the number of components was selected using eigenvalues greater than 1 and by examination of scree plots (18).

3. Rotation: The rotation of the components generates component loading scores. These are a measure of the relationship between an individual question and the underlying component: the greater the loading, the purer a measure of that component the item is. Components were rotated using standard mathematical processes to give as much clarity as possible about correlated items. We examined different rotation techniques. An oblique rotation was chosen (promax), based on the implausibility of independent components assumed by orthogonal rotations. For clarity, only items with the conventional loading of 0.4 and above were interpreted.

4. Components scores: For each subject included in the PCA, we calculated component scores. These scores are estimates of the scores each individual would have received on each of the components if they had been measured directly (see the online supplement for details).

5. Component validity: To validate the components, we performed a multivariate analysis of variance (MANOVA) with PCA scores as outcomes, and lung physiology, atopy, and maternal asthma as predictors. If the predictor terms were significantly related to the set of PCA components (Pillai’s test), individual associations were examined using specific tests.

RESULTS

Of 1,085 children born into the study, we reviewed 1,068 at age 3 years. Of these, 122 were prenatally randomized to an environmental control regime (11, 19, 20) and excluded from this analysis. Of the remaining 946 children, 904 attended the follow-up at age 5 years. Lung function data were available in 533 children at age 3 and 782 at age 5 years; 811 were skin tested at age 3, 798 at age 5, and 521 had IgE measured at age 5 years (Figure 1). Of the subjects, 20.2 and 27.1% were sensitized to at least one allergen at ages 3 and 5 years, respectively. Component Generation

Age 3 years. Twenty-one itemswere included in the PCA(Kaiser- Meyer-Olkin measure of sampling adequacy, 0.92; Bartlett’s test of sphericity,

Age 5 years. The age 5 questionnaires contained a section on allergic and irritant triggers of wheeze, which was not included at age 3; 32 items were included (Kaiser-Meyer-Olkin measure of sampling adequacy, 0.89, Bartlett’s test of sphericity, 1.35). The questionnaire items loading onto each component and the variance they explain are shown in Table 2. We selected the fivecomponent solution, because the six-component solution split the chest congestion component into two, describing congestion with colds and chronic congestion. These two components were not significantly discriminated in the subsequent MANOVA, and appear to be less valid.

Different rotation techniques were examined (oblique promax and orthogonal varimax) but produced extremely similar results, demonstrating the stability of the components.

Correlations between components. At both ages, correlations among components from the promax solution were weak to moderate (Tables E3a and E3b). Each component at age 3 correlated most strongly with the equivalent component at age 5 (Table E3c). The two additional wheeze components at age 5 (wheeze with irritants and wheeze with allergens) did not correlate with the wheeze component at age 3 but did correlate with cough, colds, and chronic symptoms.

Correlations between the component scores at different ages provide a further indicator of validity, suggesting stability over time.

Symptom Components, Lung Physiology, and Atopy

Age 3. In the overall multivariate model, baseline lung function (P = 0.001) and the interaction between maternal asthma and child’s atopy (P = 0.01) were significantly associated with the wheeze (P

Age 5. In a model that used atopic sensitization as a dichotomous variable, several physiologic variables were significantly related to symptom components: baseline lung function (P = 0.001), airway reactivity (P = 0.016), the interaction between maternal asthma and child’s baseline lung function (P = 0.007), and maternal asthma and child’s airway reactivity (P = 0.047). Four of five symptom components were significant in this multivariate model (wheeze, P=0.001; cough, P

In contrast, in a model using atopy as a continuous variable (i.e., the absolute level of specific IgE), the nature of these relationships changed. In this model, a sum of specific IgE (P

DISCUSSION

Key Results

We have demonstrated that PCA can be successfully used to produce respiratory symptom components in preschool-age children from validated questionnaires administered in a population-based birth cohort. As expected, questions pertaining to wheeze comprised a component that explained the largest proportion of the variance at both age 3 and 5 years. At age 3, other components included questions pertaining to cough, colds, and chronic symptoms. At age 5 years, in addition to the existing wheeze component, two further wheeze-related components emerged (wheeze with irritants and wheeze with allergens); these questions had not formed part of the assessment at age 3.

The components we identified have face validity (as they seem intuitively correct) and content validity (as we observed significant relationships with objective measures of respiratory function and known risk factors for asthma, e.g., maternal asthma). In addition, we observed a degree of consistency over time, suggesting their stability. Viewing atopic sensitization as a dichotomous trait in its relationship to respiratory symptom components obscured the nature of their relationships, which only became apparent when atopy was considered as a continuous trait.

Limitations

The validity and reliability of the results are dependent on the validity of the questionnaires and the reliability of the responses. Although we have used comprehensive, well-established, and validated questionnaires, collected prospectively in a large cohort, we cannot exclude the possibility that important symptom questions were excluded. Only about half of the variance is explained by the selected components; this is, however, comparable to other similar analyses (5, 6, 21). Furthermore, as with all studies in preschool children, we relied on parental reporting of a child’s symptoms and accept the limitations of this approach. However, one strength of PCA is its capacity to embrace all the symptom information simultaneously rather than relying on a single dichotomous answer to the question “Has your child wheezed in the last 12 months?”

The different questionnaire items used at two time points may account for the differences in the symptom components identified. The majority of the additional questions at age 5 described wheezing episodes, and the circumstances in which they occurred. By age 5 years, children are more likely to have been exposed to a wider range of environmental factors that may precipitate wheezing. Moreover, the additional wheeze components identified (wheeze with allergens and wheeze with irritants) were extremely poorly correlated with the wheeze component at age 3 years, implying that these are truly independent emerging symptom components.

PCA is an exploratory analysis and the inherent assumptions and limitations of PCA should be taken into account. Not all questions were included in the PCA; excluding repetitive and correlated questionnaire items presupposes that they will contribute nothing and the subjective selection of which items to remove may affect the results. The choice of rotation may also alter the outcome of the analysis, with some studies preferring orthogonal rotations such as the varimax (6, 21, 22). Orthogonal rotations are useful in that they maximize the differences between the components, but the resulting factors do not correlate, implying etiologies for each component involving distinct nonoverlapping risk factors and no correlation in exposure to them. Oblique rotations are generally considered more natural, because they generate components that may correlate. In the current study, the choice of rotation had no material effect on the results.

Interpretation

The timing of onset and resolution of respiratory symptoms and the circumstances in which they occur may provide an indication of underlying pathologic processes. Wheeze is not a feature of normal respiratory development but is a clinical symptom caused by various pathophysiologic processes and may be difficult to interpret without considering other symptoms. In contrast, cough and congestion symptoms may occur transiently in otherwise healthy children (e.g., in the context of respiratory virus infection), but may also be features of chronic respiratory disorder (e.g., asthma). Furthermore, where a child lies on the continuum between health and disease can be difficult for a parent or clinician to judge. Distinct, clearly defined symptom components may be more informative of the probability of chronic disease than a transient phenotype. However, to use this information, the components need to be valid, and their relationship established with the known risk factors and physiologic measures.

The symptom components generated by thePCAat both age 3 and 5 years were clear in character. The age 3 components correlated little with each other, apart from the wheeze and cough components. At age 5, the wheeze and cough components again show moderate correlations, but chest congestion seemed to be a separate dimension. Similarly, there was a stability of these main components as the children aged, and the correlations over time were reassuringly specific, despite the differences in the questionnaires used (i.e., the correlations of corresponding symptom components at two time points were consistently stronger that those between the different components at the same age). Overall, the component correlation coefficients were not strong between the two time points studied, most likely due to the transient nature of symptoms in some of the children. These components all remained separate when the varimax rotation of the model was used, confirming they are distinct and probably have different etiologies. This multivariate analysis has revealed novel relationships between symptoms, known risk factors for asthma, and objective measures of lung function and atopy. For example, at age 3 years, sRaw was not only related to wheeze but also independently to the cough component. Moreover, the interaction between maternal asthma and child’s atopy was independently related to both cough and wheeze.Wehave previously demonstrated a significant effect of the interaction between child’s atopy and maternal asthma on lung function among asymptomatic children at age 3 years (14), and suggested that these features affect the development of wheeze via their effect on lung function. However, it was apparent in the current analysis that lung function was related to symptom components independent of the interaction between child’s atopy and maternal asthma, raising questions about the underlying pathophysiologic mechanisms.

Analysis at age 5 years suggests different associations, implying different pathologies for each symptom component. When atopy was considered as a dichotomous variable, the symptom components were not related to child’s atopic status. However, using atopy as a continuous trait revealed the associations between symptom components, lung function, airway reactivity, and level of allergen- specific IgE. Our findings suggest that endorgan susceptibility and systemic immune responses contribute independently to distinct symptom components and that their effect differs between components.

The additional questions at age 5 years enabled characterization of three separate wheeze components (wheeze, wheeze with allergens, and wheeze with irritants), each with different relationships to physiologic hallmarks of asthma. This raises a fundamental question as to whether all early childhood wheezing should be treated by the same antiasthma drugs (23-25).

Generalizability

We wish to emphasize that the prevalence of allergic sensitization among the parents of the children in our cohort is similar to that of young adults in the United Kingdom (26). This suggests that the subjects are representative of the general population, and that our results are generalizable.

It would be of value to explore similar symptom components in the other large birth cohort studies. This could be achieved either by each study generating its own “syndromes” from its datasets and comparing those between the studies, or by testing the components described here within the other datasets (provided the questionnaires used are identical). Another approach would be to identify such components in a pooled dataset, allowing a more generalized definition of syndromes, which can be used as endpoints in etiologic analyses or identification of treatment groups.

We acknowledge the relative complexity of this approach to the analysis of datasets collected using standardized questionnaires with multiple questions. However, once determined, the components become continuous clinical outcome variables in their own right, which can be used in further analyses. The advantage of this approach is that these components retain the appropriately weighted information collected from numerous questions, while reducing the problem of multiple testing when each individual question is used as a dichotomous variable.

Conclusions

Our analysis supports the need to move beyond the presence or absence of individual symptoms; indeed, in our dataset, the questionnaire items representing the presence of wheeze or cough were redundant, because they were not discriminatory. More useful information may be gained from examining syndromes of coexisting symptoms that are more likely to reflect the underlying pathophysiologic processes. Such an approach may eventually help identify individuals who would benefit from a particular treatment/ intervention. Within this context, abandoning both asthma and atopic sensitization in favor of distinct symptom components and quantitative allergy may be more useful both in diagnostics and treatment decision making.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Acknowledgment: The authors thank the Manchester Asthma and Allergy Study (MAAS) children and their parents for their continued support and enthusiasm. They also acknowledge the dedication of the MAAS study team.

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

In epidemiologic studies of respiratory symptoms, children are often assigned a phenotype based on the response to a single question (e.g., presence/absence of wheeze).

What This Study Adds to the Field

This study demonstrates the need to move beyond the presence of individual symptoms and demonstrates that, in children aged 3 and 5 years, syndromes of coexisting symptoms are significantly related lung function and risk factors for asthma.

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Jaclyn A. Smith1, Richard Drake2, Angela Simpson1, Ashley Woodcock1, Andrew Pickles3, and Adnan Custovic1

1Respiratory Research Group, 2Divisions of Psychiatry and 3Biostatistics, Health Methodology Research Group, University of Manchester, Manchester, United Kingdom

(Received in original form September 25, 2007; accepted in final formMarch 19, 2008)

Supported by Asthma UK grant 04/014 and Moulton Charitable Trust.

Correspondence and requests for reprints should be addressed to Dr. Jaclyn A. Smith, M.D., Ph.D., University of Manchester, ERC Building, Second Floor, Wythenshawe Hospital, Manchester M23 9LT, UK. E-mail: jacky.smith@manchester. ac.uk

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 177. pp 1358-1363, 2008

Originally Published in Press as DOI: 10.1164/rccm.200709-1419OC on March 20, 2008

Internet address: www.atsjournals.org

Copyright American Thoracic Society Jun 15, 2008

(c) 2008 American Journal of Respiratory and Critical Care Medicine. Provided by ProQuest Information and Learning. All rights Reserved.




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