1 Division of Cancer Prevention, National Cancer Institute, Bethesda, MD.
2 Office of Disease Prevention, Office of the Director, National Institutes of Health, Bethesda, MD.
3 Marshfield Medical Research and Education Foundation, Marshfield, WI.
4 Division of Hematology-Oncology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT.
Received for publication June 19, 2002; accepted for publication November 4, 2002.
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ABSTRACT |
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ethnic groups; family characteristics; genetic predisposition to disease; neoplasms; questionnaires; sex factors
Abbreviations: Abbreviations: CI, confidence interval; PLCO, Prostate, Lung, Colorectal, and Ovarian; SEER, Surveillance, Epidemiology, and End Results.
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INTRODUCTION |
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The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is a large, ongoing, national, multicenter cancer screening trial which includes a baseline questionnaire component with a family cancer history section (4). Data from this study provide us with an opportunity to assess reported family history of cancer in a large group of volunteers in a cancer-related study and to indirectly assess the validity of such data. Although we do not have direct verification of reported cancers, the large size of this study allows us to examine with great precision the effects of factors such as age, sex, and race/ethnicity on reported family history of cancer. The studys size also makes it feasible to compare the reported rates of various cancers with the rates expected on the basis of national population-based registries, and thus to help identify which cancers may be absolutely or relatively under- or overreported. Internal analysis of the family history data reported, together with analysis of the corresponding expected rates, may provide clues to assessing the validity of these data and may help us determine whether any systematic biases are present. Assessment of the validity of these data is important not only for future studies based on PLCO data but also for performing and examining family history studies based on similar questionnaire data.
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MATERIALS AND METHODS |
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Around the time of randomization, study subjects were asked to complete a written, self-administered baseline questionnaire that included questions on demographic factors, medical history, history of smoking and other health-related behaviors, and familial and personal history of cancer. The family history section of the questionnaire (questions 1821) is displayed in figure 1. Respondents were asked to list each parent, sibling, or child with a history of cancer (not including basal-cell skin cancer) and to specify the type(s) of cancer and the age(s) of diagnosis; respondents were also asked about the total numbers of sisters and brothers that they had. The open-ended responses on cancer type were coded at each screening center according to a standardized protocol.
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Logistic regression was used to model the odds that a family member had a history of cancer as a function of various covariates. Confidence intervals for the ratio of reported rates of cancer to expected rates were calculated assuming fixed expected rates and a Poisson distribution for the reported rates.
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RESULTS |
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As table shows, male respondents reported a significantly lower family history prevalence (53.1 percent) than females (61.0 percent) (difference = 7.9 percent, 95 percent confidence interval (CI): 7.4, 8.4). Table also displays the percentages of mothers, fathers, brothers, and sisters with a reported history of cancer, by the sex of the respondent. Male respondents reported significantly lower prevalences than females for all four types of relatives (p < 0.0001). Logistic modeling also demonstrated a significant interaction between the sex of the respondent and the sex of the relative (p < 0.0001); specifically, the underreporting of family history by male respondents as compared with females was lower for male relatives than for female relatives. This can be seen in table , where this underreporting was 28 percent for sisters (i.e., 100 x [1 8.6/11.9]) and 21 percent for mothers, as compared with 13 percent and 9 percent for brothers and fathers, respectively. The proportion of cancers reported to be of unknown type was significantly greater for male respondents (5.8 percent) than for female respondents (2.7 percent); as above, there was a significant interaction in that the differential between male and female respondents unknown percentages was significantly greater for female relatives than for males. Among relatives reported to have had cancer, the proportion reported to have had multiple types of cancer was significantly lower for male respondents (6.5 percent) than for female respondents (9.2 percent).
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Cancer history rates are displayed in table by the race/ethnicity of the respondent. Logistic modeling, which controlled for the age and sex of respondents, showed that Black, Hispanic, and Asian respondents each reported significantly (p < 0.0001) lower overall family history rates and lower rates for mothers, fathers, sisters, and brothers than did non-Hispanic White respondents. Blacks also had significantly (p < 0.0001) lower ratios of reported rates to expected rates in brothers and sisters (0.40 and 0.53, respectively) than did Whites (0.68 and 0.79, respectively). Brothers of Blacks had 25 percent higher expected rates than did brothers of Whites, while sisters of Whites had expected rates similar to those of sisters of Blacks. All four racial/ethnic groups demonstrated significantly lower reported rates for male versus female respondents, with the male:female ratio being lower among Blacks, Hispanics, and Asians than among Whites (data not shown).
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As table shows, the reported family history rates for siblings increased significantly with the age of the respondent, while the reported rates for parents decreased significantly with the age of the respondent (p < 0.0001 for both trends). These age trends for siblings and parents were seen for both male and female respondents and male and female relatives (not shown in the table). The percentage of reported parental cancers that were of unknown type significantly increased with the respondents age (p < 0.0001); for siblings, there was no linear trend with age, although the rates in the oldest age group were elevated (table ).
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Results by cancer type
Table displays the percentage of respondents reporting any family history for various types of cancer. The four cancers most commonly reported in families were breast (11.8 percent), lung (10.1 percent), colorectal (9.4 percent), and prostate (7.3 percent) cancer. Breast, lung, and colorectal cancers each had approximately 1 percent of respondents reporting two or more relatives with the given cancer (table ). A total of 26 respondents (0.02 percent) had families meeting the Amsterdam criteria for hereditary nonpolyposis colon cancerthat is, three or more relatives of at least two generations with colorectal cancer, at least two of whom are first-degree relatives of the third and at least one of whom was diagnosed by age 50 (6). A total of 250 respondents (0.2 percent) had a family history consistent with breast-ovarian syndromethat is, three or more cases of breast or ovarian cancer in first-degree relatives. For most cancer types, parents and siblings comprised more than 90 percent of the reported cases; types for which offspring accounted for at least 10 percent of cases were testicular cancer (35 percent), cervical cancer (17 percent), lymphoma (14 percent), and melanoma (12 percent). Of cancers diagnosed in childhood (age <20 years) among any type of relative, the four most commonly reported types were leukemia (32 percent), brain tumors (13 percent), Hodgkins disease (10 percent), and bone cancer (8 percent).
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Blacks reported significantly lower family history rates than did Whites for all cancers listed except prostate, lung, and stomach cancer, for which the rates were essentially identical. Asians and Hispanics reported 3.0- and 1.5-fold higher rates, respectively, of a family history of stomach cancer than did Whites, and Asians also reported significantly higher rates of liver, pancreatic, and esophageal cancer than did Whites. All other cancers were reported at significantly lower rates by Hispanics and Asians than by Whites, with the exception of vaginal and uterine cancer, which Hispanics and Whites reported at essentially the same rates.
Age of diagnosis was reported for approximately 90 percent of sibling cancer cases (the other 10 percent included instances where no age was given and instances of multiple cancers where the age of diagnosis of each cancer type was not distinguished). The age distributions did not differ appreciably by the sex of the respondent. The reported median age at diagnosis was close to that expected for most cancer types, as was the reported percentage diagnosed before age 50. The reported and expected medians were within 3 years except for uterine cancer (6 years younger than expected), leukemia in females (4 years younger than expected), esophageal cancer in females (5 years older than expected), and bone cancer in males and females, where the reported medians (and percentages over 50) were much greater than expected. The percentage of cases diagnosed after age 50 also differed appreciably for uterine cancer (53 percent reported vs. 76 percent expected) and testicular cancer (33 percent reported vs. 17 percent expected).
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DISCUSSION |
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Rates of reported family history of cancer for other racial/ethnic groups were substantially lower than those for Whites. Blacks also had considerably lower reported:expected ratios than did Whites (expected rates were not calculated for Asians and Hispanics). Note that Hispanics and Asians are very heterogeneous groups, and this study population is not representative of these groups in the United States as a whole. Most of the Asians included in this study came from the PLCO center in Hawaii.
The 2000 National Health Interview Survey contained questions on family history of cancer; we obtained the raw data tapes and conducted basic analyses of data from this survey (10). The family history rates in the age group 5574 years (n = 7,120) were generally similar to though slightly lower than those found here. The structure of the family history questions was different in the National Health Interview Survey than in the PLCO Trial (e.g., individual questions were asked about the cancer history of the respondents mother, father, sisters, and brothers), and the National Health Interview Survey was a telephone survey, so it would not be expected to produce identical results. The National Health Interview Survey data showed a sex-specific trend, with males reporting approximately 20 percent lower rates of a sibling history of cancer than females and 7 percent lower rates for a mothers history of cancer (the reported rates for fathers were similar). The National Health Interview Survey also found that Blacks and Hispanics had 3040 percent lower rates than did Whites. There were too few Asians for a meaningful comparison.
Expected rates were not computed for respondents parents, because a large fraction of parents cancers would have occurred before 1973, the earliest year for which SEER registries have data. However, we can estimate expected rates of overall cancer utilizing two different scenarios. Data from the Connecticut cancer registry showed overall age-adjusted cancer rates increasing by an average of 1.7 percent per year in males and by 0.55 percent per year in females from the late 1930s to the late 1960s (11). We calculated expected values under this (increasing) scenario by assuming that the rate in each age group increased by the above amounts each year. We also calculated expected values under the constant scenario of pre-1973 rates set equal to 1973 rates. The expected rates for fathers were 31.5 and 33.6 under the increasing and constant scenarios, respectively. Corresponding expected rates for mothers were 29.3 and 30.1. With these expected rates, the reported:expected ratio for fathers was similar to that for brothers, and the ratio for mothers was similar to that for sisters.
The expected cancer history rate in parents (under either scenario) was essentially constant with the respondents age; however, the reported rates decreased 22 percent from the lowest respondent age groups to the highest, as seen in table . Thus, this decrease in reported rates for parents with the age of the respondent may be partly due to recall bias. The calculations for expected rates also produce the expected average time remoteness of the cancer events (i.e., the time between the event and the respondents filling out the questionnaire). The expected average time remoteness increased from 19 years for the youngest age group to 29 years for the oldest age group, which may have contributed to the decrease in reported rates. The recall bias hypothesis is strengthened by the fact that the unknown cancer-type rate for parents cancers also significantly increased with the respondents age. Kerber and Slattery (3) found that the sensitivity of family history reports was lower for older respondents than for younger respondents.
Reported rates in siblings increased with the age of the respondent, though at a rate that was somewhat lower than expected. The expected average time remoteness of sibling events was fairly constant with the respondents age, with the overall average being about 11 years. There was no clear trend with respondents age in the rate of siblings cancers being reported to be of unknown type; this may relate to the fact that, unlike the case with parents, the time remoteness of the events was not increasing with the respondents age.
Reported:expected ratios of well under 1 for a given cancer could be caused by actual underreporting (i.e., not reporting events that truly did occur) or by the actual rates in this population being lower than SEER rates, or some combination of the above. A similar argument holds for ratios above 1. However, it is unlikely that the true rates in this population differ from SEER rates by more than 2040 percent for any given type of cancer. In fact, most individual cancer types were reported at rates reasonably close to those expected and with the expected age distribution, with a few important exceptions.
Reported:expected ratios greatly above 1 for liver and bone cancer and somewhat above 1 for brain cancer were probably due to the fact that respondents mistakenly reported sites of metastasis as the primary tumor site. Thirty-one percent of siblings reported to have had liver or bone cancer had multiple reported cancers; in contrast, overall only 8 percent of siblings with reported cancer had multiple reported cancers. However, even if multiple cancers were removed from the liver and bone cancer totals, the reported:expected ratios would still be well over 1. Stomach cancer also had reported:expected ratios significantly above 1, which may be indicative of misclassification by the respondent.
Cancers with reported rates much lower than expected included lymphoma, melanoma, bladder cancer, and testicular cancer. Respondents may have underreported melanoma because they mistook it for basal-cell skin cancer, a cancer that was not supposed to be reported according to the baseline questionnaire. Testicular cancer is one of the most curable cancers, so this may be a factor in its underreportage; in addition, this cancer was likely to have occurred a long time in the past because of its young age distribution (5). There were a number of instances in which respondents specified "lymph nodes" as the cancer site. According to SEER data, almost all (>99 percent) primary cancers at this anatomic site are classified morphologically under lymphoma (12). If these were all added to the reported lymphomas, the (female-) reported:expected ratio would increase from 0.40 to 0.60. However, since many cancers spread to the lymph nodes, some respondents may have denoted a primary cancer at another site that spread to the lymph nodes as "lymph node" cancer. A large proportion of bladder cancers are low-grade and treated with periodic local excision, so family members may not report these lesions as cancers (13).
Airewele et al. (1), in a direct verification study, found that liver and bone cancer, along with stomach cancer and gynecologic cancers, tended to be reported less accurately than other cancers. Kerber and Slattery (3) showed decreased validity for reports of uterine cancer in comparison with breast, colon, and prostate cancer.
In conclusion, this study shows important differences in rates of reporting of a family history of cancer by the sex, race/ethnicity, and age of the respondent. For the most part, these differences appear to be due to relative underreporting according to the above factors, as opposed to true differences in family rates. Most individual cancer types were reported by females at rates 1040 percent below the rates expected, although a few appeared greatly over- or underreported. These findings should be taken into consideration when performing epidemiologic or other analyses based on these or similar family history data obtained from questionnaires.
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APPENDIX |
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We used age-, sex-, and calendar-year-specific Surveillance, Epidemiology, and End Results (SEER) cancer incidence rates, cancer mortality rates, and life tables to compute the probability of ever getting cancer (overall or type-specific) for a given birth year, end year (i.e., the year of the baseline questionnaire), and sex, employing the method of Feuer et al. (14). The SEER data begin in 1973 and are current (as of this writing) through 1998, and the life table data cover 19002000 (12, 15). We applied the 1973 rates for years prior to 1973 and the 1998 rates for years after 1998. For most cancers, we estimated that the majority of cases in siblings (85 percent) were diagnosed from 1973 onward; and for all cancers, only a small proportion would have been diagnosed after 1998. For cancers for which a large percentage of cases would be expected to have been diagnosed before 1973 (e.g., testicular cancer), we performed sensitivity analyses using the Connecticut cancer registry rates, which go back to 1935. The only cancer for which the expected rates would have changed appreciably was testicular cancer, and here the expected rate decreased by only 10 percent.
The final step was to compute, for each sex of respondent and sibling, the weighted average of the above probabilities of ever getting cancer over the distribution of birth year and end year in the sibling population, in order to obtain expected probabilities for the siblings. Data were not collected on the ages of the siblings, so we assumed a 0 mean distribution on the age difference between siblings and the respondent (the final results were quite robust to the exact nature of the distribution). The age of the respondent, the age difference, and the end year then specified the birth year of the sibling.
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NOTES |
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REFERENCES |
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