original article

Annals of Oncology 22: 13321338, 2011 doi:10.1093/annonc/mdq595 Published online 3 December 2010

Carbohydrate intake, glycemic load, glycemic index, and risk of ovarian cancer
C. M. Nagle1*, F. Kolahdooz2, T. I. Ibiebele1, C. M. Olsen3, P. H. Lahmann3, A. C. Green4 & P. M. Webb1; Australian Cancer Study (Ovarian Cancer) and the Australian Ovarian Cancer Study Group
1 Gynaecological Cancer Group, Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane, Australia; 2Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; 3Cancer Control Group; 4Cancer and Population Studies Group, Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane, Australia

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Received 20 June 2010; revised 24 August 2010; accepted 31 August 2010

Background: Our objective was to determine the relationship between dietary glycemic load (GL), glycemic index
(GI), carbohydrate intake, and ovarian cancer risk in a population-based casecontrol study.

Patients and methods: A self-administered questionnaire was used to collect data on demographic and lifestyle
factors, and a food frequency questionnaire was used to collect dietary information from 1366 women with ovarian cancer and 1414 population controls. Results: GL was positively associated with ovarian cancer. The adjusted odds ratio (OR) for the highest versus the lowest quartile of intake was 1.24 [95% condence interval (CI) 1.001.55, P for trend = 0.03]. Fiber intake was inversely associated with risk. The OR comparing women in the highest ber-intake group with those in the lowest was 0.78 (95% CI 0.620.98, P for trend = 0.11). We found no association between GI, carbohydrate intake, and ovarian cancer. In analyses stratied by body mass index, the risk estimates for GL, carbohydrate, and sugar were higher among overweight/obese women; however, the interaction term was only signicant for sugar (P for interaction = 0.004). Conclusions: Our results suggest that diets with a high GL may increase the risk of ovarian cancer, particularly among overweight/obese women, and a high intake of ber may provide modest protection. Key words: glycemic index, glycemic load, ovarian cancer

original article

introduction
Few of the established risk factors for ovarian cancer are readily modiable. Multiparity, oral contraceptive (OC) use, breastfeeding, previous tubal sterilization, or hysterectomy are all established protective factors, while advancing age and family history are associated with increased risk of ovarian cancer [1]. The search for ways to reduce risk has led to interest in investigating dietary correlates of disease. Longterm consumption of a diet high in carbohydrates can lead to chronic hyperinsulinemia and it has been hypothesized that hyperinsulinemia may increase risk of ovarian cancer by lowering insulin-like growth factor binding protein (IGFBP) concentrations, thereby increasing the bioavailability of insulin-like growth factor 1 (IGF-1) [2, 3]. Increased IGF-1 reduces apoptosis, stimulates cellular proliferation and sex steroid synthesis, and decreases the concentration of sex hormonebinding globulin (SHBG), all
*Correspondence to: Dr C. M. Nagle, Genetics and Population Health Division, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Queenlands 4029 Australia. Tel: +61-7-3362-0265; Fax: +61-7-3845-3502; E-mail: Christina.Nagle@qimr.edu.au

of which have been implicated in the development of ovarian cancer [2, 3]. Previous epidemiological studies of dietary carbohydrates in relation to ovarian cancer risk have yielded inconsistent results [49]. However, because postprandial insulin response varies by the type, amount, and rate of digestion of carbohydrates, it has been hypothesized that the quantity and quality of carbohydrate consumed might be important in ovarian carcinogenesis [1013]. On this basis, three previous studies have examined the association between glycemic load (GL), glycemic index (GI), and ovarian cancer risk and two of these studies have observed increased risks, particularly among postmenopausal women [1315]. Fiber may also play a role in ovarian carcinogenesis by lowering circulating concentrations of estrogens and increasing concentrations of IGFBP-3, the primary binding protein for IGF-1 [16, 17]. The results of previous epidemiological studies are mixed, with two prospective studies showing no evidence of an association [5, 18]. We tested the hypothesis that high GL and GI are associated with increased ovarian cancer risk and secondly, that dietary carbohydrate and ber intake are also implicated in the

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Annals of Oncology

original article
college, and university), log transformed energy intake (kilocalorie), menopausal status (premenopausal and postmenopausal), and body mass index (BMI) (in kilogram per meter square). BMI was classied according to World Health Organization denitions [BMI 25 (normal weight), 2529.9 (overweight), 30 (obese)] [26]. Other potential confounders that were not included in the nal models since they did not alter risk estimates by >10% were family history of breast or ovarian cancer in a rst-degree relative, use of hormone replacement therapy (HRT), tubal ligation, hysterectomy, talc use, smoking, and alcohol consumption. Results are presented as odds ratios (ORs) and 95% condence intervals (CIs) compared with the lowest intake category. All tests were two-sided, and P values <0.05 were considered statistically signicant. We conducted subgroup analyses to examine whether the associations between dietary carbohydrates, GL, and GI were modied by BMI (<25 and 25), menopausal status (premenopausal and postmenopausal), or HRT use (never and ever, among postmenopausal women). The statistical signicance of any observed stratum differences was assessed by including a cross-product term in regression models. The analyses were also carried out separately by ovarian cancer subtype (serous, mucinous, endometrioid, and clear cell). All analyses were conducted using the SAS statistical package (SAS Institute Inc., Cary, NC). The study was approved by the human research ethics committees at the Peter McCallum Cancer Centre, Queensland Institute of Medical Research, University of Melbourne; the cancer councils of New South Wales, South Australia, and Victoria; the Cancer Foundation of Western Australia; and all participating hospitals.

development of ovarian cancer. As the magnitude of the insulin response to carbohydrate intake is substantially greater in the presence of insulin resistance [19], we also hypothesized that positive associations between GL, GI, and dietary carbohydrates might be stronger among overweight and obese women.

patients and methods

The Australian Ovarian Cancer Study (AOCS) was an Australia-wide, population-based casecontrol study conducted between January 2002 and June 2005. Women aged 1879 years diagnosed with epithelial ovarian cancer during this period were ascertained through treatment clinics and state cancer registries. Full details of the study recruitment and data collection have been reported previously [20]. Briey, 2745 women with suspected ovarian cancer were invited to participate and, of these, 2319 (84%) agreed to take part. After surgery, 590 women recruited before surgery were excluded because their nal diagnosis was not primary epithelial ovarian cancer, 19 because their cancer was rst diagnosed before the start of the study period, and 1 because she was not an Australian resident at the time of her diagnosis. Of the nal 1709 cases, 1612 (94%) returned the main study questionnaire. We randomly selected potential control women from the Australian Electoral Roll between 2002 and 2005 (enrollment to vote is compulsory in Australia), frequency matched to the case series by age (in 5-year groups) and state of residence. Of the 3442 eligible women contacted, 1615 (47%) consented to participate, 6 women with a history of ovarian cancer, 99 who reported a previous bilateral oophorectomy, and 1 who did not complete the main study questionnaire were excluded, leaving 1509 control women. Women provided detailed health and lifestyle information via a selfadministered questionnaire [20]. Dietary information was obtained using a 136-item semiquantitative food frequency questionnaire (FFQ) based on the instrument developed by Willett et al. [21], but modied for use in Australia [22, 23]. Controls were asked to report how often they consumed a specied amount of each food item in the previous year. Cases were asked to report their usual frequency of consumption in the year before their diagnosis or, if their diet had changed in the last 612 months, their usual diet. To calculate GL and GI, we used an Australian GI database (FoodWorks: Professional Edition, 2007) that compiled GI values based on carbohydrate-containing food items to reect their blood glucose response. Data not available in FoodWorks were supplemented with GI values obtained from tables compiled by Atkinson et al. (2008) [24]. We calculated total dietary GL of a food item by multiplying the amount of carbohydrate contained in a specied serving size of the food by the quantity of that food item consumed per day and its corresponding GI value (using glucose as the reference food). We then summed the values for all carbohydratecontaining foods reported on the FFQ to estimate total GL [24, 25]. The overall GI was calculated by dividing the total dietary GL by the total available carbohydrate intake. For the present analyses, we excluded 157 cases and 48 controls who did not return the FFQ, 26 cases and 3 controls with more than 10% of FFQ items missing, and 63 cases and 44 controls whose estimated calorie intake was extreme (<700 or >4000 kcal), leaving a nal group of 1366 cases and 1414 controls for analysis. Tests for trend were carried out over categories of intake, modeling the median values of each category as a single continuous variable. Analysis of variance was used to test for differences in means for continuous variables, and the chi-square test was used for categorical variables. Unconditional multivariate logistic regression models were used to estimate the relative risk of ovarian cancer associated with each dietary constituent, adjusted for potential confounders including age (years), parity (0, 12, and 3), OC use (never, <60 months, and 60 months), level of postschool education (none,

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results
Cases were slightly older than controls (mean 57.6 versus 56.3 years) and were less likely to have continued their education beyond high school (Table 1). Cases were more likely to be nulliparous, postmenopausal, have a family history of breast or ovarian cancer, and were also more likely to have had a hysterectomy, report being a current smoker, use talc in the perineal region. Cases were less likely than controls to have ever used OCs, to have had a tubal ligation, and to drink alcohol (all P < 0.05). GL was positively associated with risk of ovarian cancer (Table 2). Compared with women in the lowest quartile, those in the highest quartile had a 24% increased risk of ovarian cancer (95% CI 1.001.55) and there was a statistically signicant doseresponse (P for trend = 0.03). Further adjustment for dietary ber intake strengthened the association; the ORs across quartiles of GL were 1.00, 1.12, 1.28, and 1.32 (95% CI 1.051.65, P for trend = 0.008). We repeated these analysis excluding women who reported a history of diabetes (n = 165) or polycystic ovary syndrome (n = 48) and found the same associations. We also found that higher intake of ber was inversely associated with risk of ovarian cancer; the OR for women in the highest quartile was 0.78 (95% CI 0.620.98); however, there was no signicant doseresponse (P for trend = 0.11). With additional adjustment for GL, the risk estimates across quartiles of ber intake were essentially unchanged; however, the doseresponse became statistically signicant (P for trend = 0.04). Further adjustment for fruit and vegetable intake attenuated the OR for the highest versus the lowest berintake group (OR 0.87, 95% CI 0.641.19). This suggests that the observed association between ber and ovarian cancer risk was at least partly due to fruit and vegetable intake.

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original article
Table 1. Comparison of nondietary, dietary, and lifestyle characteristics of 1366 cases and 1414 controls included in this study Characteristics Cases, N Controls, N 56.3 6 12.5 719 (50.9) Pa 0.003 0.05

Annals of Oncology

Age (mean 6 standard 57.6 6 11.9 deviation) College/university 644 (47.1) education Parity 0 267 (19.6) 12 557 (40.9) 3+ 539 (39.6) Oral contraceptive use Never 431 (31.7) <60 months 364 (26.8) 60+ months 563 (41.5) Tubal ligation 316 (23.2) Hysterectomy 319 (23.4) Postmenopausal 978 (71.6) Ever use of HRTb 458 (47.2) Ever use of talc in the 675 (49.5) perineal region 255 (18.7) Family historyc Body mass index (kg/m2) <25 560 (42.4) 2529.9 450 (34.0) 30 312 (23.6) Smoking status Never 775 (56.7) Past smoker 370 (27.1) Current smoker 221 (16.2) Alcohol intake (g/day) 0 313 (22.9) 0.19.9 749 (54.8) 10 304 (22.3) Dietary factorsd (median daily intake) Energy (kcal) 2088 Available carbohydrate (g) 232 Glycemic index 50.2 Glycemic load 116.1 Protein (g) 94.4 Sugar (g) 131 Starch (g) 97 Dietary ber (g) 31.7 Fat (g) 70.7
a

166 (11.7) 608 (43.0) 640 (45.3) 297 347 766 386 275 936 478 625 (21.1) (24.6) (54.3) (27.3) (19.5) (66.2) (51.1) (44.3)

<0.0001

associations between GI, GL, dietary carbohydrates, and the different ovarian cancer subtypes (serous, mucinous, endometrioid, and clear cell). When we stratied by BMI (<25 and 25 kg/m2), we found that the relationship between sugar intake and risk of ovarian cancer was stronger among overweight/obese women (BMI 25) compared with leaner women (BMI < 25) (P for interaction = 0.004) (Table 3). Similar associations were also observed for GL and total carbohydrates among overweight/obese women but the tests for interaction did not reach statistical signicance. There was no signicant effect modication by menopausal status or HRT use (results not shown).

<0.0001

discussion
In this large-study population of Australian women, we found modest independent associations between GL, ber intake, and risk of ovarian cancer. Women in the highest quartile of GL had a 24% excess risk compared with women in the lowest quartile, while women with the highest ber intake (3877 g/day) had a 22% reduced risk compared with women with the lowest ber intake (1027 g/day). No signicant associations with ovarian cancer were observed for high intakes of GI, total carbohydrates, sugar, or starch. Our results also suggested that the associations with GL, total carbohydrates, and sugar were stronger among overweight women. Our ndings for GL and ovarian cancer are in agreement with the ndings from two of three previous observational studies [1315]. In a large (n = 1031) Italian casecontrol study, the risk of ovarian cancer was nearly twofold higher when comparing the highest quartile of GL with the lowest (OR 1.7, 95% CI 1.32.1, P for trend < 0.01) [13]. Likewise, in a Canadian prospective study with 16.4 mean years of followup and 264 incident cases, GL was associated with an increased risk of ovarian cancer (HR 1.72, 95% CI 1.132.62, P for trend = 0.004) [14]. Although both these studies reported stronger associations among postmenopausal women, like us, neither found statistical signicant effect modication by menopausal status. In contrast, a recent USA prospective study of dietary patterns with 475 cases found an inverse association with increasing quintiles of GL (OR for the highest versus the lowest quintile 0.48, 95% CI 0.280.84, P for trend = 0.029) [15]; however, they were unable to adjust for menopausal status which the authors state could explain this nding although, given our results, this seems unlikely. For GI, total dietary carbohydrates, sugar, and starch, we found no clear association in our casecontrol analyses. Our ndings for GI are similar to the previous cohort studies [14, 15] but are in contrast to the hospital-based casecontrol study that found a positive association between GI and ovarian cancer risk [13]. The nding of an association with GL but not GI suggests that the proportion of high-GI foods in the diet may not be as good as an indicator of physiological response to carbohydrates as GL, which also takes into account the quantity of intake of rapidly absorbed carbohydrates [27]. The main mechanism by which carbohydrate-rich foods and their GL or GI could inuence ovarian cancer risk relates to modulation of the IGF axis. Long-term consumption of a diet high in carbohydrate can lead to chronic hyperinsulinemia that
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0.01 0.01 0.002 0.09 0.006 <0.0001 0.1

184 (13.0) 642 (46.0) 429 (30.7) 325 (23.3) 837 (59.2) 416 (29.5) 160 (11.3) 238 (16.8) 793 (56.1) 383 (27.1) 2078 230 49.9 112.9 95.6 128 95 32.2 71.6

0.0009

0.0001

0.9 0.4 0.1 0.2 0.6 0.3 0.7 0.3 0.9

All statistical tests were two-sided. Chi-square statistics were used to compare proportions, and analysis of variance was used to compare means. b Hormone replacement therapy (HRT) use restricted to postmenopausal women. c Family history of breast or ovarian cancer in a rst-degree relative. d Median daily intakes are unadjusted for energy.

There were no signicant associations or doseresponse trends for higher intakes of GI, total carbohydrates, sugar, or starch. Further adjustment for dietary ber made no material difference in risk estimates for GI, total sugar, and starch; however, for total carbohydrates, adjusted risk estimates modestly increased across quartiles 1.00, 0.99, 1.16, and 1.28 (95% CI 1.021.62, P for trend = 0.02). There were no notable

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Quartile of intake Q1 P for trend Q2 48 (4750) 330/365 0.98 (0.791.22) 0.98 (0.791.22) 110 (102116) 333/362 1.10 (0.891.36) 1.06 (0.851.32) 225 (213235) 321/374 0.92 (0.751.14) 0.92 (0.731.14) 122 (111132) 325/370 0.90 (0.731.11) 0.93 (0.741.16) 91 (8298) 350/345 1.09 (0.881.35) 1.03 (0.831.29) 30 (2732) 318/377 0.71 (0.580.88) 0.73 (0.580.91) Q3 52 (5053) 351/344 1.13 (0.921.40) 1.15 (0.921.44) 123 (116131) 353/342 1.23 (0.991.52) 1.21 (0.971.51) 245 (235256) 348/347 1.10 (0.891.36) 1.06 (0.851.32) 143 (132155) 327/368 0.90 (0.721.11) 0.88 (0.711.10) 105 (98114) 344/351 1.06 (0.851.30) 1.06 (0.851.33) 35 (3238) 343/352 0.82 (0.661.01) 0.83 (0.661.04) Q4 55 (5371) 350/345 1.11 (0.901.38) 1.09 (0.871.36) 141 (131235) 362/333 1.32 (1.071.63) 1.24 (1.001.55) 272 (256360) 364/331 1.20 (0.971.48) 1.15 (0.921.44) 172 (155302) 371/324 1.16 (0.941.43) 1.14 (0.911.42) 126 (114249) 337/358 1.03 (0.831.28) 1.00 (0.811.25) 43 (3877) 336/359 0.78 (0.620.96) 0.78 (0.620.98) 0.17 0.25 0.006 0.03 0.04 0.11 0.20 0.33 0.85 0.91 0.08 0.11
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Table 2. Odds ratios (ORs) and 95% condence intervals (CIs) associated with glycemic load (GL), glycemic index (GI), total carbohydrates, sugar, starch, and ber intake (daily) and risk of ovarian cancer

GI Median (range) Number of cases/controls Age-adjusted ORa Multivariate ORb GL Median (range) Number of cases/controls Age-adjusted ORa Multivariate ORb Total carbohydrates (g) Median (range) Number of cases/controls Age-adjusted ORa Multivariate ORb Total sugar (g) Median (range) Number of cases/controls Age-adjusted ORa Multivariate ORb Total starch (g) Median (range) Number of cases/controls Age-adjusted ORa Multivariate ORb Total ber (g) Median (range) Number of cases/controls Age-adjusted ORa Multivariate ORb
a

45 (2447) 335/360 1.0 1.0 92 (21102) 318/377 1.0 1.0 197 (94213) 333/362 1.0 1.0 96 (39111) 343/352 1.0 1.0 72 (2782) 335/360 1.0 1.0 23 (1027) 369/326 1.0 1.0

ORs and 95% CI adjusted for age. Multivariate ORs and 95% CI adjusted for age, oral contraceptive use (never, <60 months, and 60 months), level of postschool education (none, college, and university), parity (0, 12, and 3), body mass index (<25, 2529.9, and 30 kg/m2), menopausal status (premenopausal and postmenopausal), and energy intake (log transformed).
b

down regulates IGFBP and thus increases free IGF-1 [2, 3, 10]. Biologic evidence from in vitro studies has shown that IGF-1 directly promotes cellular proliferation and reduces apoptosis; and it can also affect downstream signaling pathways involved in cell growth and proliferation [28, 29]. Insulin and IGF-1 are also powerful negative regulators of SHBG synthesis in vitro and thus may stimulate ovarian cancer risk through a hormonal pathway; however, this has not been clearly demonstrated [3, 30]. An interaction between IGF-1, sex hormones, and insulin has also been implicated in the etiology of other hormonally driven cancers such as breast [31] and prostate [32]. We had hypothesized a priori that the associations between GL, GI, and dietary carbohydrates might be stronger among heavier women because obesity is an important determinant of insulin resistance that exaggerates the adverse metabolic responses to altered carbohydrate intake. The modest positive associations we observed between GL, total carbohydrates, and sugar among overweight/obese women were consistent with this hypothesis.

Evidence suggests that slowly absorbed, low-GL/GL foods, such as fruits, vegetables, and grainy breads, improve insulin sensitivity through their maintenance of relatively low plasma fatty acid levels [33]. There is also evidence that dietary ber may reduce endogenous sex hormone levels, specically estrone and estradiol, by increasing SHBG leading to lower circulating levels of unbound estrogen [16, 34, 35]. Like our results, most previous casecontrol studies have supported a benecial role of ber [3640], and furthermore, fruit and vegetable dietary patterns and vitamins and ber patterns [41] have been inversely associated with ovarian cancer in some studies. Two prospective studies, arguably the strongest study design, have not shown a reduced risk [5, 18]; however, they were small (n = 264 and n = 139 cases) and thus possibly suffered from a lack of power to detect modest effects. Major strengths of our casecontrol study include its large sample size, population-based design, and high-case response rate. In addition, we had detailed information on many potential confounders and the FFQ we used has been shown to

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Multivariate ORa by quartile of intake Q1 Q2 Q3 GI BMI (kg/m2) <25 25 GL BMI (kg/m2) <25 25 Total carbohydrates BMI (kg/m2) <25 25 Total sugar BMI (kg/m2) <25 25 Total starch BMI (kg/m2) <25 25 BMI (kg/m2) Total ber <25 25
a

Annals of Oncology

Table 3. ORs and 95% CIs associated with GL, GI, total carbohydrates, starch, ber, and sugar intake and risk of ovarian cancer by body mass index (BMI) P for trend Q4 P for interaction

1.0 1.0

0.85 (0.601.19) 1.08 (0.801.44)

1.26 (0.901.76) 1.07 (0.801.44)

1.10 (0.781.56) 1.12 (0.841.49)

0.21 0.47

0.36

1.0 1.0

0.95 (0.681.33) 1.16 (0.871.54)

1.02 (0.731.44) 1.35 (1.011.80)

1.00 (0.711.41) 1.51 (1.132.01)

0.88 0.003

0.34

1.0 1.0

0.88 (0.631.24) 0.93 (0.691.24)

0.85 (0.601.20) 1.23 (0.931.64)

0.94 (0.671.32) 1.34 (1.001.79)

0.72 0.05

0.30

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1.0 1.0

0.65 (0.460.90) 1.24 (0.931.66)

0.70 (0.500.99) 1.05 (0.791.40)

0.73 (0.521.02) 1.61 (1.202.16)

0.11 0.008

0.004

1.0 1.0

0.89 (0.631.25) 1.15 (0.871.56)

0.88 (0.631.23) 1.17 (1.881.56)

0.94 (0.671.31) 1.05 (0.791.40)

0.73 0.73

0.51

1.0 1.0

0.61 (0.430.87) 0.84 (0.631.12)

0.78 (0.551.10) 0.87 (0.651.16)

0.77 (0.551.09) 0.75 (0.551.01)

0.34 0.09

0.39

Multivariate ORs and 95% CI adjusted for age, oral contraceptive use (never, <60 months, and 60 months), level of postschool education (none, college, and university), parity (0, 12, and 3), energy intake (log transformed), menopausal status (premenopausal and postmenopausal).

be a valid measure of diet when compared with weighted food measures [42]. Assessment of our FFQ relative to an average of 12 days of weighed food records showed moderate correlation coefcients of 0.52, 0.47, and 0.50 for total carbohydrates, starch, and sugar, respectively, for women [42]. Our study also has several limitations. Estimating food and nutrients intakes by questionnaires is associated with measurement error and has been shown to attenuate effect estimates [43]. It is also likely that systematic error may be present due to underreporting of intakes within specic population subgroups, such as overweight women underreporting their sugar consumption. We have not validated the assessment of GI or GL using another dietary method or against an objective standard. It has also been suggested that GL/GI may not always adequately reect the glycemic or insulinemic response to food in mixed meals; however, others have shown that GI values can be used to accurately predict the effect of mixed meals on blood glucose levels [44, 45]. Another limitation of our study was the relatively low participation rate among controls (47%). This might be of particular importance because carbohydrate intake, GI, and GL could be associated with factors such as socioeconomic status, BMI, and smoking history that might differ between those women willing to participate compared with nonparticipants. We assessed this issue by comparing data from our control group with data from the 2004 Australian National Health Survey (NHS) (a representative survey of the Australian adult population) [46]. Distributions of education

level, BMI, parity, and ever versus never smoking among our controls were almost identical to those from the NHS, suggesting that bias among our control group is an unlikely explanation of our results [47]. Despite these limitations, we have shown in the largest study to date that diets with a high GL may modestly increase risk of ovarian cancer, whereas high intake of ber may decrease risk and that these effects appear to be independent of each other. These ndings raise the possibility that adopting a low-GL high-ber diet may result in small but potentially valuable reductions in the occurrence of ovarian cancer. We believe that these ndings warrant further investigation as potentially important modiable exposures in investigations of risk of cancer and other chronic diseases.

funding
The AOCS was supported by the U.S. Army Medical Research and Materiel Command (grant no. DAMD17-01-1-0729); the Cancer Council Tasmania and Cancer Foundation of Western Australia; the Australian Cancer Study was supported by the National Health and Medical Research Council of Australia (grant no. 199600); these analyses were supported by the Cancer Council Queensland (grant no. 496680); the National Health and Medical Research Council of Australia to PW and CN; CO is supported by a grant from the Xstrata Community Partnership Program, Australia.

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acknowledgements
Full membership of the AOCS Group is listed at http:// www.aocstudy.org/; the Australian Cancer Study Investigators are A. Green, P. Parsons, N. Hayward, P. Webb, and D. Whiteman. We gratefully acknowledge the support and assistance of the Survey of Womens Health study research group and the cooperation of the following institutions: New South Wales: John Hunter Hospital, North Shore Private Hospital, Royal Hospital for Women, Royal North Shore Hospital, Royal Prince Alfred Hospital, Westmead Hospital, and New South Wales Cancer Registry; Queensland: Mater Misericordiae Hospital, Royal Brisbane and Womens Hospital, Townsville Hospital, Wesley Hospital, and Queensland Cancer Registry; South Australia: Flinders Medical Centre, Queen Elizabeth II, Royal Adelaide Hospital, and South Australian Cancer Registry; Tasmania: Royal Hobart Hospital; Victoria: Freemasons Hospital, Mercy Hospital For Women, Monash Medical Centre, Royal Womens Hospital, and Victorian Cancer Registry; Western Australia: King Edward Memorial Hospital, St John of God Hospitals Subiaco, Sir Charles Gairdner Hospital, Western Australia Research Tissue Network, and Western Australia Cancer Registry. We acknowledge Maria Celia Hughes from the Queensland Institute of Medical Research for preparation of the dietary data and Nirmala Pandeya of the Queensland Institute of Medical Research for her statistical advice and would like to thank all the women who participated in the study.

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disclosure
The authors have declared no conict of interest.

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