1 From the Division of Research, Kaiser Permanente, 3505 Broadway, Oakland CA 946115714 (e-mail: ljh{at}dor.kaiser.org)
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ABSTRACT |
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anthropometry; breast neoplasms; nutrition; risk factors
Abbreviations: CI, confidence interval; OR, odds ratio
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INTRODUCTION |
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Kaiser Permanente, a health maintenance organization, has provided medical care in northern California since 1946. Some members who joined the health plan as children in the 1940s and 1950s were still enrolled in the plan, with or without interruptions in their membership 20, 30, and even 40 years later, when they were diagnosed with breast cancer. This afforded us the opportunity to use information on childhood height recorded prospectively in the medical record to examine the hypothesis that greater prepubescent height is associated with greater adult breast cancer risk.
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MATERIALS AND METHODS |
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Of the 391 cases initially identified, 177 were ineligible at chart review. Of these, 164 were older than age 12 years upon entry into the plan, with this large number resulting from our use of the medical record number as a proxy for year of entry into the health plan. We designed this approach to be sensitive but not specific. In addition, two ineligible cases had been treated but not diagnosed at Kaiser Permanente, three had a history of breast cancer before 1974, seven had inaccessible charts, and one had not really developed breast cancer.
The controls included women who were members of Kaiser Permanente during the period when incident cancer cases were ascertained (19731995) and, like the cases, first joined Kaiser Permanente when they were age 12 years or younger. One control was selected for each eligible case, and the controls were frequency matched to the cases on the following: year of birth (19341939, 19401944, 19451949, 19501954, and 19551962) and age at entry in Kaiser Permanente (ages 04, 58, and 912 years). In addition, controls were assigned a reference date at which they were active members of the health plan, so that the distribution of reference dates for the controls corresponded to the distribution of diagnosis dates for the cases. There were 214 eligible and 119 ineligible controls, with all of the latter being older than age 12 years at entry into the plan.
Data collection
Information on height, weight, demographic characteristics, menstrual and reproductive characteristics, and benign breast disease was obtained from the medical record by a single trained medical record analyst. The medical record was reviewed from the first chart date to the diagnosis or reference date. However, a family history of cancer was not ascertained if the note was recorded within the 6 months preceding the reference date because the case's chart might have more complete information on family history once breast cancer was suspected (even though it had not yet been diagnosed). Every measurement of height and weight recorded in the medical record through age 24 years was ascertained. We sought to obtain the heights of the mother and father, but the father's height was missing for 106 of the cases.
Data analysis
For each subject, we computed height and weight at each year of age as well as the age of the measurement to one-tenth of a year (e.g., 8.5 years). If a subject had multiple measurements at age 8 years, for example, one at age 8.2 years and one at age 8.6 years, we computed the mean of the measurements as well as the mean of the ages.
The body mass index was computed as weight (kg)/height (m2). The Pearson correlation coefficients of age-specific height with age at menarche, adult height, and mean parental height were estimated. The growth curves of the cases and controls were plotted and visually inspected. Age-specific height and body mass index were coded into tertiles by using cutpoints based on the distribution in the controls. There were relatively large numbers of subjects without a measurement in any particular year of age, and we put these subjects into a separate exposure category, "missing." In additional analyses, we increased the sample size in each category by grouping girls who had at least one height measurement during the age intervals 35, 68...1518 years. For example, if a girl had been measured only at age 4 years, her height at that age was compared with the tertiles of height among the controls who were aged 4 years at measurement, and she was categorized as short, medium, or tall. A girl who was measured only at age 3 years was compared with the tertiles of height among controls who were age 3 years at measurement. Thus, a girl categorized as short in the age group 35 years could have been in the lower tertile at age 3, 4, or 5 years.
The distributions of height and body mass index, both as continuous variables and as tertiles (with missing values being treated as an additional category), were compared between cases and controls in contingency tables and in logistic regression analysis using the Statistical Analysis System (9). Maximum likelihood methods were used to estimate the odds ratios for the associations of height and body mass index with breast cancer risk at each year of age after adjustment for confounding factors, and the 95 percent confidence intervals were calculated using standard errors.
The following were examined as potential confounding factors through adjustment: the matching variables birth year and age at entry, and marital status, alcohol use, race, parity, age at first birth, and menopausal status. Maternal breast cancer history was examined as a confounding factor by excluding women who reported a family history. None of these variables confounded the relations. In addition, we sought to examine whether age-specific height in early adolescence was associated with breast cancer risk strictly through an effect on age at menarche and whether deviation from mother's height, a partial measure of genetic height potential, was associated with breast cancer risk. We attempted to examine the association of height 1 or 2 years prior to the onset of menses with risk, but the available sample size was too small (because of missing values for height during this brief period) to permit meaningful interpretation of the results. We also sought to examine the relation separately in pre- and postmenopausal women, but had an adequate sample to examine premenopausal women only.
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RESULTS |
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DISCUSSION |
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However, the study has several limitations. We observed a case-control difference in the level of missing information on covariates. This difference was particularly noticeable for variables measuring events in adulthood, such as marital status, alcohol use, and menopausal status. We believe through indirect evidence that the case-control difference in the level of missing information can be attributed to earlier identification of breast cancer among women who are relatively heavy utilizers of the health plan and who would have undergone more frequent breast cancer screening. These women would also have had greater opportunity to provide information on their covariate levels. Evidence for this comes from the comparison of the proportion of ductal carcinoma in situ in our sample (20 percent) relative to the proportion in the entire health plan (15 percent) during the period 1974 1995 (10).
The growth characteristics of our sample are roughly similar to a representative sample of children residing in Berkeley, California, as described by Thissen et al. (11) in the Berkeley Growth Study. Growth characteristically has prepubertal and adolescent components, each of which is driven by genetic and environmental factors, the primary factors being nutrition and disease (12
). Adult height is largely driven by prepubescent growth (13
). Early nutrition influences the balance of hormones (both growth hormones and sex hormones) important in growth and development, and these hormones drive prepubertal growth, the timing of the adolescent growth spurt, and the onset of puberty (14
16
). Indeed, an affluent diet drives rapid growth and early puberty, and age-specific height can be taken as a monitor of nutritional status (17
).
It has been hypothesized that childhood nutrition increases breast cancer risk by changing the hormonal profile. Thus, the increasing incidence rates of breast cancer observed in second- and third-generation migrants from Asia to the United States, as well as the secular trend in breast cancer risk among Asian residents, are postulated to result from improved childhood nutrition (18).
We observed little evidence for an association of childhood height with risk of breast cancer beyond that expected based on the relation of childhood height with adult height and the known relation of adult height with risk of breast cancer (1921
). The strongest association of age-specific height with breast cancer risk did not occur with prepubertal height, as we had hypothesized, but rather with height in the latest years of childhood (1518 years).
Only one other study has ascertained childhood exposures prospectively. Le Marchand et al. (22) observed that Hawaiian girls of Japanese descent aged 1014 years born from 1918 to 1943 and at the highest tertile of body mass index were at 70 percent (p < 0.05) lower risk of premenopausal breast cancer relative to girls in the lowest tertile. They observed no important associations with height. Li et al. (23
), using recalled height in a study of 747 cases, observed that women who reached their adult height at age 18 years or older were at 30 percent (95 percent CI: 0.5, 1.0) lower risk than women who had reached their adult height at age 13 years or younger. We were unable to confirm their findings because of our limited sample size. In the Nurses' Health Study, peak height velocity in the highest quintile relative to the lowest, estimated from recalled age at menarche, recalled body fatness at 10 years of age, and adult stature, was associated with a 30 percent increased risk of breast cancer (24
).
Three studies have observed associations of premenopausal breast cancer with recalled adolescent body mass index (2527
), but the results have conflicted, with one indicating a direct association, the second indicating an inverse association, and the third indicating a U-shaped association. In addition, two studies have reported associations with recalled adolescent diet (27
, 28
).
Our main result--that prepubertal height was not associated with breast cancer risk beyond its association with adult height--is not adequate to refute the hypothesis that nutritional status early in life affects the risk of breast cancer. Because the girls included in our study were born to relative prosperity in northern California during 19341963, there may have been too little diet-related variation in age- specific height in our population. Thus, the coefficient of variation for height at the age of peak height velocity (10 years) was only 5 percent. Age-specific height shows greater variation across time and internationally, so we cannot rule out that nutritional status, as measured by age-specific height, would correlate with the international pattern in breast cancer risk.
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NOTES |
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REFERENCES |
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