Dietary Patterns and Prostate Cancer in the NHEFS Cohort. CONTRACTING ORGANIZATION: Fox Chase Cancer Center Philadelphia, Pennsylvania 19111

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1 V-., Award Number: DAMD TITLE: Dietary Patterns and Prstate Cancer in the NHEFS Chrt PRINCIPAL INVESTIGATR: Marilyn Tseng, Ph.D, NTRACTING RGANIZATIN: Fx Chase Cancer Center Philadelphia, Pennsylvania REPRT DATE: June 2 3 TYPE F REPRT: Final PREPARED FR: U.S. Army Medical Research and Materiel Cmmand Frt Detrick, Maryland DISTRIBUTIN STATEMENT: Apprved fr Public Release; Distributin Unlimited The views, pinins and/r findings cntained in this reprt are thse f the authr(s) and shuld nt be cnstrued as an fficial Department f the Army psitin, plicy r decisin unless s designated by ther dcumentatin

2 REPRT DCUMENTATIN PAGE Frm Apprved MB N Public reprting burden fr this cllectin f infmnatin Is estimated t average 1 hur per respnse, Including the time fr reviewing Instructins, searching existing data surces, gathering and maintaining the data needed, and cmpleting and revievking this cllectin f infrmatin. Send cmments regarding this burden estimate r any ther aspect f this cllectin f infrmatin. Including suggestins fr reducing this burden t Washingtn Headquarters Services, Directrate fr Infrmatin peratins and Reprts, 1215 JelTersn Davis Highway. Suite 124, Arlingtn, VA , and t the ffice f Management and Budget, Papenrrit Reductin Prlect (74-188). Washingtn, DC AGENCY USE NLY (Leave blank) 2. REPRT DATE June TITLE AND SUBTITLE Dietary Patterns and Prstate Cancer in the NHEFS Chrt 6. AUTHR(S) Marilyn Tseng, Ph.D. 3. REPRT TYPE AND DATES VERED Final (1 Jun 2-31 May 3) 5. FUNDING NUMBERS DAMD PERFRMING RGANIZATIN NAME{S) AND ADDRESS(ES) Fx Chase Cancer Center Philadelphia, Pennsylvania M_tseng@fccc.edu 9. SPNSRING / MNITRING AGENCY NAME(S) AND ADDRESS(ES) U.S. Army Medical Research and Materiel Cmmand Frt Detrick, Maryland PERFRMING RGANIZATIN REPRT NUMBER 1. SPNSRING / MNITRING AGENCY REPRT NUMBER 11. SUPPLEMENTARY NTES 12a. DISTRIBUTIN / AVAILABILITY STATEMENT Apprved fr Public Release; Distributin Unlimited 12b. DISTRIBUTIN DE 13. ABSTRACT (Maximum 2 Wrds) Eclgic studies implicate a "western" diet in prstate cancer, but whether dietary patterns measured in individuals are assciated with risk has nt been studied previusly. We used prspective data frm the NHANES I Epidemilgic Fllw-up Study, with 136 cases amng 3,779 men fllwed t Using principal cmpnents analysis, three patterns were identified: vegetable-fruit, red meat-starch, and suthern. In prprtinal hazards mdels, suthern pattern intake shwed a risk reductin (3rd vs. 1st tertile RR.6, 95% CI.4-1.1) that apprached statistical significance, was bserved in black and nn-black men, and was nt attributable t intake f any individual fds r nutrients. A suthern pattern may reflect a histry f living in the Suth and serve as a marker f sunlight expsure and prtectin thrugh 1,25-hydrxyvitamin D prductin. ther findings in the same sample als suggest the imprtance f a vitamin D-related pathway: Dairy intake (RR 2.2,95% CI ), lwfat milk (RR 1.6,95% CI ), and calcium (RR 2.4,95% CI ) were assciated with risk, while vitamin D intake was inversely assciated (RR.5,95% CI.3-1.). High calcium intake may suppress 1,25-hydrxyvitamin D prductin, increasing prstate cancer risk. Hwever, mechanisms linking dairy/calcium t prstate cancer shuld be clarified and cnfirmed. 14. SUBJECT TERMS Nutritinal epidemilgy, prstate cancer, dietary patterns 15. NUMBER F PAGES PRICE DE 17. SECURITY CLASSIFICATIN F REPRT Unclassified 18. SECURITY CLASSIFICATIN F THIS PAGE Unclassified 19. SECURITY CLASSIFICATIN F ABSTRACT Unclassified 2. LIMITATIN F ABSTRACT Unlimited NSN Standard Frm 298 (Rev. 2-89) Prescribed by ANSI Std. Z

3 f > Table f Cntents Cver 1 SF298 2 Intrductin 4 Bdy 4 Key Research Accmplishments 13 Reprtable utcmes 13 Cnclusins 14 References 14 List f Persnnel 15 Appendices 15

4 M Tseng INTRDUCTIN While epidemilgic studies and interventin trials n diet and prstate cancer have fcused primarily n specific factrs in the diet, assciatins f dietary patterns v^ith prstate cancer risk have nt been studied previusly. We undertk this research t examine the assciatin between dietary patterns and prstate cancer risk using principal cmpnents analysis t measure intake f dietary patterns. Specifically, we sught t (1) cnfirm the presence f the "western" and "prudent" dietary patterns in a natinally representative sample f men, (2) test the hypthesis that a "western" diet is assciated with prstate cancer risk, (3) determine if dietary pattern assciatins with prstate cancer are strnger than thse fund fr mre cnventinal measures f dietary intake, such as ttal fat, saturated fat, and red meat intake, and (4) examine the extent t which the difference in prstate cancer risk between black and white men in the US can be attributed t interethnic differences in dietary pattern intake. Belw, we describe ur wrk twards the tasks utlined in ur Statement f Wrk, as well as the results f additinal analyses fcusing n dairy, calcium, and vitamin D intake. BDY Task 1. Acquisitin and setup f NHEFS data (mnths 1-5) As described in ur prgress reprt, we btained relevant subsets f NHEFS data frm Dr. Rsalind Breslw (Centers fr Disease Cntrl), and frm Dr. Regina Ziegler (Natinal Cancer Institute) at n cst. Task 2. Identificatin f dietary patterns (mnths 6-12) a. Perfrm principal cmpnents analyses t identify dietary patterns As described previusly, we used principal cmpnents analysis (PCA) n frequency respnses t the NHEFS dietary questinnaire t identify patterns f fd intake. Three dietary patterns emerged cnsistently acrss the split samples (Table 1): (1) a "vegetable-fruit" pattern with high ladings fr vegetables, fruits, and seafd (fish and shellfish); (2) a "red meat-starch" pattern with high ladings fr red meats, ptates, salty snacks, cheese, and sweets and desserts; and (3) a "suthern" pattern with high ladings fr beans, rice, and such traditinally suthern fds as cmbread, grits, sweet ptates, and kra. The same three patterns emerged when we cnducted the analysis in black men nly. b. Cnduct sensitivity analyses t cnfirm rbustness f results As described previusly, when we repeated analyses cllapsing the 15 fd items int 37 predefined fd grups (1), nly tw patterns resembling the vegetable-fruit and red meat-starch patterns emerged. We chse nt t cllapse fd items fr tw main reasns. First, creating grups f ptentially dissimilar fds may diminish the ability t identify mre specific patterns. Secnd, gruping fds prir t PCA may attenuate r increase the variance f measures f assciatin between dietary patterns and disease (2). Additinal sensitivity analyses are described under sectin (d).

5 M Tseng c. Assess reliability and validity f dietary patterns identified ur assessment f cnstruct validity was described in the previus prgress reprt. Briefly, v^e examined distributins f selected scidemgraphic and health-related characteristics (3-5) acrss pattern tertiles (Table 2). We fund that assciatins f the dietary patterns with scidemgraphic and health-related characteristics were as expected based n bservatins f the histrical emergence f thse patterns (3), cnfirming the validity f their measurement using PCA. d. Calculate cmpnent scres t represent level f intake f each dietary pattern fr each subject As described previusly, we calculated cmpnent scres t quantify each individual's level f intake fr each pattern by taking the unweighted sum f standardized frequencies f intake fr each fd assciated with the pattern. These scres were used t examine assciatins f dietary patterns with prstate cancer risk. Task 3. Examinatin f dietary pattern - prstate cancer risk assciatins (mnths 13-18) a. Cnduct statistical analyses t quantify assciatins between dietary patterns and prstate cancer risk Results frm ur examinatin f dietary pattern - prstate cancer assciatins were described in ur previus prgress reprt. Briefly, we fund that in Cx prprtinal hazards mdels (Table 3), prstate cancer risk was nt assciated with the vegetable-finit r red meat-starch pattern, but higher intake f the suthern pattern shwed a reductin in risk (3'^'' vs. 1*' tertile relative risk =.6, 95% cnfidence interval:.4,1.1; trend p =.8) that apprached statistical significance. The inverse assciatin was bserved in black and nn-black men. A suthern dietary pattern may reflect a histry f living in the Suth and serve as an integrative marker f sunlight expsure and prtectin thrugh 1,25 hydrxyvitamin D prductin. b. Perfrm sensitivity analyses Risk estimates were nt materially different when we excluded 14 prstate cancer cases diagnsed within a year f the dietary interview, re-classified 47 "prbable" cases as nn-cases, used age rather than time-n-study as the time scale, r excluded cases identified after 1986, when the US Fd and Drug Administratin apprved the prstate-specific antigen (PSA) test fr mnitring prstate cancer prgressin. c. Quantify assciatins between single nutrients/fds and prstate cancer risk fr cmparisn with dietary pattern findings We explred pssible explanatins fr the inverse assciatin fr the suthern pattern by examining each f the fds assciated with it, but nne were assciated with prstate cancer risk. Much f ur wrk ver the past year has been in pursuing ur serendipitus finding that dairy and calcium are assciated with prstate cancer risk in this sample. ur finding is cnsistent with ther previus wrk (6-1). In this

6 M Tseng analysis, calcium intake was estimated by multiplying reprted frequency f intake f each fd in the dietary interview by prtin-specific nutrient cntent estimated fi-m sex- and age-specific 24-hur recall data frm the secnd Natinal Health and Nutritin Examinatin Survey. We used the same prcedures t assign sex- and age-specific vitamin D cntent per prtin size t fd items. Values f lu vitamin D per 1 g f fd were drawn firm the current US Department f Agriculture (USD A) nutrient database (11), supplemented with ther published values (12). Fr mixed dishes, vitamin D- cntaining ingredients were identified based n recipes available frm the USDA Survey Nutrient Database fr the Cntinuing Survey f Fd Intakes by Individuals (13) and ther recipe surces (14,15) in rder t estimate the amunt f vitamin D in the entire mixed dish. In Cx prprtinal hazards mdels (table 4), dairy fd intake (3^'^ vs. 1^* tertilerr =2.2; 95 percent CI: 1.3,4.; trend p =.3) was strngly assciated with prstate cancer risk. When each dairy fd was examined individually, the increase in risk was bserved fr lw fat milk (3'^'' vs. V^ tertile RR = 1.6; 95 percent CI: 1.2,2.1; trend p =.4) but nt fr whle milk. Calcium intake was als strngly assciated with risk (3'^'' vs. 1^^ tertile RR = 2.4; 95 percent CI: 1.5, 3.9; trend p =.5). In mdels fr dairy fds that were additinally adjusted fr calcium intake, assciatins fr verall dairy (3'^'' vs. 1^' tertile RR = 1.3; 95 percent CI:.6,2.9; trend p =.45) and lw fat milk (3"" vs. 1'' tertile RR =1.1; 95 percent CI:.7, 1.6; trend p =.71) were attenuated, while RR estimates and trend p-values fr calcium were nt meaningfully changed (table 4). In additin, when we lked at calcium frm lw fat milk, whle milk, and ther fd surces, nly calcium frm lw fat milk was assciated with risk (3'^ vs. 1'' tertile RR =1.8; 95 percent CI: 1.2,2.6; trend p =.4). We als saw n assciatin fr use f calcium supplements (RR =.9; 95 percent CI:.3, 2.9), but we identified nly 88 men as calcium supplement users. Multivitamins were nt included as calcium supplements because f their generally lwer calcium cntent, but use f multivitamins was nt assciated with risk in these data (RR =.9; 95 percent CI:.6,1.4). Phsphrus was nt assciated with risk f prstate cancer when calcium was als cnsidered (3'"'' vs. 1^' tertile RR =.9; 95 percent CI:.5,1.6; trend p =.82), nr did we see evidence fr an interactin between phsphrus and calcium intake (p=.45). In cntrast, wdth adjustment fr calcium intake, vitamin D was inversely assciated with prstate cancer risk (3*^^ vs. 1^' tertile RR =.5; 95 percent CI:.3,1.; trend p =.5). The assciatin fr vitamin D was nt clearly attributable t any single fd r fd grup when we lked at vitamin D frm lw fat milk, whle milk, r ther fds such as fish r shellfish. Current use f cd liver il was als nt assciated vdth prstate cancer risk (RR =.9; 95 percent CI:.2,4.), but, as in the case fr calcium supplements, nly a small number f men (N=5) reprted its use. When we examined relative risks fr individuals crss-classified accrding t bth calcium and vitamin D intake, risk was elevated primarily in men with high intake f bth calcium and vitamin D. Ntably, men in this categry had

7 M Tseng especially high intake f lwfat milk (median 7 servings/week, vs. <2 in ther categries), but nt f whle milk r ther dairy fds. ur findings are cnsistent with the hypthesis that dairy intake increases risk f prstate cancer, pssibly thrugh its calcium cntent, while vitamin D is prtective. Reasns fr the finding that elevated risk was assciated specifically with lw fat milk, hwever, are unclear. Given the implicatins f these findings with respect t current recmmendatins regarding bth calcium intake and cnsumptin f lw fat milk, the mechanisms by which calcium might increase risk shuld be clarified and cnfirmed t verify that calcium is indeed the risk factr f interest. d. Evaluate dietary patterns as mediatr f higher prstate cancer risk in African American vs. white men in NHEFS chrt Dietary patterns were nt pursued as a mediatr f the higher prstate cancer risk in African American men because black men remained at higher risk fr prstate cancer despite their higher intake f an apparently prtective suthern pattern. Dairy/calcium intake were nt pursued as mediatrs because African American men did nt cnsume higher amunts f these dietary factrs than white men. Task 4. Final analyses, reprt writing, and preparatin f manuscripts (mnths 19-24) A manuscript describing dietary pattern results has been submitted t the jurnal Cancer Epidemilgy, Bimarkers & Preventin. A manuscript describing dairy/calcium/vitamin D results has been cmpleted and is being reviewed by cauthrs.

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10 M Tseng TABLE 3. Relative risk (RR) estimates and 95% cnfidence intervals (CI) by dietary pattern intake (N=3,616). Dietary pattern Prstate cancer Minimal mdef Full mdel" cases Vegetable-fruit tertile tertile (.9-1.8) 1.5(.9-2.3) tertile (.7-1.8) 1.2(.7-2.) p fr trend*^ Red meat-starch tertile tertile (.5-1.2).7(.5-1.2) tertile (.6-1.3).8(.4-1.4) p fr trend Suthern tertile tertile (.6-1.3).9(.6-1.4) tertile (.4-1.).6(.4-1.1) p fr trend.6.8 ^ Mdels adjusted fr age, race, and design variables. '' Mdels adjusted fr age, race, design variables, regin, urban/rural residence, educatin, recreatinal sun expsure, smking status, leisure physical activity level, energy intake (tertiles), and alchl intake. '^ p-value fr trend was btained fr each pattern by including in the mdel a variable representing the median value fr each tertile. 1

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13 M Tseng KEY RESEARCH ACMPLISHMENTS successfully cnducted planned analyses twards research bjectives - namely: - in a natinally representative sample f men, cnfirmed the presence f the tw dietary patterns expected a priri, and identified a new dietary pattern in the sample - examined dietary patterns in relatin t prstate cancer risk, finding n assciatin fr the red meat-starch pattern as was riginally expected, but finding an inverse assciatin fr the suthern pattern - fund strnger assciatins fr the suthern pattern than fr any single fd in the suthern pattern successfully pursued a serendipitus finding f higher risk assciated with dairy and calcium intake, with the fllwing findings: - in a natinally representative sample f men, intake f dairy fds and calcium was assciated with strng increased risk fr prstate cancer - elevated risk bserved fr dairy fds was seen nly fr lw fat milk and nt fr any ther dairy items - vitamin D intake was inversely assciated with prstate cancer risk - an effect nt attributable t any specific vitamin D-rich fds, but evident nly when all dietary surces were cnsidered tgether REPRT ABLE UTMES Manuscripts 1. Tseng M, Breslw R, DeVellis RF, Ziegler R. Dietary patterns and prstate cancer in the NHANES I Epidemilgic FUwup Study Chrt. Submitted manuscript. 2. Tseng M, Breslw R, Ziegler R. Dairy, calcium, and vitamin D intake and prstate cancer risk in the NHEFS Chrt. Manuscript in preparatin. Abstracts 1. Tseng M, Breslw R, Babb J, DeVellis RF, Ziegler R. Dietary patterns and prstate cancer in the NHANES I Epidemilgic Fllwup Study Chrt (abstr). Prc Am Assc Cancer Res 43: 933, Tseng M, Breslw R, Babb J, DeVellis RF, Ziegler R. Dietary patterns and prstate cancer in the NHANES I Epidemilgic Fllwup Study Chrt (abstr). Am J Epidemil 155: S55, M Tseng, R Breslw, J Babb, RF DeVellis, R Ziegler. Dairy, Calcium, and Prstate Cancer in the NHANES I Epidemilgic Fllwup Study (abstr). Am J Epidemil 155: S55, 22. Presentatins 1. Tseng M, Breslw R, Babb J, DeVellis RF, Ziegler R. (22). Dietary patterns and prstate cancer in the NHANES I Epidemilgic Fllwup Study Chrt. Presented as pster at the American Assciatin fr Cancer Research meeting, San Francisc, CA, and at the Sciety fr Epidemilgic Research meeting. Palm Desert, CA. 13

14 M Tseng 2. M Tseng, R Breslw, J Babb, RF DeVellis, R Ziegler. (22). Dairy, Calcium, and Prstate Cancer in the NHANES I Epidemilgic Fllwup Study. Presented at the Sciety fr Epidemilgic Research meeting. Palm Desert, CA. NCLUSINS We fund that prstate cancer risk was nt clearly assciated with either the red meat-starch r the vegetable-fruit pattern, but we bserved a suggestive, inverse assciatin fr the suthern pattern. The assciatin was bserved in bth black and nn-black men and was nt attributable t any individual fds within the pattern r t any nutrients f prir interest. A suthern dietary pattern may reflect a histry f living in the Suth and serve as an integrative marker f sunlight expsure and prtectin thrugh 1,25 hydrxyvitamin D prductin. Hwever, better characterizatin f the pattern wuld ffer mre infrmatin n ptentially beneficial features f the diet r f its assciated lifestyle. Thus, ur findings shuld be explred and cnfirmed in ther data t clarify interpretatin f these bservatins. While a pattern apprach might yield a valuable perspective in diet-disease studies, strategies fr imprving methds f identifying and evaluating dietary patterns als require fiirther cnsideratin. Cnsistent with ur hypthesis that a vitamin D-related pathway is prtective, we fund that prstate cancer risk was elevated with higher intake f dairy fds and calcium, particularly calcium frm lw fat milk, while risk was inversely assciated with intake f vitamin D. Reasns fr the finding that elevated risk was assciated specifically with lw fat milk, hwever, are unclear. Given the implicatins f these findings with respect t current recmmendatins regarding bth calcium intake and cnsumptin f lw fat milk, the mechanisms by which calcium might increase risk shuld be clarified and cnfirmed t verify that calcium is indeed the risk factr f interest. REFERENCES 1. Hu F, Rimm E, Smith-Warner S, et al. Reprducibility and validity f dietary patterns assessed with a fd-frequency questinnaire. American Jurnal f Clinical Nutritin 1999;69: McCann SE, Marshall JR, Erasure JR, Graham S, Freudenheim JL. Analysis f patterns f fd intake in nutritinal epidemilgy: fd classificatin in principal cmpnents analysis and the subsequent impact n estimates fr endmetrial cancer. Public Health Nutritin 21;4: Levenstein HA. Revlutin at the Table : The Transfrmatin f the American Diet. New Yrk: xfrd University Press, Mclntsh EN. American Fd Habits in Histrical Perspective. Westprt, CT: Praeger Publishers, Pillsbury R. N Freign Fd: The American Diet in Time and Place. Bulder, : Westview Press, Chan JM, Givannucci EL. Dairy prducts, calcium, and vitamin D and risk f prstate cancer. Epidemilgic Reviews 21;23: Chan JM, Givannucci E, Anderssn S, Yuen J, Adami H, Wlk A. Dairy prducts, calcium, phsphrus, vitamin D, and risk f prstate cancer (Sweden). Cancer Causes and Cntrl 1998;9:

15 M Tseng 8. Chan JM, Stampfer MJ, Ma J, H GP, Gazian JM, Givannucci EL. Dairy prducts, calcium, and prstate cancer risk in the Physicians' Health Study. American Jurnal f Clinical Nutritin 21;74: Givannucci E, Rimm EB, Wlk A, et al. Calcium and fructse intake in relatin t risk f prstate cancer. Cancer Research 1998;58: Kristal AR, Chen JH, Qu P, Stanfrd JL. Assciatins f energy, fat, calcium, and vitamin D with prstate cancer risk. Cancer Epidemilgy, Bimarkers and Preventin 22;11: US Department f Agriculture. Cmpsitin f Fds: Raw, Prcessed, Prepared. USDA Nutrient Database fr Standard Reference, Release 15. Beltsville, MD, Penningtn JAT. Bwes & Church's Fd Values f Prtins Cmmnly Used. 17th editin ed. Philadelphia: Lippinctt, US Department f Agriculture Cntinuing Survey f Fd Intakes by Individuals and related survey materials Claibme C. New Yrk Times Ckbk. New Yrk: HarperCllins, freerecipe.rg. LIST F PERSNNEL Marilyn Tseng, Ph.D., Principal Investigatr James Babb, Ph.D., Bistatistician APPENDICES Tseng M, Breslw R, Babb J, DeVellis RF, Ziegler R. Dietary patterns and prstate cancer in the NHANES I Epidemilgic Fllwup Study Chrt. Submitted manuscript. 15

16 DIETARY PATTERNS AND PRSTATE CANCER RISK IN THE NHEFS HRT Marilyn Tseng,' Rsalind A. Breslw, Rbert F. DeVellis, Regina G. Ziegler Divisin f Ppulatin Science, Fx Chase Cancer Center, Philadelphia, PA [M.T.]; Natinal Institute n Alchl Abuse and Alchlism, Bethesda, MD [R.A.B.]; Department f Health Behavir and Health Educatin, University f Nrth Carlina, Chapel Hill, NC [R.F.D.]; Epidemilgy and Bistatistics Prgram, Divisin f Cancer Epidemilgy and Genetics, Natinal Cancer Institute, Bethesda, MD [R.G.Z.] Running head: Dietary Patterns and Prstate Cancer

17 Tseng M Page 2 ABSTRACT Eclgic studies implicate a "western" diet in prstate cancer develpment, but whether dietary patterns measured in individuals are assciated with risk has nt been studied previusly. We examined this issue using prspective data frm the natinally representative US Health Examinatin Epidemilgic Fllw-up Study. Amng 3,779 men fllwed frm t 1992,136 incident cases were identified. Using principal cmpnents analysis n respnses t a 15-item dietary questinnaire, three distinct patterns were identified: a vegetable-fruit pattern, a red meat-starch pattern characterized by red meats, ptates, cheese, salty snacks, and desserts, and a suthern pattern characterized by such fds as cmbread, grits, sweet ptates, kra, beans, and rice. In adjusted prprtinal hazards mdels, prstate cancer risk was nt assciated with the vegetable-fruit r red meat-starch pattern, but higher intake f the suthern pattern shwed a reductin in risk (3'^'' vs. 1^' tertile relative risk =.6, 95% cnfidence interval:.4, 1.1; trend p =.8) that apprached statistical significance. The inverse assciatin was bserved in black and nn-black men and was nt attributable t intake f any individual fds r nutrients. A suthern dietary pattern may reflect a histry f living in the Suth and serve as an integrative marker f sunlight expsure and prtectin thrugh 1,25 hydrxyvitamin D prductin. Further evaluatin and better characterizatin f the pattern wuld ffer mre infrmatin n ptentially beneficial features f the diet r its assciated lifestyle.

18 Tseng M Page 3 INTRDUCTIN In 23, prstate cancer is expected t remain the mst cmmnly diagnsed cancer and the secnd leading cause f cancer death in US men (1). Althugh risk factrs fr prstate cancer have been identified, nly age, ethnicity, and family histry f prstate cancer are wellestablished (1). Thus, feasible measures fr primary preventin f the disease remain limited. Epidemilgic and labratry research suggest that dietary intake is ne factr that might be mdified t reduce risk (2, 3). In particular, eclgic (4-6) and migrant (7) studies have implicated a "western" dietary pattern as a risk factr fr prstate cancer. Whether dietary patterns measured at the level f the individual are assciated with prstate cancer risk has nt been studied previusly, in part because f the relative nvelty f the apprach but als because standard methds fr identifying, measuring, and interpreting dietary patterns are nly nw being develped. By examining expsure t several related dietary factrs simultaneusly, quantifying the aggregate risk assciated with a particular cmbinatin f fds, and ffering results that are based n actual dietary practice and mre easily translated int useful recmmendatins, a dietary pattern apprach prvides a useful cmplement t findings based n single nutrients r single fd grups. In research using principal cmpnents analysis (PCA) t identify and quantify dietary patterns, tw patterns emerge fairly cnsistently in US samples: ne characterized by intake f vegetables and fruits, and a western-style pattern based n red meat and starch (8-1). The western pattern has been related t increased risk f cln cancer (8,11), cardivascular disease (12), and diabetes (13). The bjectives f ur analyses were t identify dietary patterns in a natinally representative sample f US men using PCA and t examine fr the first time their

19 Tseng M Page 4 assciatins with prstate cancer risk in prspectively cllected data, with the gal f clarifying the imprtance f specific dietary patterns t the develpment f prstate cancer. MATERIALS AND METHDS Study ppulatin The study sample included male participants in the first Natinal Health and Nutritin Examinatin Survey (NHANES I) Epidemilgic Fllw-up Study (NHEFS). NHANES I, cnducted between 1971 and 1975, used a multistage sampling design t btain a natinal prbability sample f the nninstitutinalized civilian ppulatin f the United States, excluding Alaska, Hawaii, and Native American reservatin lands (14,15). The elderly and persns residing in pverty areas were versampled. Abut 7 percent f thse sampled were bth interviewed and medically examined in NHANES I. NHEFS was a lngitudinal study f the 14,47 participants between the ages f 25 and 74 years at the time f the initial survey (16-19). Participants were fllwed fr health and vital status thrugh At interviews cnducted in ,1986,1987, and 1992, participants r their prxies were interviewed. Als, health recrds were btained fr instances in which participants reprted an vernight stay in a health care facility between the baseline examinatin and last fllw-up visit. Death certificates were btained fr deaths during the fllw-up perid and were identified by the Natinal Death Index r ther tracing mechanisms. Health recrds were btained fr ver 7 percent f reprted vernight stays and death certificates were btained fr 99 percent f deaths ccurring between and the 1992 fllw-up (19). Because fd frequency data btained in the interview included questins n nly 13 brad fd categries, we used mre detailed data frm a 15-item fd frequency

20 Tseng M Page 5 questinnaire administered in Thus, served as the baseline fr these analyses. f the 14,47 NHEFS participants, 5,811 were men. f these, 1,22 died prir t the interview, 351 culd nt be traced, and 333 were nt interviewed in Subjects were further excluded frm the remaining study sample if they had a diagnsis f prstate cancer at r befre the interview (n = 57), did nt cmplete the diet questirmaire (n = 79), r had energy intake f < 5 r > 4,4 kcal/day (n = 1), leaving 3,779 men available fr analysis. Identificatin f prstate cancer cases Cases f invasive prstate cancer were identified fllwing a prcedure described by Breslw et al. (2). Briefly, ptential cases were all men with an Internatinal Classificatin f Diseases, Ninth Revisin, Clinical Mdificatin cde f 185 (invasive prstate cancer), (prstate carcinma in situ), v 1.46 (persnal histry f malignant prstate neplasm), r (prstatectmy surgical prcedures) recrded in at least ne f the fllwing surces f data: (1) a first diagnsis f prstate cancer reprted at any f the fllw-up interviews cnducted in 1986,1987, r 1992; (2) ne r mre hspital stays during the fllw-up perid with a discharge diagnsis cded as any f the cdes given abve; (3) a death certificate with underlying r nnunderlying cause f death cded as any f the cdes given abve. Archived recrds f interviews and vernight health care facility stays were then reviewed. "Definite" case status was assigned if it culd be cnfirmed frm histpathlgy reprts r medical recrds. Determinatins based nly n interview r death certificate data were assigned "prbable" case status, althugh self-reprted cases were uncnfirmed by hspital recrds in sme instances because f lack f respnse frm sme hspitals. f 136 cases diagnsed during the fllw-up

21 f the 3,779 men frm the interview, 89 were cnsidered "definite" cases, and an additinal 47 were cnsidered "prbable" cases. Tseng M Page 6 Data cllectin Infrmatin n dietary intake was btained frm a 15-item fd frequency questinnaire administered in the interview. The questinnaire was designed t include fds cmmnly cnsumed in the US diet and cvered the majr fd grups, including meats, fish, pultry, grains, fruits, vegetables, dairy prducts, sweets, snacks, and beverages. Intake f specific nutrients such as energy, ttal fat, and vitamin A was estimated by multiplying frequency f intake f each fd by the nutrient cntent fr the fd's prtin size. Because the NHEFS dietary interview cllected nly frequency infrmatin, infrmatin n nutrient cntent and prtin size fr each fd was based n sex- and age-specific 24-hur recall data frm the secnd Natinal Health and Nutritin Examinatin Survey (NHANES II), a separate natinal survey cnducted in A detailed descriptin f the methd used t assign nutrient cntent and prtin size t each fd item in the NHEFS dietary questinnaire using NHANES II data has been published (21). ther infrmatin available frm the interview included race, place f residence, lngest held ccupatin, family incme, first-degree family histry f prstate cancer, current weight, alchl intake, smking behavir, sun expsure, level f physical activity, and current multivitamin use. Infrmatin n height and level f educatin was available frm the interview.

22 Tseng M Page? Identificatin f dietary patterns Patterns f fd intake were identified by PCA (22,23) using fi-equency respnses t the dietary questinnaire. (An example f SAS prgramming statements used t run the analysis is prvided at Individuals were randmly placed int ne f tw equally sized grups, r split-samples. Fr the first splitsample, a matrix f crrelatins amng fi-equency f cnsumptin fr the questinnaire fd items was cnstructed and entered in the PCA. Extractin f principal cmpnents was fllwed by rthgnal rtatin f retained cmpnents t allw fr interpretability (22,23). The number f cmpnents t retain fr rtatin was based n examinatin f scree plts and interpretability f the cmpnents (23); althugh anther cmmn strategy is t rtate all factrs with eigenvalues greater than 1., this methd has been shwn t verestimate the number f cmpnents (23). The analysis was repeated in the secnd split-sample in rder t cnfirm reprducibility f patterns identified. Crnbach's cefficient alpha (24) was used t evaluate internal cnsistency fr each cmpnent retained. In psychmetric research, a cefficient alpha f >.7 generally indicates acceptable reliability (25), althugh in previus research, dietary pattern scales with cefficient alphas as lw as.5-.6 were predictive f disease (26). As an additinal assessment f the rbustness f the patterns identified, we used blique rather than rthgnal rtatin, but the same patterns emerged. A cmpnent scre was calculated fr each dietary pattern fr each individual t represent the individual's level f intake fr the pattern. The scre fr each pattern was cmputed as a linear cmpsite f the fds with meaningful ladings (>.2 ) fr nly that pattern. Scres were calculated by taking the unweighted sum f standardized fi-equencies f intake fr each fd assciated with the pattern. When we cmputed pattern scres as a linear cmpsite f all

23 variables weighted based n regressin results (27), scres calculated the tw different ways were highly crrelated (r >.85), and estimates f relative risk (RR) fr prstate cancer were similar. We examined cnstruct validity f the patterns, r the extent t which they behave as Tseng M Pages expected theretically with respect t ther variables (28), by describing their assciatins with scidemgraphic and lifestyle variables amng 3,544 men with cmplete variable data. The variables, selected based n scial and histrical descriptins f the develpment f thse patterns (29-31), included age, place f residence (rural, urban, suburban), sciecnmic status (SES), and varius health-related behavirs. Data analysis Fllw-up time was calculated by subtracting the interview date frm last date knwn t be alive and free f prstate cancer (date f last interview, cntact, r death) fr nncases, r frm date f prstate cancer diagnsis fr cases. Fr fur cases identified frm death certificate data nly, the interview date was subtracted frm date f death rather than frm date f diagnsis. Adjusted RR f prstate cancer was estimated fr tertiles f pattern scres using Cx prprtinal hazards mdels while adjusting fr age (cntinuus years) and race (white, black, r ther race). ther variables - including US regin, urban/rural residence, educatin, first-degree family histry f prstate cancer, current bdy mass index, recreatinal physical activity, recreatinal and ccupatinal sun expsure, multivitamin use, smking status, and past and current alchl cnsumptin - were evaluated as cnfunders based n their assciatins with predictr and respnse variables, and by cmparing unadjusted and adjusted estimates frm

24 Tseng M Page 9 regressin analyses. Final multivariate mdels included 3,616 men with cmplete cvariate data and adjusted fr age, race, US regin (Nrtheast, Midwest, Suth, West), residence (rural, urban, suburban), educatin (< high schl, high schl cmpletin, > high schl), recreatinal sun expsure (little, ccasinal, frequent), recreatinal physical activity (little/nne, mderate, much), smking status (never, frmer, current), current alchl intake (nne, little, mderate, heavy), and energy intake (tertiles). All cvariates were cded using dummy variables t allw fr nn-linear assciatins acrss categries. Cntrlling fr energy as a cntinuus variable prduced n meaningful changes in estimates. P-values fr linear trend were btained fr each dietary pattern by including an rdinal variable representing the scaled median value fr each tertile in the multivariate mdel cntrlling fr the cvariates listed abve. T examine the pssibility f effect mdificatin by race, we ran prprtinal hazards mdels in black and nn-black men separately; men f ethnicities ther than white r black were t few (n = 46) t allw fr separate analysis. Because f the small number f black cases (n = 27), we dichtmized pattern scres fr all men at the median value fr black men. P-values fr interactin were btained frm a mdel including all men, with a pattern categry x race interactin term. In multivariate mdels cntrlling fr the same cvariates, we als examined the effects f specific fds and nutrients ptentially related t risk f prstate cancer, including red meat, dairy, fruits and vegetables, tmates, energy, ttal and saturated fat, calcium, vitamin A, and dietary fiber (32-35). Nutrient values were lg-transfrmed as necessary and energy-adjusted using the residual methd (36). RRs were estimated fr tertiles f intake relative t the lwest tertile, but fr infrequently cnsumed items such as kra and grits, estimates were fr cnsumptin v^. nn-cnsumptin. T accunt fr sample weighting frm the survey design, all

25 final mdels als included the fllwing design variables: age (< 65 v^. > 65 years), pverty Tseng M Page 1 census enumeratin district (residence vs. nn-residence), and family incme (< $3,, $3,- $6,999, $7,-$9,999, $1,-$14,999, and > $15,) (37), althugh results frm mdels with and withut design variables were similar. RESULTS Mean age f the men in the study sample was 58 years, 11 percent were African-American, and their usual residence was rughly equally distributed amng the fur regins f the US. ver a mean fllw-up f 7.6 years (range <1-1.7 years), 136 prstate cancer cases were identified in the chrt f 3,779 men. In PC A, three dietary patterns emerged cnsistently acrss the split samples (table 1): (1) a "vegetable-fruif pattern with high ladings fr vegetables, fruits, fish, and shellfish; (2) a "red meat-starch" pattern with high ladings fr red meats, ptates, salty snacks, cheese, and sweets and desserts; and (3) a "suthern" pattern with high ladings fr beans, rice, and such traditinally suthern US fds as cmbread, grits, sweet ptates, and kra. The same three patterns emerged when we cnducted the analysis in black men nly (results nt shwn). Thus, calculatin f pattern scres was based n the PCA slutin including all men. As an assessment f cnstruct validity, we described the distributins f selected scidemgraphic and health-related characteristics acrss pattern tertiles (table 2). Men with high intake f the vegetable-fruit pattern were mre likely t be white and f higher SES, t live in the nrtheastern and western US and in suburbs, and t use muhivitamins, exercise, and nt smke. Men with high intake f the red meat-starch pattern were mre likely t be white and yunger in age, t live in rural areas and in the Midwest, and t smke, exercise, and nt use

26 Tseng M Page 11 multivitamins. Assciatins f the red meat-starch pattern with SES indicatrs reflected neither especially high nr especially lw SES: men with high intake were mre likely t have graduated high schl but nt cllege and were mre likely t be abve the pverty level but nt at the highest incmes. In cntrast, men with high intake f the suthern pattern were mre likely t be black, t be f lwer SES, t live in rural areas and in the Suth, and t smke and nt use multivitamins. In Cx prprtinal hazards mdels (table 3), while the red meat-starch pattern was nt assciated with prstate cancer, intermediate intake f the vegetable-fruit pattern shwed a slight elevatin f risk (RR = 1.5; 95 percent cnfidence interval (CI):.9,2.3). Hwever, fr neither pattern was there evidence f a trend, and nne f the pint estimates reached statistical significance. Higher intake f the suthern pattern shwed a trend (p=.8) and a reductin in risk in the third tertile (3'** vs. 1'' tertile RR =.6; 95 percent CI:.4, 1.1) that apprached statistical significance. Risk estimates were nt materially different when we excluded 14 prstate cancer cases diagnsed within a year f the dietary interview, re-classified 47 "prbable" cases as nn-cases, cnducted analyses using SUDAAN (38), r used age rather than time-n- study as the time scale (39). In race-specific analyses, the assciatin between the suthern dietary pattern and prstate cancer risk was mre prnunced in black men (abve vs. belw median RR =.2; 95 percent CI:.2,.6), but estimates were based n a small number f cases, and the p-value fr interactin was nt significant. We explred pssible explanatins fr the inverse assciatin fr the suthern pattern by examining each f the fds assciated with it, but nne were assciated with prstate cancer risk (results nt shwn). Dietary patterns were als crrelated with intake f ther specific fds and nutrients that have previusly been linked t prstate cancer risk (table 2), but with the

27 exceptin f dairy fds and calcium (described in a separate manuscript), nne f these were clearly assciated with disease in ur data; RR estimates were all arund ne and shwed n trend in either directin (results nt shwn). Hwever, men with an intermediate level f fruit Tseng M Page 12 intake had a nn-significantly elevated risk (2"'' vs. 1^' tertile RR = 1.3; 95 percent CI:.8,2.1). Since 1986, when the US Fd and Drug Administratin apprved the prstate-specific antigen test fr mnitring prstate cancer prgressin, incidence has increased mre steeply in men f higher SES and, presumably, with better awareness f r access t screening mdalities (4). T explre the pssibility f detectin bias, we cnducted additinal analyses including nly cases identified befre The inverse assciatin fr the suthern pattern persisted (3'^'' vs. 1^' tertile RR =.4; 95 percent CI:.2,.9), but estimates were based n nly 46 cases. DISCUSSIN In a natinally representative sample f men, we identified three dietary patterns: a vegetable-fruit pattern, a red meat-starch pattern, and a suthern pattern. The red meat-starch pattern was nt assciated with disease, but intermediate intake f the vegetable-fruit pattern was nn-significantly assciated with increased prstate cancer risk. Intake f the suthern pattern shwed a trend that was suggestive f an inverse assciatin and that culd nt be attributed t any specific fds within the pattern. Identificatin f the vegetable-fruit and western patterns in this sample is cnsistent with findings f previus US studies (8-1) and with anthrplgical and histrical accunts f traditinal American eating habits (29-31). Mrever, their assciatins with scidemgraphic and health-related characteristics were as expected based n bservatins f the histrical emergence f thse patterns (29), cnfirming the validity f their measurement using PCA (28,

28 41). Althugh ther studies have identified patterns specific t Mexican Americans (26,42), Tseng M Page 13 urs is the first, t ur knwledge, t identify a suthern US pattern in a sample nt limited t a specific ethnic r reginal grup. ur results further suggest that the pattern is nt a spurius finding: The pattern emerged acrss split samples in ur analyses, was easily recgnizable as a distinct pattern, and its assciatins with scidemgraphic characteristics were cnsistent with scial/cultural descriptins f the pattern (31), supprting the pattern's cnstruct validity. We surmise that we were able t identify the suthern pattern because the fd frequency questinnaire included such specifically suthern items as cmbread, grits, and kra, and because we did nt grup the 15 fd items frm the questinnaire fr the analysis. We chse nt t cllapse fd items fr several reasns. First, creating grups f ptentially dissimilar fds may diminish the ability t identify mre specific patterns. Indeed, when we cllapsed fds int 35 predefined fd grups (9), nly tw rather than three patterns clearly emerged - the vegetable- fruit and red meat-starch patterns (results nt shwn). Ability t identify dietary patterns, therefre, is strngly dependent bth n the fd items included in the instrument and n hw fds are aggregated int grups fr analysis. That the suthern pattern was reprducible acrss split-samples and was assciated with ther variables as theretically expected suggests that its identificatin in ur data was nt a spurius finding; rather, cllapsing fds int grups might have prevented finding a true pattern. Gruping fds prir t PCA may als attenuate r increase the variance f measures f assciatin between dietary patterns and disease (43). Cllapsing fds int grups wuld likely have prduced patterns that explained mre f the ttal variatin in fd intake than the 11% explained by the three patterns in ur study. Hwever, the primary bjective f perfrming PCA in diet-disease studies is nt t explain ttal variatin, but t examine assciatins f

29 Tseng M Page 14 cnceptually meaningful patterns with disease risk. Indeed, McCann et al. (43) have demnstrated that increasing the amunt f variance explained by cllapsing fds int grups des nt imprve estimates f disease risk. Factrs that might have bscured r biased assciatins in ur study merit discussin. Using PCA t quantify dietary patterns may invlve sme measurement errr, fr example. Hwever, reasnably high (>.6) cefficient alphas fr the three patterns indicate gd internal reprducibility fr each pattern, and using an alternative methd t calculate pattern scres (27) prduced similar assciatins with risk. Althugh prstate-specific antigen testing was relatively uncmmn befre 1991 (44), sme bias in detecting prstate cancer cases remains pssible as well, given the assciatins f dietary patterns with urban/rural residence and SES. RR estimates were largely unchanged when we cntrlled fr scidemgraphic factrs that may be linked t screening such as educatin (4), and when we limited cases t thse identified befre gvernment apprval f prstate-specific antigen testing in Hwever, infrmatin n access t screening and screening behavir was nt available t evaluate this pssibility mre directly. We fund a slightly elevated prstate cancer risk with intermediate intake f the vegetablefruit pattern but n clear trend. When we examined fruits and vegetables separately, we bserved n assciatin fr vegetables, but a slightly elevated risk fr an intermediate level f fruit intake. ur finding is similar t that f ther studies that bserved a psitive assciatin with fruit intake (32), but the explanatins fr this finding are nt knwn. We bserved n elevatin in risk fr selected nutrients assciated with fhiit r vegetable intake. ur results d nt supprt the hypthesis that a western pattern increases risk f prstate cancer. In ur sample, red meat-starch pattern intake, intake f red meat as a fd grup, and

30 Tseng M Page 15 intake f energy, ttal fat, and saturated fat were nt assciated with disease, althugh previus chrt studies have fairly cnsistently fund psitive assciatins fr red meat and fr saturated and animal fat (34). Besides detectin bias, this may als reflect simply the lack f strng influence f verall adult diet n risk, insufficient variability in intake, r inaccurate measurement f the underlying pattern. A clearer understanding f dietary pattern measurement is warranted befre mre definite cnclusins can be drawn. Ntably, a western pattern was als nt assciated with clrectal r breast cancer in recent analyses in the Swedish Mammgraphy chrt (45,46). We bserved a nn-significant but suggestive inverse asscatin fr the suthern pattern. This finding is especially intriguing because black men were mre likely t cnsume this pattern yet remained at higher risk fr prstate cancer. In race-specific analyses, the apparent inverse assciatin persisted in bth black and nn-black men. The assciatin was nt attributable t any individual fds within the pattern r t any nutrients f prir interest. ur finding suggests that prstate cancer incidence might increase with mvement away frm a traditinal suthern cuisine. Alternatively, the finding raises additinal questins regarding interpretatin f dietary pattern measures. Fr example, a suthern dietary pattern may reflect a histry f living in the Suth and serve as an integrative marker f sunlight expsure (47) rather than a simple measure f verall dietary habits. Sunlight has been hypthesized t prtect against prstate cancer thrugh 1,25 hydrxyvitamin D prductin (48), and recent wrk als ffers evidence that bth childhd and cumulative, lifetime sun expsure are assciated with reduced risk (49). Althugh we cntrlled fr ther lifestyle factrs in ur analysis (including current residence in the Suth) and cnsidered several thers as ptential cnfunders in preliminary analyses, it remains pssible that ur measure fr the suthern pattern represents earlier-life r lng-term sunlight