- Email: [email protected]
The Cooperative Familial Registry for Breast Cancer Studies
Journal of Clinical Epidemiology 54 (2001) 93–98
The Cooperative Familial Registry for Breast Cancer Studies: design and first year recruitment rates in Ontario Heather J. Sutherlanda,*, Jeanie Lacroixb, Julia Knightb, Irene L. Andrulisc, Norman F. Boydd, the Ontario Cancer Genetics Networke a
The Ontario Familial Breast Cancer Registry, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada b Cancer Care Ontario, Toronto, Ontario, Canada c Ontario Cancer Genetics Network and Lunenfeld Institute, Mount Sinai Hospital, Toronto, Ontario, Canada d Epidemiology, Statistics and Behavioral Research, Ontario Cancer Institute, Toronto, Ontario, Canada e Ontario Cancer Genetics Network, Cancer Care Ontario, Toronto, Ontario, Canada Received 7 January 2000; received in revised form 4 April 2000; accepted 17 April 2000
Abstract The Ontario Familial Breast Cancer Registry (OFBCR) is one of six international sites of the Cooperative Familial Registry for Breast Cancer Studies collecting family history, epidemiologic information, and blood samples from families (with various patterns of familial risk) for the purpose of studying the etiology of breast cancer. To invite 2361 female breast cancer patients residing in Ontario to take part in the Registry, a package was sent that included a Family History Questionnaire. Several variations of mailing and follow-up strategies were employed. Overall, the response rate was 67%. The best response (74%) was achieved by following up our introductory package of information with a postcard 10 days later and a telephone call several weeks thereafter. Given the design of the project, which involves a considerable commitment on the part of both patients and their family members, we are impressed by the positive response of these women. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Familial breast cancer; Recruitment methods
1. Introduction Family studies of breast cancer have shown that there is an inherited component to the etiology of the disease and have led to the discovery of genes that are associated with a striking increase in risk [1,2]. These studies have been carried out mainly in highly selected families with several members affected by the disease, and not identified as a result of any defined sampling strategy. To generate unbiased estimates of the risks of disease associated with these genes, and of their interaction with other risk factors, we need to study families selected from the population in a systematic manner. Further, to ensure that the families selected are representative of the population from which they were selected we must achieve a high response rate from those approached. To promote interdisciplinary studies in the etiology of breast cancer, and to foster translational research in this area, the National Institutes of Health issued a Request for
* Corresponding author. Tel.: (416) 946-4409; fax: (416) 946-4410. E-mail address: [email protected]
Applications (RFA) in 1994 to establish a Cooperative Familial Registry for Breast Cancer Studies (CFRBCS). The purpose of the Registry was to collect pedigree information, epidemiological data, and biological specimens from subjects with a family history of breast cancer, and to identify a population at high risk for breast cancer that will participate in the evaluation of new preventive and therapeutic strategies. The CFRBCS comprises six sites, four in the United States, one in Australia, and one in Canada (Ontario). Three sites utilize high-risk cancer genetics clinics for recruitment and three are population-based registries. The consortium will undertake cooperative studies using pooled data. In this article we describe the development and first-year recruitment experience of one of the population-based sites, the Ontario Familial Breast Cancer Registry. Specifically, this report describes the effect of different mailing and follow-up strategies on response rates to a questionnaire used to identify patterns of cancer in families of patients with newly diagnosed breast cancer. Only the experience with female participants is reported here as males were targeted for another provincial study during the first year of recruitment for the Registry. The Registry is still accruing subjects (year
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2000) and is expected to complete all data collection by the year 2002.
2. Methods 2.1. General method The Ontario Familial Breast Cancer Registry (OFBCR) is a resource of families willing to participate in this and future studies related to familial breast cancer. Using defined criteria, the Registry contains “high to moderate” risk families (with any one of a number of characteristics described below) and a random sample of families designated “low” familial risk. The general method being used in the OFBCR is to identify, through pathology reports in the Ontario Cancer Registry, all incident cases of breast cancer in the population of Ontario diagnosed during 1996–1998, to obtain information about familial breast and other cancers in these individuals, and to select, using explicit criteria, subjects who are asked to provide further information. Physicians are approached and asked to provide approval before their patients are contacted. Subsequently, family history information is collected and families are classified regarding familial risk using defined criteria. Epidemiologic information and blood samples are sought from probands and some of their relatives. Existing tissue samples are requested for all those within a family who have had a diagnosis of breast or ovarian cancer. 2.2. Background information 2.2.1. Catchment area The population of Ontario is approximately 11 million (1998 figures) living in an area of about 412,000 square miles although the majority of the population lives in the southern regions. It is a largely urban population with only 20% considered to be rural in the 1991 census. About half of the population is of British descent with the remainder from a variety of European and non-European backgrounds. No other group comprises more than 10% of the population. Ontario has age-specific rates of breast cancer similar to Canada as a whole, and the age-adjusted rate (to the world population) is 78 per 100,000 per year [3]. The current estimate is that approximately one in nine women will develop breast cancer during their lifetime [4]. 2.2.2. The Ontario Cancer Registry (OCR) Since the inception of the Ontario Cancer Registry in 1964, almost all cases of invasive neoplasia newly diagnosed among residents in Ontario have been registered. The OCR is the largest patient-specific, population-based cancer registry in Canada. It employs a passive voluntary system of registration that is quite complete because of the overlap that exists among its reporting sources. A recent study of the estimate for completeness of case ascertainment for breast cancer indicated it to be in excess of 97% [5].
2.3. OFBCR materials and procedures (ongoing) 2.3.1. Registry eligibility criteria As described above, probands identified through the Ontario Cancer Registry must be diagnosed with pathologyconfirmed, invasive breast cancer between January 1996 and December 1998. Those eligible include all women diagnosed at ages 20 through 54, a random sample of 35% of women diagnosed at ages 55 through 69, and all men diagnosed with breast cancer at ages 20 through 79. All must be residents of Ontario and able to read and speak English or have access to a translator in order to be included. Eligibility criteria for relatives are described in Table 1. For these participants, place of residence is not limited. 2.3.2. Questionnaires The Family History Questionnaire requests information about parents, children, and siblings as to age, date of birth, status alive or dead, age and date of death, whether or not the relative has had cancer, its type and the age and date of diagnosis, and details of any cancers in other relatives. This questionnaire has been shown to yield sufficiently accurate information to screen breast cancer patients by mail in order to identify families suitable for further investigation [6]. The Personal History Questionnaire requests information about risk factors associated with the development of breast cancer. It includes questions about height and weight, alcohol use, smoking history, medical and reproductive history, use of hormones, radiation exposure, and exercise. It also elicits demographic information such as country of the family’s origin, marital status, religion, and educational level. The questionnaire was developed by the CFRBCS and has been pilot tested for ease of use and understanding. The Diet Questionnaire was developed and validated by the University of Hawaii [7]. It inquires about the intake of an extensive, multiethnic list of foods (approximately 177 food items). It is scannable and includes photographs of representative food items with variable serving sizes. 2.3.3. Announcement of the Registry Prior to the initiation of the data collection, physicians throughout the province were made aware of the project by letter. They, and any who were missed in the initial mailing, also received a brochure describing the Registry on the first occasion that we wrote to them. 2.3.4. Data collection procedures for probands Once a case is identified, pathology reports are obtained and a letter is sent to the surgeon named on the report. It describes the purpose of the study and his/her role in it, which includes granting permission to contact the patient (or providing the name of a more appropriate doctor) and supplying the patient’s address. After permission is received, patients are contacted by mail and asked to complete an initial questionnaire to identify the number of cases of breast or ovarian or other cancers within the family. At this mailing, a letter of introduction, a Family History Questionnaire (described above), two consent forms (one to sign and return,
H.J. Sutherland et al. / Journal of Clinical Epidemiology 54 (2001) 93–98 Table 1 Criteria for selecting eligible relatives for the Ontario Familial Breast Cancer Registry • Proband’s 1st degree relatives (children, siblings, parents). • Living relatives with breast/ovarian cancer ⫹ their 1st degree relatives. • If relative with breast/ovarian cancer is deceased then their 1st degree relatives are still included. • Relatives with an adult onset cancer at a young age (⬍50 years). Excluded are cervical, testicular, leukemia, and lymphoma. • Half siblings on the “at risk” side.
one to keep), a brochure describing the study, and a stamped addressed return envelope are included. When the completed Family History Questionnaire is received, a genetic counsellor reviews it using a set of criteria (Table 2) and determines whether the family is considered “moderate to high risk” or not. Those who are deemed moderate/high risk, and a 25% sample of those at low risk, are telephoned. The family history is expanded and the further steps in the project are explained. These steps involve completing Personal History and Diet Questionnaires (described above) and providing the names and addresses of eligible relatives for contact. The final step in the process involves obtaining a blood sample for genetic testing from all moderate/high-risk and a small number of low-risk probands. Prior to giving blood, genetic counselling is offered and when genetic testing is completed results are made available to each participant who wishes to have this information. With the patient’s permission, existing tissue samples are requested from hospitals. During the course of the project, all tissue of probands will be reviewed and the pathology confirmed. Three separate consent forms are signed granting permission to use the family history, epidemiologic data, and biospecimens. 2.3.5. Data collection procedures for relatives After receiving mailed information about the Registry, relatives who agree to participate complete the epidemioTable 2 Criteria defining moderate/high-risk families used by the OFBCR • • • • • • • • • • •
Proband ⫹ ⭓1 1st degree relative with breast or ovarian cancer. Proband ⫹ ⬎2 2nd degree relatives with breast or ovarian cancer. Proband diagnosed with breast cancer at age ⭐35. Proband ⫹ 1 2nd degree or ⭓1 3rd degree relative diagnosed at age ⭐35 breast or ⭐60 ovarian. Male proband. Proband with 1 2nd degree or ⭓1 3rd degree relative with male breast cancer. Proband with breast and ovarian or multiple breast cancers. Proband ⫹ 1 2nd degree relative or ⭓1 3rd degree relative with breast cancer and ovarian cancer. Proband ⫹ 1 2nd degree or ⭓1 3rd degree relative with multiple breast cancers. ⭓3 1st degree relatives (of each other) with breast, ovarian, colon, prostate, sarcoma, or pancreas, 1 diagnosed ⭐50 years of age. Of Ashkenazi Jewish descent (at least 1 grandparent).
These are intended to capture a wide range of patterns of breast cancer within the families.
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logic questionnaires (Personal History and Diet Questionnaires). They are also offered counselling and asked to provide a blood sample. For those who have had breast or ovarian cancer, permission is sought to retrieve existing tissue from surgeries for review. An attempt is made to confirm all cases of cancer in both living and deceased relatives by requesting pathology reports. Consent forms are signed at each stage. A report of the OFBCR’s experience in recruiting relatives will be described at a later date. 2.3.6. Mailing and follow-up strategies for first-year recruitment We have tried a number of approaches, all of which have been based on modifications of mailing strategies described by Dillman [8] that are designed to produce a high response rate in mailed surveys. Certain features are incorporated into these mailings to make each package seem personalized rather than mass produced. For example, the principal investigator (I.A.) signed each letter and commemorative stamps were used on the outside envelope. After the initial package was sent, we either telephoned, sent a postcard, or did both. In one mailing, the same material was sent a second time to nonrespondents. The variations are described in the order in which they occurred and are summarized in Table 3. (A) Two mailings in September and October 1996 (408 patients) were sent and phone calls were made to nonresponders beginning 3 weeks after the mailing and continuing for a number of weeks thereafter. (B) The same strategy as used in A was used in the November 1996 mailing (93 patients), with the addition of a form, to be returned, which allowed the patient to indicate that she was declining or was unable to participate currently but would do so at a later date, which she specified. This form was included in all subsequent mailings. (C) In the January and February 1997 mailings (270 patients), a postcard was sent 10 days after the original mailing followed by a phone call. Phone calls began 3 weeks after the postcard reminder and contact occurred, in some cases, many weeks after the initial mailing. (D) In the March and April 1997 mailings (330 patients), the package was sent followed by the postcard follow-up and 4 weeks later a second complete package was mailed to those who had not responded. No phone follow-up was done. (E) The final method used in the last mailing of the 12-month period (1260 patients) employed the same strategy as in the January/February mailing except phone calls were made exactly 3 weeks after the postcard was mailed. Because of the large number of phone calls made, other tasks were put aside until calling was completed. Because patients were approached at different times, we have compared all strategies for response rates for a 30-week period. 2.4. Statistical analysis Descriptive statistics were used to report patient characteristics and response rates for the various mailing strategies. Kruskall-Wallis and chi-square tests were used to determine differences in age and place of residence, respec-
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tively, among those who responded, did not reply, or declined. Place of residence was deemed to be rural, Toronto, or other urban (a town/small city). Postal codes were used to make this determination. Toronto was separated from other urban because of the very large multicultural population and the many research groups and facilities vying for research subjects. For this analysis, a patient was called a nonrespondent if we had received no response to our various follow-up approaches within 30 weeks. If a Family History Questionnaire was subsequently returned, status was changed. This occurred very infrequently. If physicians declined approval for patient contact or if patients did not wish to participate (at any stage), an attempt was made to find out the reason for refusal. 3. Results 3.1. Characteristics of eligible participants There were 3462 incident cases of breast cancer for whom physician approval was sought during the first year of the Registry’s development. The first patient mailing was in September 1996. Thus, we have taken September 1996 to August 1997 as the first year of recruitment. Of the 2361 women approached by August 1997, age and geographic residence were the only data, aside from diagnosis, available for each person. The mean age was 50.3 years (SD 9.2) with a range of 31 to 69 years. Note that this does not reflect the mean age of women with breast cancer as older women were sampled. Place of residence for these women was as follows; 536 (23%) lived in Toronto, 1428 (60%) lived in other urban areas, and 397 (17%) were rural dwellers.
medical/emotional factors (n ⫽ 60), the patient declined when asked by the physician (n ⫽ 40), the patient was deceased (n ⫽ 28), or didn’t reside in Ontario (n ⫽ 27), or had language difficulties (n ⫽ 11). For the remaining 48 patients, no reason for refusal was given. It should be noted that for 166 women for whom permission was granted, letters were not sent because of incomplete or incorrect patient information. 3.3 Patient response rates to first contact Of the 2409 patients considered eligible for contact, 48 were not included in this summary (11 were deceased, 4 were ineligible, 12 asked for a postponement, 21 had no address identified). Of the remaining 2361, 1589 (67%) participated, 245 declined (10%), and 527 (22%) were nonrespondents. Documented reasons for nonparticipation included seriously ill (n ⫽ 36), language difficulties (n ⫽ 20), alienated or did not know family history (n ⫽ 19), and concerns about confidentiality (n ⫽ 6). The remainder (n ⫽ 164) provided no comment. For those who completed the FHQ, ethnicity information was also available. The majority described themselves as white (n ⫽ 1360); other categories were Asian (n ⫽ 50), Chinese (n ⫽ 33), Jewish (n ⫽ 30), black (n ⫽ 18), Native (n ⫽ 6), and other/mixed (n ⫽ 34). Fifty-one gave no response and seven did not know their ethnicity. There was a significant difference in age between participants, nonresponders, and those who declined with the latter being significantly older (P ⭐ 0.0001). Women living in Toronto were significantly more likely to refuse or not respond than women living in rural areas or towns/small cities (P ⭐ 0.001) (Table 4).
3.2. Physician response rates It should be noted that while some physicians asked each patient if she wished to be involved before approving our request for contact, the vast majority of doctors did not. Physicians gave permission for 2575 (74%) patients to be contacted; 214 (6%) requests were declined and 673 (20%) were still pending (but may have been received later) at the cutoff date for this report. Reasons for refusal included
Table 3 Summary of key components of mailing strategies Mailinga
Questionnaire package Postcard 10 days after package Phone call 3 or more weeks after mailings Phone call exactly 3 weeks after mailings Form of postponement or refusal Questionnaire package resent
A
B
C
D
E
⫹
⫹
⫹
⫹
⫹ ⫹ ⫹
⫹ ⫹
⫹ ⫹
⫹
⫹
⫹ ⫹
⫹ ⫹
a A ⫽ September and October 1996. B ⫽ November 1996. C ⫽ January and February 1997. D ⫽ March and April 1997. E ⫽ May through August 1997.
3.4. Success of mailing and follow-up strategies The response rates for the various strategies are shown in Fig. 1. For this project, the greatest response rate (73.7%) was achieved by sending a postcard after the package and following up with a phone call to nonrespondents (strategy C). It did not appear to matter when the phone call took place. The second-best response rate involved phone follow-up alone but the initial response was less than with a postcard reminder. The poorest response rate (61.3%) was found with the November mailing (strategy B). This mailing, with telephone follow-up, included a response form whereby the patient could directly decline or postpone participation to a more suitable time. We have included this form in subsequent mailings without any obvious adverse effect. We suggest that the reduced response rate in November could be due to seasonal variations. From our experience November, as well as July and August, appear to be inopportune times to approach patients. Note that no mailing was done in December. Interestingly, a second complete mailing of the information package and questionnaire had an abrupt conclusion with no further responses after 21 weeks.
H.J. Sutherland et al. / Journal of Clinical Epidemiology 54 (2001) 93–98 Table 4 Patient characteristics (N ⫽ 2361)
Age (years) Mean (SD) Geographic location (%) Toronto Other urban Rural a b
Participate (n ⫽ 1589)
Decline (n ⫽ 245)
No response (n ⫽ 527)
P-value
50.3 (9.3)
52.8 (9.5)
49.2 (8.8)
0.0001a
19.3 61.6 19.1
29.8 55.1 15.1
29.6 59.8 10.6
0.001b
Kruskall Wallis. Chi-square.
4. Discussion The design and magnitude of this provincial project have made it most challenging to operationalize. Three distinct phases of data collection involving the patient-participants plus two phases for their relatives, collection of tissue blocks as well as fresh frozen tissue, confirmation of diagnoses by pathology reports, coordination of genetic counselling and blood collection, handling and testing of the biospecimens, and follow-up with patients concerning their carrier status has provided the research team an opportunity in which a wealth of experience has been gained.
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There are few data to draw upon for a benchmark against which to measure the success of accrual for this type of project. Certainly, the physicians and surgeons who have been approached have been most cooperative and supportive of this research and we expect to exceed the 80% projected response rate for physicians by the end of the project. During the first year of recruitment, we had responses from 77% of the patients who were approached. Of the total population contacted, a majority (67%) completed the Family History Questionnaire, the entry point for the Registry. At the time of writing of this report, the expected proportion and numbers meeting the Registry criteria and, therefore, proceeding with the other phases of the project (approximately 300 families per year meeting moderate/high risk criteria) has been achieved. Our data indicate that older women and those who live in Toronto, the largest city in the province, are the most likely to decline or not respond. Other reports of accrual experience in clinical studies confirm the finding that older subjects and those living in urban areas may be less interested in making such commitments [9,10]. We hypothesize, based on experience and anecdotal information from patients, that investigators in the large number of teaching hospitals in Toronto (with both in-house research and multicenter/site projects) approach many of these patients soon after diagno-
Fig. 1. Comparisons of response rates to various strategies for recruitment (September 1996 to August 1997). A ⫽ September and October 1996; B ⫽ November 1996; C ⫽ January and February 1997; D ⫽ March and April 1997; E ⫽ May through August 1997.
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sis for entry into a variety of studies. By the time we approached them, many felt that they had made their contribution to research. For this project, the best patient response rates resulted when our follow-up included a post card and a phone call. This call could occur many weeks following the initial approach. We discovered in our phone conversations that many patients go to great lengths to obtain family information and that this can take many weeks. For example, some women were waiting until a family reunion occurred in order to obtain information for completing the questionnaire. Based on our experience, we suggest additional strategies that may facilitate recruitment. Prior to the initiation of any study with similar requirements, an introductory letter outlining the project and a brochure could be sent to participating surgeons. For the names of potential physician-participants for this study, we used lists of users (surgeons and others) of the estrogen/progesterone receptor labs and medical and radiation oncologists registered in the province. We also tailored our response formats to the physician’s wishes. For example, some physicians preferred to have their letters faxed rather than mailed to them. Some gave us “blanket” permission to contact any of their patients and arranged to have addresses available through their offices. We also published a short description of the project in the Canadian Family Physician journal to which many family physicians subscribe [11]. As well, at the end of the first year we changed our brochure to include information that we learned from our follow-up phone calling would be helpful. We included a section of common responses (with commentaries) to promote accrual. For example, “No one in my family has cancer, so the researchers won’t be interested in my answers on the Family History Questionnaire.” (Comment: This is a province-wide study. It is very important to learn about various kinds of families including those with one, several or many relatives affected by cancer.) “I forgot to fill out the Family History Questionnaire when it arrived. It is probably too late to send it now.” (Comment: It isn’t too late to return the questionnaire, as the study will be continuing for a number of years.) Given the many competing studies targeting patients with breast cancer, as well as the emphasis on recruiting
many family members, we believe that we have been very successful in our efforts to obtain family histories of breast cancer, given the complex nature of the involvement in this population-based project. In the future we will report our success in obtaining the epidemiologic information and the biospecimens from this group of patients and their relatives.
Acknowledgments This work was supported by: The Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, RFA# CA-95-003 and Cancer Care Ontario.
References [1] Miki, Y, Swenson, J, Shattuck-Eidens, D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66–71. [2] Wooster, R, Bignell, G, Lancaster, J. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995;378:789–92. [3] Parkin, DM, Whelan, SL, Ferlay, J, Raymond, L, Young, J, editors. Cancer Incidence in Five Continents, Volume VII. Lyon: International Agency for Research on Cancer, 1997. [4] Canadian Cancer Statistics 1998. Toronto, Canada: National Cancer Institute of Canada, 1999. [5] Nishri, D. Capture-recapture study of completeness in the OCR. (Work in progress). [6] Theis, B, Boyd, N, Lockwood, G, Tritchler, D. Accuracy of family cancer history in breast cancer patients. Eur J Cancer Prev 1994;3/4: 321–7. [7] Hankin, JH, Wilkens, LR. Development and validation of dietary assessment methods for culturally diverse populations. Am J Clin Nutr 59(suppl.): 1994;198S–200S. [8] Dillman, DA. Mail and Telephone Surveys: The Total Design Method. New York: John Wiley & Sons, 1978. [9] Kreiger, N, Nishri, D. The effect of nonresponse on estimation of relative risk in a case-control study. Ann Epidemiol. 1997;7:194–9. [10] Gilbart, E, Kreiger, N. Improvement in cumulative response rates following implementation of a financial incentive. Am J Epidemiol 1998;148:97–9. [11] Andrulis, IL, Boyd, NF, Sutherland, HJ. New Ontario familial breast cancer registry to facilitate genetic and epidemiologic studies. Can Fam Physician 1997;43:949–50.
The Cooperative Familial Registry for Breast Cancer Studies: design and first year recruitment rates in Ontario Heather J. Sutherlanda,*, Jeanie Lacroixb, Julia Knightb, Irene L. Andrulisc, Norman F. Boydd, the Ontario Cancer Genetics Networke a
The Ontario Familial Breast Cancer Registry, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada b Cancer Care Ontario, Toronto, Ontario, Canada c Ontario Cancer Genetics Network and Lunenfeld Institute, Mount Sinai Hospital, Toronto, Ontario, Canada d Epidemiology, Statistics and Behavioral Research, Ontario Cancer Institute, Toronto, Ontario, Canada e Ontario Cancer Genetics Network, Cancer Care Ontario, Toronto, Ontario, Canada Received 7 January 2000; received in revised form 4 April 2000; accepted 17 April 2000
Abstract The Ontario Familial Breast Cancer Registry (OFBCR) is one of six international sites of the Cooperative Familial Registry for Breast Cancer Studies collecting family history, epidemiologic information, and blood samples from families (with various patterns of familial risk) for the purpose of studying the etiology of breast cancer. To invite 2361 female breast cancer patients residing in Ontario to take part in the Registry, a package was sent that included a Family History Questionnaire. Several variations of mailing and follow-up strategies were employed. Overall, the response rate was 67%. The best response (74%) was achieved by following up our introductory package of information with a postcard 10 days later and a telephone call several weeks thereafter. Given the design of the project, which involves a considerable commitment on the part of both patients and their family members, we are impressed by the positive response of these women. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Familial breast cancer; Recruitment methods
1. Introduction Family studies of breast cancer have shown that there is an inherited component to the etiology of the disease and have led to the discovery of genes that are associated with a striking increase in risk [1,2]. These studies have been carried out mainly in highly selected families with several members affected by the disease, and not identified as a result of any defined sampling strategy. To generate unbiased estimates of the risks of disease associated with these genes, and of their interaction with other risk factors, we need to study families selected from the population in a systematic manner. Further, to ensure that the families selected are representative of the population from which they were selected we must achieve a high response rate from those approached. To promote interdisciplinary studies in the etiology of breast cancer, and to foster translational research in this area, the National Institutes of Health issued a Request for
* Corresponding author. Tel.: (416) 946-4409; fax: (416) 946-4410. E-mail address: [email protected]
Applications (RFA) in 1994 to establish a Cooperative Familial Registry for Breast Cancer Studies (CFRBCS). The purpose of the Registry was to collect pedigree information, epidemiological data, and biological specimens from subjects with a family history of breast cancer, and to identify a population at high risk for breast cancer that will participate in the evaluation of new preventive and therapeutic strategies. The CFRBCS comprises six sites, four in the United States, one in Australia, and one in Canada (Ontario). Three sites utilize high-risk cancer genetics clinics for recruitment and three are population-based registries. The consortium will undertake cooperative studies using pooled data. In this article we describe the development and first-year recruitment experience of one of the population-based sites, the Ontario Familial Breast Cancer Registry. Specifically, this report describes the effect of different mailing and follow-up strategies on response rates to a questionnaire used to identify patterns of cancer in families of patients with newly diagnosed breast cancer. Only the experience with female participants is reported here as males were targeted for another provincial study during the first year of recruitment for the Registry. The Registry is still accruing subjects (year
0895-4356/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S0895-4356(00)00 2 6 3 - 8
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2000) and is expected to complete all data collection by the year 2002.
2. Methods 2.1. General method The Ontario Familial Breast Cancer Registry (OFBCR) is a resource of families willing to participate in this and future studies related to familial breast cancer. Using defined criteria, the Registry contains “high to moderate” risk families (with any one of a number of characteristics described below) and a random sample of families designated “low” familial risk. The general method being used in the OFBCR is to identify, through pathology reports in the Ontario Cancer Registry, all incident cases of breast cancer in the population of Ontario diagnosed during 1996–1998, to obtain information about familial breast and other cancers in these individuals, and to select, using explicit criteria, subjects who are asked to provide further information. Physicians are approached and asked to provide approval before their patients are contacted. Subsequently, family history information is collected and families are classified regarding familial risk using defined criteria. Epidemiologic information and blood samples are sought from probands and some of their relatives. Existing tissue samples are requested for all those within a family who have had a diagnosis of breast or ovarian cancer. 2.2. Background information 2.2.1. Catchment area The population of Ontario is approximately 11 million (1998 figures) living in an area of about 412,000 square miles although the majority of the population lives in the southern regions. It is a largely urban population with only 20% considered to be rural in the 1991 census. About half of the population is of British descent with the remainder from a variety of European and non-European backgrounds. No other group comprises more than 10% of the population. Ontario has age-specific rates of breast cancer similar to Canada as a whole, and the age-adjusted rate (to the world population) is 78 per 100,000 per year [3]. The current estimate is that approximately one in nine women will develop breast cancer during their lifetime [4]. 2.2.2. The Ontario Cancer Registry (OCR) Since the inception of the Ontario Cancer Registry in 1964, almost all cases of invasive neoplasia newly diagnosed among residents in Ontario have been registered. The OCR is the largest patient-specific, population-based cancer registry in Canada. It employs a passive voluntary system of registration that is quite complete because of the overlap that exists among its reporting sources. A recent study of the estimate for completeness of case ascertainment for breast cancer indicated it to be in excess of 97% [5].
2.3. OFBCR materials and procedures (ongoing) 2.3.1. Registry eligibility criteria As described above, probands identified through the Ontario Cancer Registry must be diagnosed with pathologyconfirmed, invasive breast cancer between January 1996 and December 1998. Those eligible include all women diagnosed at ages 20 through 54, a random sample of 35% of women diagnosed at ages 55 through 69, and all men diagnosed with breast cancer at ages 20 through 79. All must be residents of Ontario and able to read and speak English or have access to a translator in order to be included. Eligibility criteria for relatives are described in Table 1. For these participants, place of residence is not limited. 2.3.2. Questionnaires The Family History Questionnaire requests information about parents, children, and siblings as to age, date of birth, status alive or dead, age and date of death, whether or not the relative has had cancer, its type and the age and date of diagnosis, and details of any cancers in other relatives. This questionnaire has been shown to yield sufficiently accurate information to screen breast cancer patients by mail in order to identify families suitable for further investigation [6]. The Personal History Questionnaire requests information about risk factors associated with the development of breast cancer. It includes questions about height and weight, alcohol use, smoking history, medical and reproductive history, use of hormones, radiation exposure, and exercise. It also elicits demographic information such as country of the family’s origin, marital status, religion, and educational level. The questionnaire was developed by the CFRBCS and has been pilot tested for ease of use and understanding. The Diet Questionnaire was developed and validated by the University of Hawaii [7]. It inquires about the intake of an extensive, multiethnic list of foods (approximately 177 food items). It is scannable and includes photographs of representative food items with variable serving sizes. 2.3.3. Announcement of the Registry Prior to the initiation of the data collection, physicians throughout the province were made aware of the project by letter. They, and any who were missed in the initial mailing, also received a brochure describing the Registry on the first occasion that we wrote to them. 2.3.4. Data collection procedures for probands Once a case is identified, pathology reports are obtained and a letter is sent to the surgeon named on the report. It describes the purpose of the study and his/her role in it, which includes granting permission to contact the patient (or providing the name of a more appropriate doctor) and supplying the patient’s address. After permission is received, patients are contacted by mail and asked to complete an initial questionnaire to identify the number of cases of breast or ovarian or other cancers within the family. At this mailing, a letter of introduction, a Family History Questionnaire (described above), two consent forms (one to sign and return,
H.J. Sutherland et al. / Journal of Clinical Epidemiology 54 (2001) 93–98 Table 1 Criteria for selecting eligible relatives for the Ontario Familial Breast Cancer Registry • Proband’s 1st degree relatives (children, siblings, parents). • Living relatives with breast/ovarian cancer ⫹ their 1st degree relatives. • If relative with breast/ovarian cancer is deceased then their 1st degree relatives are still included. • Relatives with an adult onset cancer at a young age (⬍50 years). Excluded are cervical, testicular, leukemia, and lymphoma. • Half siblings on the “at risk” side.
one to keep), a brochure describing the study, and a stamped addressed return envelope are included. When the completed Family History Questionnaire is received, a genetic counsellor reviews it using a set of criteria (Table 2) and determines whether the family is considered “moderate to high risk” or not. Those who are deemed moderate/high risk, and a 25% sample of those at low risk, are telephoned. The family history is expanded and the further steps in the project are explained. These steps involve completing Personal History and Diet Questionnaires (described above) and providing the names and addresses of eligible relatives for contact. The final step in the process involves obtaining a blood sample for genetic testing from all moderate/high-risk and a small number of low-risk probands. Prior to giving blood, genetic counselling is offered and when genetic testing is completed results are made available to each participant who wishes to have this information. With the patient’s permission, existing tissue samples are requested from hospitals. During the course of the project, all tissue of probands will be reviewed and the pathology confirmed. Three separate consent forms are signed granting permission to use the family history, epidemiologic data, and biospecimens. 2.3.5. Data collection procedures for relatives After receiving mailed information about the Registry, relatives who agree to participate complete the epidemioTable 2 Criteria defining moderate/high-risk families used by the OFBCR • • • • • • • • • • •
Proband ⫹ ⭓1 1st degree relative with breast or ovarian cancer. Proband ⫹ ⬎2 2nd degree relatives with breast or ovarian cancer. Proband diagnosed with breast cancer at age ⭐35. Proband ⫹ 1 2nd degree or ⭓1 3rd degree relative diagnosed at age ⭐35 breast or ⭐60 ovarian. Male proband. Proband with 1 2nd degree or ⭓1 3rd degree relative with male breast cancer. Proband with breast and ovarian or multiple breast cancers. Proband ⫹ 1 2nd degree relative or ⭓1 3rd degree relative with breast cancer and ovarian cancer. Proband ⫹ 1 2nd degree or ⭓1 3rd degree relative with multiple breast cancers. ⭓3 1st degree relatives (of each other) with breast, ovarian, colon, prostate, sarcoma, or pancreas, 1 diagnosed ⭐50 years of age. Of Ashkenazi Jewish descent (at least 1 grandparent).
These are intended to capture a wide range of patterns of breast cancer within the families.
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logic questionnaires (Personal History and Diet Questionnaires). They are also offered counselling and asked to provide a blood sample. For those who have had breast or ovarian cancer, permission is sought to retrieve existing tissue from surgeries for review. An attempt is made to confirm all cases of cancer in both living and deceased relatives by requesting pathology reports. Consent forms are signed at each stage. A report of the OFBCR’s experience in recruiting relatives will be described at a later date. 2.3.6. Mailing and follow-up strategies for first-year recruitment We have tried a number of approaches, all of which have been based on modifications of mailing strategies described by Dillman [8] that are designed to produce a high response rate in mailed surveys. Certain features are incorporated into these mailings to make each package seem personalized rather than mass produced. For example, the principal investigator (I.A.) signed each letter and commemorative stamps were used on the outside envelope. After the initial package was sent, we either telephoned, sent a postcard, or did both. In one mailing, the same material was sent a second time to nonrespondents. The variations are described in the order in which they occurred and are summarized in Table 3. (A) Two mailings in September and October 1996 (408 patients) were sent and phone calls were made to nonresponders beginning 3 weeks after the mailing and continuing for a number of weeks thereafter. (B) The same strategy as used in A was used in the November 1996 mailing (93 patients), with the addition of a form, to be returned, which allowed the patient to indicate that she was declining or was unable to participate currently but would do so at a later date, which she specified. This form was included in all subsequent mailings. (C) In the January and February 1997 mailings (270 patients), a postcard was sent 10 days after the original mailing followed by a phone call. Phone calls began 3 weeks after the postcard reminder and contact occurred, in some cases, many weeks after the initial mailing. (D) In the March and April 1997 mailings (330 patients), the package was sent followed by the postcard follow-up and 4 weeks later a second complete package was mailed to those who had not responded. No phone follow-up was done. (E) The final method used in the last mailing of the 12-month period (1260 patients) employed the same strategy as in the January/February mailing except phone calls were made exactly 3 weeks after the postcard was mailed. Because of the large number of phone calls made, other tasks were put aside until calling was completed. Because patients were approached at different times, we have compared all strategies for response rates for a 30-week period. 2.4. Statistical analysis Descriptive statistics were used to report patient characteristics and response rates for the various mailing strategies. Kruskall-Wallis and chi-square tests were used to determine differences in age and place of residence, respec-
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tively, among those who responded, did not reply, or declined. Place of residence was deemed to be rural, Toronto, or other urban (a town/small city). Postal codes were used to make this determination. Toronto was separated from other urban because of the very large multicultural population and the many research groups and facilities vying for research subjects. For this analysis, a patient was called a nonrespondent if we had received no response to our various follow-up approaches within 30 weeks. If a Family History Questionnaire was subsequently returned, status was changed. This occurred very infrequently. If physicians declined approval for patient contact or if patients did not wish to participate (at any stage), an attempt was made to find out the reason for refusal. 3. Results 3.1. Characteristics of eligible participants There were 3462 incident cases of breast cancer for whom physician approval was sought during the first year of the Registry’s development. The first patient mailing was in September 1996. Thus, we have taken September 1996 to August 1997 as the first year of recruitment. Of the 2361 women approached by August 1997, age and geographic residence were the only data, aside from diagnosis, available for each person. The mean age was 50.3 years (SD 9.2) with a range of 31 to 69 years. Note that this does not reflect the mean age of women with breast cancer as older women were sampled. Place of residence for these women was as follows; 536 (23%) lived in Toronto, 1428 (60%) lived in other urban areas, and 397 (17%) were rural dwellers.
medical/emotional factors (n ⫽ 60), the patient declined when asked by the physician (n ⫽ 40), the patient was deceased (n ⫽ 28), or didn’t reside in Ontario (n ⫽ 27), or had language difficulties (n ⫽ 11). For the remaining 48 patients, no reason for refusal was given. It should be noted that for 166 women for whom permission was granted, letters were not sent because of incomplete or incorrect patient information. 3.3 Patient response rates to first contact Of the 2409 patients considered eligible for contact, 48 were not included in this summary (11 were deceased, 4 were ineligible, 12 asked for a postponement, 21 had no address identified). Of the remaining 2361, 1589 (67%) participated, 245 declined (10%), and 527 (22%) were nonrespondents. Documented reasons for nonparticipation included seriously ill (n ⫽ 36), language difficulties (n ⫽ 20), alienated or did not know family history (n ⫽ 19), and concerns about confidentiality (n ⫽ 6). The remainder (n ⫽ 164) provided no comment. For those who completed the FHQ, ethnicity information was also available. The majority described themselves as white (n ⫽ 1360); other categories were Asian (n ⫽ 50), Chinese (n ⫽ 33), Jewish (n ⫽ 30), black (n ⫽ 18), Native (n ⫽ 6), and other/mixed (n ⫽ 34). Fifty-one gave no response and seven did not know their ethnicity. There was a significant difference in age between participants, nonresponders, and those who declined with the latter being significantly older (P ⭐ 0.0001). Women living in Toronto were significantly more likely to refuse or not respond than women living in rural areas or towns/small cities (P ⭐ 0.001) (Table 4).
3.2. Physician response rates It should be noted that while some physicians asked each patient if she wished to be involved before approving our request for contact, the vast majority of doctors did not. Physicians gave permission for 2575 (74%) patients to be contacted; 214 (6%) requests were declined and 673 (20%) were still pending (but may have been received later) at the cutoff date for this report. Reasons for refusal included
Table 3 Summary of key components of mailing strategies Mailinga
Questionnaire package Postcard 10 days after package Phone call 3 or more weeks after mailings Phone call exactly 3 weeks after mailings Form of postponement or refusal Questionnaire package resent
A
B
C
D
E
⫹
⫹
⫹
⫹
⫹ ⫹ ⫹
⫹ ⫹
⫹ ⫹
⫹
⫹
⫹ ⫹
⫹ ⫹
a A ⫽ September and October 1996. B ⫽ November 1996. C ⫽ January and February 1997. D ⫽ March and April 1997. E ⫽ May through August 1997.
3.4. Success of mailing and follow-up strategies The response rates for the various strategies are shown in Fig. 1. For this project, the greatest response rate (73.7%) was achieved by sending a postcard after the package and following up with a phone call to nonrespondents (strategy C). It did not appear to matter when the phone call took place. The second-best response rate involved phone follow-up alone but the initial response was less than with a postcard reminder. The poorest response rate (61.3%) was found with the November mailing (strategy B). This mailing, with telephone follow-up, included a response form whereby the patient could directly decline or postpone participation to a more suitable time. We have included this form in subsequent mailings without any obvious adverse effect. We suggest that the reduced response rate in November could be due to seasonal variations. From our experience November, as well as July and August, appear to be inopportune times to approach patients. Note that no mailing was done in December. Interestingly, a second complete mailing of the information package and questionnaire had an abrupt conclusion with no further responses after 21 weeks.
H.J. Sutherland et al. / Journal of Clinical Epidemiology 54 (2001) 93–98 Table 4 Patient characteristics (N ⫽ 2361)
Age (years) Mean (SD) Geographic location (%) Toronto Other urban Rural a b
Participate (n ⫽ 1589)
Decline (n ⫽ 245)
No response (n ⫽ 527)
P-value
50.3 (9.3)
52.8 (9.5)
49.2 (8.8)
0.0001a
19.3 61.6 19.1
29.8 55.1 15.1
29.6 59.8 10.6
0.001b
Kruskall Wallis. Chi-square.
4. Discussion The design and magnitude of this provincial project have made it most challenging to operationalize. Three distinct phases of data collection involving the patient-participants plus two phases for their relatives, collection of tissue blocks as well as fresh frozen tissue, confirmation of diagnoses by pathology reports, coordination of genetic counselling and blood collection, handling and testing of the biospecimens, and follow-up with patients concerning their carrier status has provided the research team an opportunity in which a wealth of experience has been gained.
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There are few data to draw upon for a benchmark against which to measure the success of accrual for this type of project. Certainly, the physicians and surgeons who have been approached have been most cooperative and supportive of this research and we expect to exceed the 80% projected response rate for physicians by the end of the project. During the first year of recruitment, we had responses from 77% of the patients who were approached. Of the total population contacted, a majority (67%) completed the Family History Questionnaire, the entry point for the Registry. At the time of writing of this report, the expected proportion and numbers meeting the Registry criteria and, therefore, proceeding with the other phases of the project (approximately 300 families per year meeting moderate/high risk criteria) has been achieved. Our data indicate that older women and those who live in Toronto, the largest city in the province, are the most likely to decline or not respond. Other reports of accrual experience in clinical studies confirm the finding that older subjects and those living in urban areas may be less interested in making such commitments [9,10]. We hypothesize, based on experience and anecdotal information from patients, that investigators in the large number of teaching hospitals in Toronto (with both in-house research and multicenter/site projects) approach many of these patients soon after diagno-
Fig. 1. Comparisons of response rates to various strategies for recruitment (September 1996 to August 1997). A ⫽ September and October 1996; B ⫽ November 1996; C ⫽ January and February 1997; D ⫽ March and April 1997; E ⫽ May through August 1997.
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sis for entry into a variety of studies. By the time we approached them, many felt that they had made their contribution to research. For this project, the best patient response rates resulted when our follow-up included a post card and a phone call. This call could occur many weeks following the initial approach. We discovered in our phone conversations that many patients go to great lengths to obtain family information and that this can take many weeks. For example, some women were waiting until a family reunion occurred in order to obtain information for completing the questionnaire. Based on our experience, we suggest additional strategies that may facilitate recruitment. Prior to the initiation of any study with similar requirements, an introductory letter outlining the project and a brochure could be sent to participating surgeons. For the names of potential physician-participants for this study, we used lists of users (surgeons and others) of the estrogen/progesterone receptor labs and medical and radiation oncologists registered in the province. We also tailored our response formats to the physician’s wishes. For example, some physicians preferred to have their letters faxed rather than mailed to them. Some gave us “blanket” permission to contact any of their patients and arranged to have addresses available through their offices. We also published a short description of the project in the Canadian Family Physician journal to which many family physicians subscribe [11]. As well, at the end of the first year we changed our brochure to include information that we learned from our follow-up phone calling would be helpful. We included a section of common responses (with commentaries) to promote accrual. For example, “No one in my family has cancer, so the researchers won’t be interested in my answers on the Family History Questionnaire.” (Comment: This is a province-wide study. It is very important to learn about various kinds of families including those with one, several or many relatives affected by cancer.) “I forgot to fill out the Family History Questionnaire when it arrived. It is probably too late to send it now.” (Comment: It isn’t too late to return the questionnaire, as the study will be continuing for a number of years.) Given the many competing studies targeting patients with breast cancer, as well as the emphasis on recruiting
many family members, we believe that we have been very successful in our efforts to obtain family histories of breast cancer, given the complex nature of the involvement in this population-based project. In the future we will report our success in obtaining the epidemiologic information and the biospecimens from this group of patients and their relatives.
Acknowledgments This work was supported by: The Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, RFA# CA-95-003 and Cancer Care Ontario.
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