The Effects of Non-Response in a Prospective Study of Cancer: 15-Year Follow-Up

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1 Internatinal Jurnal f Epidemilgy Internatinal Epidemilglcal Assciatin 1991 Vl. 20, N. 2 Printed in Great Britain The Effects f Nn-Respnse in a Prspective Study f Cancer: 15-Year Fllw-Up LANCE K HEILBRUN.* ABRAHAM NMURAt AND GRANT N STEMMERMANNt Heilbnjn LK (Divisin f Hematlgy-nclgy, Wayne State University Schl f Medicine, Detrit Ml, USA), Nmura A and Stemmermann GN. The effects f nn-respnse in a prspective study f cancer: 15-year fllw-up. Internatina/Jurnal f Epidemilgy 1991; 20: ut f Japanese men identified n the island f ahu, Hawaii in 1965 by the Hnlulu Heart Prgram, 8006 respnded t a mailed questinnaire and were examined. Sme 1871 respnded nly t the mailed questinnaire, and 1259 did nt respnd at all. After 15 years f fllw-up, the examined men had significantly lwer risk f death frm all causes and death frm cancer. Minr differences were als nted between the tw grups in the risk f cancer f the lung, stmach, cln, and rectum. Hwever, the examined men had a significantly higher risk f prstate cancer. In general, the strength f these nn-respnse effects was mainly due t risk differences in the first five years f the 15- year fllw-up perid. The relative risk (RR) f each f the seven endpint events tended twards 1.0 as each f the three successive five-year fllw-up intervals were cnsidered. An exceptin t this was the prstate cancer incidence RR which favured the unexamined men thrughut the entire 15 years, but significantly s nly in the last five-year fllw-up interval. When the 8006 examined and 1871 unexamined men wh respnded t the mailed questinnaire were evaluated with respect t the assciatin f cigarette smking with lung cancer incidence, the RR fr smkers was 9.77 fr the examined men, and 6.73 fr the unexamined men. Since these RRs are nt significantly different, there shuld be little bias in RR estimates f cigarette smking fr lung cancer if the bservatin was limited t nly the examined men. With regard t the assciatin f bdy mass index (BMI) with cln cancer in lder men, the RRs fr men in the highest BMI quintile were quite cmparable, at 1.37 fr the examined grup and 1.60 fr the unexamined men. We cnclude that althugh sme nn-respnse effects n cancer incidence exist in this chrt, they d nt appear t be serius enugh t have changed cnclusins drawn abut risk relatinships. Nn-respnse by a prtin f the target ppulatin in an epidemilgical study can lead t bias in the study results. ljt Many such studies encunter initial nnrespnse rates f 30% r mre. Assessment f nnrespnse bias effects in a prspective chrt study is ften precluded by lack f data n the nn-respnders with respect t baseline variables and/r relevant disease endpints. Several kinds f bias can result frm substantial nnrespnse in ppulatin-based prspective studies: (1) bias in estimates f the prevalence f expsure factrs due t the differential participatin f subjects; (2) bias in estimates f disease utcme als due t the differential participatin f subjects; r (3) bias in relative * Divisin f Hematlgy-nclgy, Wayne State University Schl f Medicine, Detrit, MI, USA. tjapan-hawaii Cancer Study, Kuakini Medical Center, 347 Nrth Kuakini Street, Hnlulu, Hawaii Reprint requests t Dr Nmura. risk (RR) estimates determined by cmparing the incidence rates f disease in the expsed and unexpsed grups. Sme f these biases have been discussed by thers. 3 The first ptential bias has been demnstrated by differing prevalence rates f smking amng participants and nn-participants in prspective studies. In Dll and Hill's survey f British dctrs, 31% f the male, and 40% f the female physicians did nt adequately respnd t a mailed questinnaire. 6 When the investigatrs interviewed a sample f the respndents and nn-respndents, they fund that 79% and 94%, respectively, had smked cigarettes. In the study by Criqui el al. which had a nn-respnse rate f nly 17.9% f residents in a planned suburban develpment, they als nted that mre f the nn-respndents were current smkers. 5 Several studies have prbed int the secnd ptential bias. In the Framingham Heart Study, 31.2% f the eligible cmmunity residents did nt g t the study 328

2 EFFECTS F NN-RESPNSE IN A PRSPECTIVE STUDY F CANCER 329 clinic fr examinatin. Death rates were higher fr the unexamined grup than fr the examined grup fr a five-year perid after the examinatin cycle was cmpleted. 7 In cntrast, the emplyees at the Hawthrne Wrks f the Western Electric Cmpany in Chicag had similar mrtality rates after 4.5 years f fllw-up, regardless f study participatin status. 8 Criqui et al explred the third ptential bias in their ppulatin-based cardivascular disease study. 9 They fund nly minr t mderate impact nriskrati estimates, partly because they had a respnse rate f >80%. Assessment f the nn-respnse prblem usually requires bth expsure and endpint data n the nn-respndents. In a prspective study f cancer in Hawaii Japanese men, we had the pprtunity t cmpare expsure, survival, and cancer-free survival patterns between respnders and nn-respnders. We culd als assess the third type f bias with regard t risk rati estimates, based n expsure data. The 10- year effects f nn-respnse n cancer utcmes, and the 14-year effects n heart disease utcmes have been reprted previusly. 10 " In this reprt, we present CC Z f a QJ 0.84 > b TTAL 15-year fllw-up data n respnders and nn-respnders in ne f the largest existing prspective chrt studies f cancer incidence, the Japan-Hawaii Cancer Study (JHCS). MATERIALS AND METHDS Using Wrld War II Selective Service registratin files, the Hnlulu Heart Prgram (HHP) identified and ascertained that Japanese men, brn in the perid, were residing n the island f ahu, Hawaii in l2 f the men, 8006 (71.9%) respnded t a mailed questinnaire (MQ) and were examined frm 1965 t 1968; 1871 men (16.8%) respnded t the MQ but did nt cme in fr examinatin; and the remaining 1259 men (11.3%) did nt respnd at all. Since 40% f the unexamined men did nt return the MQ, we are nt attempting a frmal estimatin f bias. 1 Instead, we have utilized the MQ expsure data n the 60% f nn-respnders fr whm it was available t estimate relative risk fr the examined versus unexamined men. Als, since we had surveillance data EXPIRED - EXAMINED MEN UNEXAMINED MEN FK I IS FIGURE I verall survival by Japan-Hawaii Cancer Study examinalin participatin status. Mrtality cases identified n ahu, Hawaii, Vertical bars indicate ± ne standard errr in the estimated cumulative prprtin surviving at a given pint in time f fllw-up.

3 330 INTERNATINAL JURNAL F EPIDEMILGY LL V) IGRI > > I ^ g2 Q. -1 CUMU EXAMINED MEN 7631 EXHEEB UNEXAM1NED MEN !r-i- -I Ip I II FIGURE 2 Survival by Japan-Hawaii Cancer Study examinatin participatin status where cancer is the nly cause f death cnsidered. All cancer types are cmbined. Cancer mrtality cases identified n ahu, Hawaii n all men, we have cmpared survival and disease-free survival between these tw grups as an indicatin f the statistical effect f nn-respnse n survival and cancer utcmes. Fr purpses f this study, mrtality surveillance f the men cvered a 15-year perid frm 1 January 1969 t 31 December It cnsisted f rutine review f death certificates filed at the Hawaii State Health Department (HSHD), a daily review f the bituary sectin f lcal newspapers, and daily calls t ahu mrtuaries. 12 When necessary the attending physicians r, ccasinally, family members were cntacted t btain a descriptin f the terminal illness. The resulting infrmatin as well as phtcpies f pertinent hspital recrds were reviewed by tw r mre HHP study physicians in regularly held mrtality cnferences. We cmpared the recrded causes f death between the HHP study physicians and the death certificates frm HSHD, and fund very gd agreement fr deaths related t cancer. ut f 2185 deaths during , 654 (29.9%) included cancer as an HHP cause f death, while 662 (30.3%) had a cancer recrded by HSHD. A ttal f 586 (26.8%) men had a cancer recrded in bth surces. In the present study, we used the mrtality infrmatin systematically recrded by HHP study physicians. Incidence cases f cln, rectum, lung, prstate, and stmach cancer diagnsed during were identified by ur hspital surveillance team with the assistance f the Hawaii Tumr Registry. 13 The surveillance team reviewed the discharge rsters f all the general hspitals n the island. The five majr civilian hspitals, accunting fr mre than 90% f the hspital admissins f the men, subscribe t the Prfessinal Activity Service. M This service prduces a semi-annual cmputer printut f all discharges with listings f race, sex, age and discharge diagnses. This printut facilitated ur surveillance peratin. Cpies f the admissin nte, discharge summary, perative ntes, pathlgy reprts, etc, were btained fr each incidence cancer case and reviewed by tw JHCS study physicians. nly cases with tissue cnfirmatin f their cancer were accepted. In the MQ, respndents were asked t check ne f

4 EFFECTS F NN-RESPNSE IN A PRSPECTIVE STUDY F CANCER CE U. Q >. < 2 3 DC 0. 3 Z TTAL EXAMINED MEN 7915 UNEXAMINED MEN I I INCIDENCE CASES 146 p I 1- I I II F1GUKE3 Lung-cancer-free survival by Japan-Hawaii Cancer Study examinatin participatin status. Lung cancer incidence cases identified n ahu, Hawaii the fllwing categries fr educatin: (1) primary schl; (2) intermediate r junir high (3) senir high; (4) technical schl; r (5) university. Fr cigarette smking the ptins were as fllws: (1) never smked cigarettes r 'If yu have ever smked cigarettes regularly, at what age did yu start?'; (2) still smking cigarettes r 'If yu have stpped smking cigarettes, at what age did yu stp?'. Fr respndents wh had ever smked cigarettes regularly, the chices fr the usual amunt smked daily were: 5,10,20, r 30 r mre daily. The never smkers had a zer fr this variable. Present height (in inches) and weight (in lbs) were als requested in the MQ. Frm these data, we calculated bdy mass index (BMI): weight (in kg) divided by the square f height (in metres) 2. Current BMI has been shwn t be psitively assciated with cln cancer risk amng examined men aged 55 r lder in the JHCS chrt." The MQ was printed in Japanese as well as English. Based n HHP results frm mailing a 20-year reprt t the surviving chrt men in 1985, it was determined that the mean rate f emigratin frm ahu amng the examined men was very lw, at 0.7 men per 1000 examinees per year ver a 20-year perid. 16 If ahu emigrants were still listed as Hawaii residents, and had died elsewhere, they were identified by ur surveillance system and the apprpriate infrmatin was btained. If they were diagnsed elsewhere with cancer and were still alive, then they were nt included in ur cancer incidence cunts. Survivrship functins and their standard errrs (SE) at given pints f fllw-up time were estimated by the actuarial methd. 17 Length f survival f examined versus unexamined men (identified by a dichtmus cvariate) was cmpared, taking age int accunt as a secnd cvariate, by Cx prprtinal hazards mdels fr censred survival data. 18 In the analysis f lung-cancer-free survival, the usual number f cigarettes smked per day was included as a third cvariate. Age was denned as f 1 January 1969, which was the cmmn starting pint fr survival fllw-up. Age-adjusted percentages f current smking and f junir high schl educatin were determined by analysis f cvariance methds." The relative risk f lung cancer was determined frm bivariate Cx mdels cntaining age and smking status as the cvariates. Age-adjusted RR was esti-

5 332 INTERNATINAL JURNAL F EPIDEMILGY U. LU DC LL Q T Z < il) DC a F TTAL EXAMINED MEN 7901 UNEXAMINED MEN 2862 INCIDENCE CASES p I II FIGURE 4 Stmach-cancer-free survival by Japan-Hawaii Cancer Study examinatin participatin status. Stmach cancer incidence cases identified n ahu, Hawaii mated by expnentiating the Cx mdel cefficient (P) fr the expsure variable in a bivariate mdel. The maximum likelihd estimates f the p's were regarded as asympttically distributed. Thus, ageadjusted 95% cnfidence limits (CL) fr an RR culd be cmputed by expnentiating [(3 ± 1.96*SE(P)]. These estimates f cvariate-adjusted RR and CL are described mre fully elsewhere. 20 All Cx mdels were fitted using iterative maximum likelihd methds. 21 RESULTS f the 8006 examined and 3130 unexamined men, 7920 (98.9%) and 2871 (91.8%), respectively, were still alive as f 1 January The difference in survival was due t the fact that death was ne f the reasns why an identified persn was nt examined. Fr this reasn, we nly cmpared mrtality (and cancer incidence) in men wh were examined r unexamined and wh were alive as f 1 January 1969, at which time the examinatins were cmpleted. The examined men were significantly yunger (p<0.001 by t-test) than the unexamined men, with mean ages as f 1 January 1969, f 56.1 and 57.1 years, respectively. This was the reasn fr including age as a cvariate in all analyses. Figure 1 presents the verall survival frm 1 January 1969 by examinatin participatin status. The examined men have significantly lnger verall survival (p<0.0001), even after adjustment fr age, against mrtality frm all causes. A similar pattern is present fr survival frm all types f cancer cmbined, as shwn in Figure 2. Subjects with cancer diagnsed prir t 1969 (144 examined men; 126 unexamined) were excluded frm this cmparisn. Next we cmpared the cancer-free-survival fr five sites: lung, stmach, cln, rectum, and prstate. Fr each separate survival cmparisn, incidence cases f that cancer site diagnsed prir t 1969 were excluded frm the analysis. Men dying frm ther causes (i.e. cmpeting risks) were cnsidered as censred bservatins fr any further risk f diagnsis f each respective cancer type. Censring was thus taken as f their death date. Figure 3 shws a cnsistent but nn-significant

6 EFFECTS F NN-RESPNSE IN A PRSPECTIVE STUDY F CANCER 333 u. HI ui Ui 1 Q. HI 13 EXAMINED MEN UNEXAMINED MEN TTAL INCIDENCE CASES p= I II FIGURE 5 Cln<ancer-free survival by Japan-Hawaii Cancer Study examinatin participatin status. Cln cancer incidence cases identified n ahu, Hawaii advantage in lung-cancer-free survival fr the examined men after adjustment fr age and smking (cigarettes/day, past r current) in the Cx mdel. Because nly 60% f unexamined men returned the MQ, and because f ccasinal missing data n smking, there were fewer subjects in the Cx regressin mdel than in the lung-cancer-free survival curve calculatins. In the trivariate (exam status, age, smking) Cx mdel analysis there were 7637 examined men including 144 incidence cases f lung cancer. Amng the unexamined men these numbers were 1604 and 29 respectively. Time until diagnsis f stmach, cln, r rectal cancer diagnsis did nt differ significantly by examinatin status after taking age int accunt (Figures 4-6). Prstate-cancer-free survival amng the unexamined men shwed an increasing advantage in the later fllw-up years (Figure 7). This difference is statistically significant verall (p = 0.024) after Cx mdel age adjustment. With a relatively lng fllw-up perid, it was pssible t examine the stability ver time f these survival patterns. Small numbers f endpint events (say, n<10) ccasinally reduced the chance f finding a significant RR in a specific five-year fllw-up interval. Table 1 illustrates hw the relative risk estimates vary ver the three successive five-year fllw-up intervals. As shwn there, the RR f death is significantly greater amng the unexamined men in each time interval, althugh the strength f this relatinship appears t be decreasing ver time. The significant advantage f examined men regarding the risk f cancer death is limited mainly t the first five years f fllw-up. An initially higher risk f lung cancer amng the unexamined men became minimal after the first five years-f fllw-up. Unexamined men had significantly higher stmach cancer risk fr the first 10 years, but that drpped ff sharply in the last five years f fllw-up. N ntable patterns ver time were fund fr the incidence f cln r rectal cancer. Nte that the magnitude f estimated RR varies cnsiderably, e.g.

7 334 INTERNATINAL JURNAL F EPIDEMILGY I.- HI LU tr u. <a > _IZ IZ t tr a. m < EXAMINED MEN UNEXAMINED MEN TTAL INCIDENCE CASES p= I I II FIGURE 6 Rectal-cancer-free survival by Japan-Hawaii Cancer Study examinatin participatin status. Rectal cancer incidence cases identified n ahu, Hawaii rectal cancer RR = 0.48 during the secndfiveyears f fllw-up. Despite this apparent risk reductin, it is nt statistically significant, presumably wing t the small number f cases. The significantly lwer risk f prstate cancer amng the unexamined men appears t be mainly due t events f the last five-year fllw-up interval. Since we were cncerned abut the pssible bias in RR determinatins due t nn-participatin, we cmpared the 8006 examined and 1871 unexamined men wh respnded t the MQ. With adjustments fr age, we nted that 52.5% f the examined men and 60.3% f the unexamined men had nly junir high schl educatin. We als fund that 56.6% f the examinees and 61.1% f the unexamined men were current cigarette smkers. Then, we calculated the age-adjusted RR f lung cancer fr current smkers versus never-smkers amng examined and unexamined men, as shwn in Table 2. Amng examinees, RR = 9.77, while it was 6.73 amng unexamined men, a 1.5-fld difference in the RR magnitude. Hwever, the extensive verlap f their age-adjusted CL indicates that these RRs are nt at all significantly different. The wide CL fr the lung cancer RR are due t such small numbers f cases amng nn-smkers. In Table 3, the assciatin f educatin with stmach cancer was determined fr the examined and unexamined men. The RRs were each clse t unity at 1.25 and 0.82, respectively. The almst cmplete verlap f respective age-adjusted 95% CL fr the RRs leaves the estimated RRs statistically indistinguishable. The assciatin f BMI and cln cancer risk amng men age 55 and ver as f 1 January 1969 is shwn in Table 4. The RRs fr men in the highest BMI tertile (cmpared t the lwest BMI tertile) were quite similar: 1.37 fr examined men, and 1.60 fr unexamined men, suggesting n ntable nn-respnse bias in this risk relatinship.

8 EFFECTS F NN-RESPNSE IN A PRSPECTIVE STUDY F CANCER II LU C u. Q z <MI DC a* HI < < Z r- Q LAT1\ s TTAL EXAMINED MEN UNEXAMINED MEN 2870 INCIDENCE CASES A I 1- -t- I II p FIGURE 7 Prstate-cancer-free survival by Japan-Hawaii Cancer Study examtnatin participatin status. Prstate cancer incidence cases identified n ahu, Hawaii DISCUSSIN We were able t assess the effects f nn-participatin in the Japan-Hawaii Cancer Study fr several reasns. We had demgraphic infrmatin n participants and nn-participants at the utset f the study, which is nt always pssible. We maintained a cmprehensive surveillance f the entire target ppulatin f men t identify death r cancer events. The study ppulatin was residentially stable and rarely went elsewhere fr medical care. Finally, 1871 (59.8%) f 3130 nn- TABLE 1 Adjusted relative risk (RR) f death (r cancer incidence) f Japan-Hawaii Cancer Study men by examinatin status and by time interval frm 1 January 1969 t death (r diagnsis f cancer). Cases identified n ahu, Hawaii Endpint Mrtality verall Cancer Cancer incidence Lung Stmach Cln Rectum Prstate RRt 1.77"" 2.21"" 2.09" 1.77" <5 years n.,n.t 314,206 64,54 22,12 29,20 29,14 28,9 27,6 Time interval since 1 January years RR n.n. 1.32"" 1.29* " 2.02"* , ,78 45,15 41,27 38,28 28,5 34,12 RR 1.21"* * " * 10 years n.,n» 641, ,76 79,28 61,17 85,18 21,8 88,19 trisk fr unexamined men, relative t examined men. RRs adjusted fr the same cvariates as in Figures 1-7, respectively. ^Number f endpint cases amng: examined men, unexamined men. p<0.10; "p<0.05; *"p<0.01; ""p<0.001.

9 336 INTERNATINAL JURNAL F EPIDEMILGY TABLE 2 Agc-adjusled relative nsk (RR) f lung cancer in examined and unexamined Japan-Hawaii Cancer Study men by smking status based n the mailed questinnaire. Cases identified n ahu, Hawaii Ttal n. N. f 95% cnfidence Smking status f men cases RR limits Examined men Cigarette smker* Nn-smker Unexamined men Cigarette smker Nn-smker Ttal Cigarette smker Nn-smker 'Excludes ex-cigarette smkers (4.95, 19.3) (1.58,28.7) (4.95, 17.0) participants mailed back a cmpleted MQ, even thugh they did nt appear fr examinatin and interview. Bth ttal mrtality and cancer mrtality were lwer amng the examined men than the unexamined men verall, but these nn-respnse effects waned with time during the 15-year fllw-up perid. With regard t ttal mrtality, this is cnsistent with the 10-year fllw-up data frm the British dctrs' study. 6 In that study, the initial survival advantage f the respndents became slight after three years f fllw-up as their death rate averaged 93% that f the nn-respndents during years fur t ten. ther chrt studies that have lked at verall mrtality differentials by nnrespnse status have differing results. The Framingham study shwed lwer death rates amng examinees afterfiveyears fllw-up, 22 whereas the Western Electric study shwed n difference in death rates after 4.5 years fllw-up. 8 It shuld be nted hwever that neither f these studies presented fllw-up data as lng as 15 years, during which the pprtunity t bserve ptential time dependencies in TABLE 3 Age-adjusted relative nsk f stmach cancer in examined and unexamined Japan-Hawaii Cancer Study men by educatinal status based n the mailed questinnaire. Cases identified n ahu, Hawaii Educatinal status Ttal n. f men Examined men Junir high schl 4071 Beynd junir high schl 3765 Unexamined men Junir high schl 1034 Beynd junir high schl 628 Ttal Junir high schl 5105 Beynd junir high schl 4393 N. f cases RR 95% cnfidence limits (0.87, 1.80) (0.40,1.67) (0.84, 1.61) 62 such mrtality risk differentials is imprved. Based n these findings it wuld appear that the chice f a study ppulatin may determine whether r nt there will be a difference in mrtality by respnse status. Cmpany emplyees (e.g. Western Electric) are usually healthy enugh t remain emplyed, s that any study nnparticipants amng them are less likely t have reduced survival. Study respndents wh have bth better vital status and mre disease histry than nnrespndents have been termed a 'wrried well' ppulatin. 33 ' 23 If nn-participants did have shrter survival due t pr health hwever, then the mrtality differential cmpared t study participants shuld diminish with increasing fllw-up time. Perhaps this is the phenmenn bserved in the British dctrs' study, 6 and in ur prspective chrt study as well. urfindingswere varied fr nn-respnse effects n site-specific cancer-free survival. Prstate cancer risk remained unifrmly lwer amng the unexamined men, significantly s during the last five years f fllw-up. This suggests that sme cmmn feature(s) present in the examinees has increased their prstate cancer risk cmpared t the unexamined men. The examined subjects had a lwer ttal and cancer mrtality than unexamined subjects. Similarly, Mrmns in the state f Utah have a lwer ttal and cancer mrtality than nn-mrmns, and their prstate cancer risk is als crrespndingly greater Hwever, the Seventh-day Adventists, anther religin-based grup, have lw prstate cancer rates. 26 The twfld higher lung cancer risk amng unexamined men during the first five years f fllw-up was reduced t nly a 20-30% excess risk thereafter. The nn-participants' 80% excess risk f stmach cancer TABLE 4 Age-adjusted relative risk (RR) f cln cancer in examined and unexamined Japan-Hawaii Cancer Study men by bdy mass index (BMI) textile based n the mailed questinnaire. Cases identified n ahu, Hawaii BMI tertile* Examined men Unexamined men Ttal Ttal n. N. f f men cases RR % cnfidence limits (0.75,2.13) (0.82, 2.29) (0.62, 4.50) (0.59, 4.31) (0.84,2.12) (0.89, 2.22) *Tertile cutpints determined frm the BMI distributin f all examined and unexamined men cmbined. Units are kg/m 1, with bdy weight in kg and height in m.

10 EFFECTS F NN-RESPNSE IN A PRSPECTIVE STUDY F CANCER 337 ver the first ten years changed t a 20% risk deficit in years Japan-brn men shuld have higher stmach cancer risk 27 than thse f ur chrt brn in Hawaii, but the prprtins f Japan-brn men were similar amng the examined and unexamined men. With the exceptin f cln cancer risk in years five t ten, variatins ver time in the cln r rectal cancer risk differentials were neither large in magnitude nr statistically significant. Thus any nn-respnse effect n theriskf cln r rectal cancer seems rather small. This is imprtant since several cln r rectal cancer risk relatinships have been reprted in this chrt ver the past decade. When explring pssible nn-respnse effects n RR estimates we first cnsidered cigarette smking and lung cancer. Smkers have cnsistently shwn a 10-fld greater lung cancerrisk which is very clse t the RR = 9.8 in ur examined men. Amng the unexamined men (wh did return the MQ), RR = 6.7, which is statistically indistinguishable frm the 9.8 RR, and still reasnably similar t the ther published estimates. Earlier reprts 30 "" had linked lw sciecnmic status with increased stmach cancer risk. Using educatinal level as an indicatr f sciecnmic status we saw nly a 25% excess risk amng the examined men with less educatin. Althugh this changed t an 18% deficit f risk amng the unexamined men f less educatin these risk differentials are small and nt at all statistically significant. Finally the previusly reprted psitive assciatin 15 f BMI and cln cancer risk amng men age &55 years was fund t differ nly slightly by respnse status. Examined men at higher BMI levels had RR = 1.3 t 1.4, whereas fr unexamined men, RR = 1.6 t 1.7. This RR differential was statistically unimprtant and hence in this risk relatinship n significant nn-respnse bias is evident. In cnclusin ur study fund that examined men had a significantly lwerriskf death due t cancer and all causes than unexamined men. The examined men may have better health practices and might be anther example f a 'wrried well' ppulatin, as termed by Criqui et al. 5 ur data suggest that nn-respnse effects in the JHCS have generally had minimal impact n lung-, stmach-, cln-, and rectal-cancer-free survival, and n three different expsure/cancer incidence risk relatinships. Hwever, there was a suggestin f a pssible nn-respnse effect n prstate-cancer-free survival. verall, it appears that based n 15 years f fllw-up data, nn-respnse effects in this prspective chrt study are nt serius enugh t have changed cnclusins drawn abut cancer risk relatinships. ACKNWLEDGEMENTS Supprted by Grant R01 CA frm the Natinal Cancer Institute, Natinal Institutes f Health, Bethesda, MD, USA. 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