IJE Advance Access originally published online on July 20, 2007
International Journal of Epidemiology 2008 37(1):36-41; doi:10.1093/ije/dym137
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Cohort Profile: The Norwegian Women and Cancer Study—NOWAC—Kvinner og kreft
1Institute of Community Medicine, University of Tromsø, 9037 Tromsø, Norway.
2Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Centre, Montebello, 0310 Oslo, Norway.
3Cancer Registry of Norway, 0310 Oslo, Norway.
*Corresponding author. Institute of Community Medicine, University of Tromsø, 9037 Tromsø, Norway. E-mail: Eiliv.lund{at}ism.uit.no
Accepted 6 June 2007
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How did the study come about? |
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 Top How did the study... What does it cover?Who is in the...What is attrition like?What has it found?What are the main...Can I get hold...The study groupAcknowledgementsReferences |
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In the early 80s, a case-control study in California found an association between use of combined oral contraceptives (OCs) and breast cancer risk1 inducing great public concern in many countries. A group of researchers in Norway and Sweden therefore decided to conduct a population-based case-control study of OCs and breast cancer among young women.2 They found an elevated breast cancer risk for both total duration and for current OC use. However, the findings were strongly debated,3 and in several later review articles possible sources of bias in this study were proposed.4,5 Because of the potential problems of selection bias, recall bias and survivor bias with case-control studies, we decided to establish a prospective cohort study to explore the original hypothesis of use of OCs being a risk factor for breast cancer, as well as explore other risk factors for breast cancer. The data collection for the Norwegian Women and Cancer (NOWAC) cohort study started in 1991. In 2002, the prospective analysis of OC use and breast cancer incidence6 confirmed the original findings from the case-control study.
The NOWAC study was founded on hypotheses related to the following comparative advantages for internationally competitive epidemiological cancer research in Norway:
- A unique opportunity for building a representative prospective study based on sampling from the national population register of Norway with sufficient external validity for estimating both relative risks and population attributable risk as an important aspect of public health priorities.
- To focus on aetiological hypotheses for cancer in areas where specific Norwegian exposure advantages exist with collection of sufficient, detailed and validated questionnaire information. As examples we will mention the following research areas: Norway had back in time a very restrictive market policy for OCs with a rather small number of different brands available, thus improving the ability to more rigorously define exposure in terms of chemical compounds related to different brands. The traditional diet in northern and western parts of Norway had a high intake of fish rich in fatty acids and D-vitamin. The geographical position of Norway far north implies large seasonal and geographic differences of UV exposure, also a source of D-vitamin.
- Validated and complete follow-up of cancer, the national mammography screening program, causes of deaths and emigrations based on national register linkages using the national birth number.
From 2003, we expanded the scope of the study by including biological material for whole-genome expression profiling by microarrays. This ‘post-genome NOWAC cohort’ will include both normal and malignant peripheral blood and breast tissue.
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What does it cover? |
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TopHow did the study...What does it cover?Who is in the...What is attrition like?What has it found?What are the main...Can I get hold...The study groupAcknowledgementsReferences |
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The overall structure of the NOWAC cohort with regard to time of recruitment, number of women and age at recruitment is shown in Figure 1. Presently, 165 772 women aged 30–70 years at recruitment participate. Almost all questionnaires in the NOWAC examine four pages of core variables: use of OCs and hormonal replacement therapy, reproductive history, age at menarche and menopause, smoking, physical activity, alcohol consumption, anthropometry, socioeconomic status, screening for breast cancer, breast cancer in the family, sun bathing habits and pigmentation and self-reported diseases. A major part of the questionnaires has in addition four pages asking for detailed information on dietary habits. As seen in Figure 1, women recruited in 1991–92 could have answered three questionnaires (one baseline and two follow-up questionnaires).
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NOWAC holds several biobanks. As part of the European Prospective Investigation into Cancer and Nutrition (EPIC) collaboration, the Norwegian biobank consists of 12 209 blood samples drawn at a doctor's office and mailed overnight to the Institute of Community Medicine, Tromsø.7 In our post-genome cohort, we have 49 633 samples of peripheral blood collected from NOWAC members (Figure 1). For some women (n = 622) two blood samples were taken a few months apart. In order to improve the preservation of mRNA from peripheral blood cells in the post-genome cohort, we used one tube of 2.5 ml blood (PAX tube) with a proprietary reagent that immediately stabilizes intracellular RNA for days at room temperature, and one tube with 9 ml citrate blood for preparation of plasma and ‘buffy coat’. The prospective collection of blood samples was partly based on the existing NOWAC study participants who have given informed consent for blood sampling and partly based on recruitment of the new women. The next part of the post-genome biobank is the collection of breast cancer biopsies that started in 2006 and will last for about 4 years. In addition to the tissue samples from breast cancer cases, we collect blood samples from them and from matched controls in the cohort. From winter 2007, we will also collect breast tissue samples from healthy women who have participated as donors of blood previously. This sampling will be done among women attending the Breast Cancer Detection Centre in Tromsø, a part of the national screening program.
Internal validity
In 2003, a test–retest study was undertaken among 2000 invited women. The kappa estimator of agreement varied from 0.95 for OC use to typical 0.50–0.70 for dietary questions.8 During 2003, we also completed our validation study of the food frequency questionnaire that has been used in NOWAC and which is part of the EPIC study. The food frequency questionnaire data were compared with four repeated 24-h recalls; 238 women were interviewed via telephone once every season.9 We have previously completed the EPIC calibration study.10 The validation of the questionnaire information on fish consumption and omega fatty acid intake showed a good correlation with measured levels in serum phospholipids levels.11 We have also validated the questionnaire information on menopausal status and use of hormonal replacement therapy in relation to biomarkers of hormonal levels, and we have started to validate information on physical activity.
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Who is in the sample? |
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TopHow did the study...What does it cover?Who is in the...What is attrition like?What has it found?What are the main...Can I get hold...The study groupAcknowledgementsReferences |
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The Norwegian Women and Cancer Study is described in more detail elsewhere,12 http://www.ism.uit.no/kk/e. The main purpose of NOWAC was to create a large prospective cohort designed to study the relationship between internal and external hormones and female cancers with focus on breast cancer. All women have been sampled randomly from the Norwegian Central Person Register which contains information on all Norwegian inhabitants including a unique identity number consisting of the date of birth and five additional numbers giving a unique combination.13 This person number is used in all linkages in order to give a complete follow-up through the national registers. The women were mailed an invitation with a photo-booklet of all OCs or hormonal replacement therapy brands and a questionnaire (http://www.ism.uit.no/kk/e/q_menu.html). Questions on diet, especially fish consumption and sun habits were added in the later mailings of the study. During the years 1991–97 altogether 179 387 women were invited of whom 102 540 women (57%) aged 30–70 years returned a questionnaire to the Institute of Community Medicine, University of Tromsø, Norway. During 2003–06 another 130 577 women born 1943–57 were invited of whom 63 232 (48.4%) returned an eight pages questionnaire (Figure 1).
We have received approval from The Regional Committee for Medical Research Ethics for the basic collection and storing of questionnaire information, blood samples and tumour tissue from present. All women have filled in an informed consent for later linkages to the Cancer Registry of Norway, the Norwegian Mammographic Screening Programme, and the register of death certificates in Statistics Norway. The informed consent formula explicitly mentions that the blood samples can be used for gene–environment analyses. The samples of blood and tumour tissue will be kept at the Institute of Community Medicine, University of Tromsø. All data are stored and handled according to the permission given from the Norwegian Data Inspectorate.
How often have they been followed up?
Repeated collections of exposure information are carried through with 
5-year intervals based on updated information on addresses given by the National Central Person Registers.
Second mailing
In 1998–2002, all women received an invitation to fill in a second questionnaire and 80 693 women replied (response rate 81% corrected for death and emigration). Of these, 37 226 women constitute the Norwegian part of the EPIC study.7
Third mailing
In 2003, we started mailing the third questionnaire to those participating in 1991–95 (Figure 1). The third questionnaire will be mailed 10–12 years after the first.
Passive follow-up by linkages
Passive follow-up is based on linkage to the Cancer Registry of Norway. Until the end of 2004, 5569 incident cases of cancer had been registered of which 1983 was breast cancer. In a linkage to the register of death certificates, we found 1568 deaths with specified causes of death.
Active follow-up
Eligible women for tumour tissue sampling are NOWAC participants born between 1943 and 1957 who filled in at least one questionnaire. At the moment, one-third of all Norwegian women born between these years have been enrolled in the NOWAC cohort. We collaborate for the tumour sampling with 11 major Norwegian hospitals and the Norwegian Breast Cancer Group (NBCG), which consists of clinicians at most Norwegian hospitals. The biopsies are stored frozen in RNA later. An additional tube of citrate blood is collected together with a questionnaire of two pages.
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What is attrition like? |
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The response rate in NOWAC has depended on age at recruitment (decreasing with age), geography (highest in North Norway) and length of questionnaire (higher for shorter questionnaires). In several validation studies, we have shown that the distribution of exposures is independent of the response rate.14 This implies a reasonable high external validity. A comparison between the observed cumulative incidence of total cancer and breast cancer vs expected national figures from the Norwegian Cancer registry for 2004 showed no marked differences (Figure 2).
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We have also studied the possible selection of participants from the first to the second mailing (Table 1). We found almost no differences, but women responding a second time was slightly younger and higher educated.
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What has it found? |
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TopHow did the study...What does it cover?Who is in the...What is attrition like?What has it found?What are the main...Can I get hold...The study groupAcknowledgementsReferences |
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NOWAC has all the way focused on specific hypothesis in the design of the study. The results from the study will be found under various study names like ‘Kvinner og kreft’, ‘The Norwegian Women and Cancer Study’, ‘NOWAC’, ‘The post-genome NOWAC cohort’, ‘EPIC’ and ‘The Women's lifestyle and health study’. A listing of publications is available at: http://www.kvinnerogkreft.uit.no.
The NOWAC study has several key research findings. We looked at the long-term consequences of OC use in relation to all hormone-dependant cancers and found that the increased risk for breast cancer6 was opposed by the protective effect on ovarian.15 The major risk factor for breast cancer was the cumulative dose of oestrogens.16 A strongly increased risk of breast cancer was found among current users of hormonal replacement therapy,17 partly due to former use of OCs18 and the specific use of testosterone-derivated progestagens. A second area of findings is related to diet. We have published results on consumption of farmed salmon and cancer,19 traditional lean fish consumption20 and traditional fish dishes with cod liver in North Norway,21 partly as a response to a debate about potential harmful effects of increased intake of organic pollutants from fatty fish. These analyses will together with measurements of UV exposure22 give us the opportunity to look at the effect of D-vitamins on cancer incidence and survival. The analysis of the association between UV light, sun habits and malignant melanoma was the first made in a prospective study.23 Based on the large amount of exposure information we have been able to explain most of the socioeconomic gradients of cancer incidence in Norway.24 Lastly, the large number of participants have given the opportunity for looking at dietary patterns in subgroups like breast cancer survivors.25
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What are the main strengths and weaknesses? |
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TopHow did the study...What does it cover?Who is in the...What is attrition like?What has it found?What are the main...Can I get hold...The study groupAcknowledgementsReferences |
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We have built a representative, population-based prospective study with complete follow-up. In addition, the statistical power has increased rapidly over the time due to more years of follow-up and recruitment of new participants. We have recruited 50 000 women with a blood sample for gene expression analysis. The ongoing collection of tumour tissue from all women in NOWAC born between 1943 and 1957 has just started.
The major problem is the logistics for collecting tumour tissue from the largest hospitals in Norway over a 4-year period. The weakness of the study is related to a somewhat seldom updating of exposure information, only around every 5 years, and that not all exposure information has been validated. We have also decided not to ask for more sensitive, personal matters like abortions, sexual abuse, etc.
Up-to-date technologies have provided us with unique opportunities for interactive studies of the genetic predisposition (DNA genome), the expression of genes (transcriptome), proteins (proteome) and metabolites (metabolome), what we in total could call a globolomic design (Figure 3). The NOWAC post-genome cohort combines all aspects of the globolome and includes lifestyle exposure information in a prospective design. This creates the opportunity for merging epidemiological research with biological pathways analysis, an epi-omic study, see figure 3, by analysing quantitatively the huge amount of data from different high-throughput platforms.
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Can I get hold of the data? Where can I find out more? |
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TopHow did the study...What does it cover?Who is in the...What is attrition like?What has it found?What are the main...Can I get hold...The study groupAcknowledgementsReferences |
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The data are held by the NOWAC research team at the Institute of Community Medicine, Medical Faculty, University of Tromsø, Norway. Information regarding study design, questionnaires and ongoing data collection is given on our website both in Norwegian and English, http://www.uit.no/kk/e. Potential collaborators should discuss ideas informally with the principal investigator (Eiliv.Lund{at}ISM.UIT.NO). Since this study is almost completely researcher-driven and funded from several research grants, all collaborators must cover all costs related to the analyses. There are already a large number of collaborative analyses linked up to our membership in several national and international projects.
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The study group |
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TopHow did the study...What does it cover?Who is in the...What is attrition like?What has it found?What are the main...Can I get hold...The study groupAcknowledgementsReferences |
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The NOWAC study is conducted by a team of researchers mainly at the University of Tromsø.
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Acknowledgements |
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TopHow did the study...What does it cover?Who is in the...What is attrition like?What has it found?What are the main...Can I get hold...The study groupAcknowledgementsReferences |
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We are grateful for the completing of questionnaires and donations of blood samples from our 165 000 participants and for their comments, phone calls and letters. Presently, the study is supported by the Norwegian Research Council, EU, The Norwegian Foundation for Health and Rehabilitation and The Norwegian Cancer Society. Bente Augdal and Merete Albertsen have been responsible for the administration of the data collection and the biobanks. Tore Nafstad Bakke in Statistics Norway is responsible for all sampling and linkages to the registries.
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References |
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TopHow did the study...What does it cover?Who is in the...What is attrition like?What has it found?What are the main...Can I get hold...The study groupAcknowledgementsReferences |
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3 Meirik O, Lund E, Adami HO, Bergstrøm R, Christoffersen T, Bergsjø P. Oral contraceptives and breast cancer. Lancet (1986) ii:1272–73. (letter).
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5 Skegg DC. Potential for bias in case-control studies of oral contraceptives and breast cancer. Am J Epidemiol (1988) 127:205–12. (Review).
6 Kumle M, Weiderpass E, Braaten T, Adami H-O, Lund E. Hormonal contraceptives and breast cancer risk in Norway and Sweden. The women's lifestyle and health cohort study. Cancer Epi Biomarkers Prev (2002) 11:1375–81.
7 Bingham S, Riboli E. Diet and cancer – the European prospective investigation into cancer and nutrition. Nat Rev Cancer (2004) 4:206–15.[CrossRef][Web of Science][Medline]
8 Parr CL, Veierød MB, Laake P, Lund E, Hjartåker A. Test-retest reproducibility of a food frequency questionnaire and estimated effects on disease risk in the Norwegian Women and Cancer Study (NOWAC). Nutr J (2006) 5:4.[CrossRef][Medline]
9 Hjartåker A, Frost Andersen L, Lund E. Comparison of diet measures from a food-frequency questionnaire with measures from repeated 24-hour dietary recalls. The Norwegian Women and Cancer Study. Public Health Nutr (2006) 5:4.
10 Slimani N, Kaaks R, Ferrari P, et al. European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study: rationale, design and population characteristics. Public Heath Nutr (2006) May;8(5):552–7.
11 Hjartåker A, Lund E, Bjerve KS. Serum phospholipid fatty acid composition and habitual intake of marine foods registered by a comprehensive food frequency questionnaire. Eur J Clin Nutr (1997) 51:736–42.[CrossRef][Web of Science][Medline]
12 Lund E, Kumle M, Braaten T, et al. External validity in a population based national prospective study – the Norwegian Women and Cancer Study. Cancer Causes Control (2003) 14:1001–08.[CrossRef][Web of Science][Medline]
13 Lunde AS, Lundeborg S, Lettenstrom GS, Thygesen L, Huebner J. The person-number systems of Sweden, Norway, Denmark, and Israel. Vital Health Stat (1980) 2:1–59.
14 Lund E, Gram IT. The impact of design on response rates and exposure estimates from postal questionnaires. A population based randomized trial of 5.000 Norwegian women aged 35–49 years. Scand J Soc Med (1998) 26:154–60.[Web of Science][Medline]
15 Kumle M, Weiderpass E, Braaten T, Adami H-O, Lund E. Risk for invasive ovarian cancer and borderline ovarian tumours following use of hormonal contraceptives: The Norwegian-Swedish Women's Lifestyle and Health Cohort Study. Br J Cancer (2004) 90:1386–91.[CrossRef][Web of Science][Medline]
16 Dumeaux V, Alsaker E, Lund E. Breast cancer and specific types of oral contraceptives: a large Norwegian cohort study. Int J Cancer (2003) 105:844–50.[CrossRef][Web of Science][Medline]
17 Bakken K, Alsaker E, Eggen AE, Lund E. Hormonal replacement therapy and hormone dependant cancer. Int J Cancer (2004) 112:130–34.[CrossRef][Web of Science][Medline]
18 Lund E, Bakken K, Dumeaux V, Andersen V, Kumle M. Hormone replacement therapy and breast cancer in former users of oral contraceptives – The Norwegian Women and Cancer study. Int J Cancer (2007) 121:645–48.[CrossRef][Medline]
19 Lund E, Engeset D, Alsaker E, et al. Cancer risk and salmon intake. Science (2004) 305:477.
20 Engeset D, Andersen V, Hjartåker A, Lund E. Consumption of fish and colon cancer in the Norwegian Women and Cancer study. Br J Nutr (2007) 10:1–7. [Epub ahead of print].[Medline]
21 Brustad M, Sandanger TM, Andersen V, Lund E. POP exposure from fish liver consumption and risk of cancer – The Norwegian Women and Cancer Study. J Environ Monit (2007) doi:10.1039/b706302b.
22 Brustad M, Alsaker E, Engelsen O, Aksnes L, Lund E. Vitamin D status of middle-aged women at 65–71°N in relation to dietary intake and exposure to ultraviolet radiation. Public Health Nutr (2004) 7:327–35.[CrossRef][Web of Science][Medline]
23 Veierød MB, Weiderpass E, Thørn M, et al. A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst (2003) 95:1530–38.
24 Braaten T, Weiderpass E, Kumle M, Lund E. Explaining the socioeconomic variation in cancer risk in the Norwegian Women and Cancer Study. Cancer Epi Bio Prev (2005) 14:2591–97.[CrossRef]
25 Skeie G, Hjartåker A, Lund E. Diet among breast cancer survivors and healthy women. The Norwegian Women and Cancer Study. Eur J Clin Nutr (2006) 60:1046–54.[CrossRef][Web of Science][Medline]
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