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Site specificity of colorectal neoplasms in families without an inherited syndrome
Site specificity of colorectal neoplasms in families without an inherited syndrome Peter Zauber, MD, Guy Lardieri, BA, Paul J. Rathouz, PhD, Neelam Khan, MD, D. Timothy Bishop, PhD Livingston, New Jersey, Chicago, Illinois, High Point, North Carolina, and Leeds, United Kingdom
Background: Relatives of patients with bowel neoplasia have an increased risk of bowel neoplasia. If there were concordance in location of neoplasia between relatives, then location-specific screening could be used. Such concordance might also assist in the understanding of the etiology of neoplasia within individual families. Methods: We have investigated the concordance in anatomic location of colonic neoplasia between first-degree relatives using a new statistical technique for paired data called alternating logistic regression. Results: A total of 146 families were ascertained, none of which had clinical evidence of a hereditary predisposition to edon neoplasia. Among those with neoplasia, there was an increased risk for right-sided disease with older age (40% for less than age 60 vs. 58% for at least 70 years of age, p = 0.008). As assessed by the odds ratio, we found no significant concordance within families for location of neoplasia (odds ratio = 1.2: CI [0.7, 2.2]), although there was a suggestion that location in family members of the same generation was more strongly associated (odds ratio 1.87: CI [0.82, 4.25]). Conclusions: The lack of concordance within families for location argues against considering family-specific bowel screening protocols and indicates that the most important causes of bowel neoplasia are not sufficiently focused on one anatomic site to facilitate etiologic research. (Gastrointest Endosc 1999;50:603-7.)
Relatives of subjects with colorectal neoplasms, w h e t h e r cancer or adenomatous polyps, have been shown to have an increased risk of neoplasm themselves. Close relatives of patients with colorectal cancer have a twofold increased risk of cancer12 and a similar increased risk of adenomatous polyps. 3 Relatives of patients with adenomatous polyps have an increased risk of colorectal cancer 4 and adenomas. 5 Family aggregation of bowel cancer m a y be seen in two dominantly inherited syndromes. Mutations in the APC gene cause familial adenomatous polyposis (FAP) and several clinically related syndromes6-S; such families are usually identifiable clinically because of the extensive polyposis in the bowel. Individuals with this syndrome account for a small fraction of bowel cancer, p e r h a p s 0.5%. Families with the hereditary non-polyposis colorecReceived October 7, 1998. For revision February 25, 1999. Accepted June 15, 1999. From the Department of Medicine, Saint Barnabas Medical Center, Livingston, New Jersey; Department of Health Studies, University of Chicago, Chicago, Illinois; High Point Regional Hospital, High Point, North Carolina; ICRF Genetic Epidemiology Laboratory, St. James's Hospital, Leeds, United Kingdom. Supported by The Harvey Nussbaum Research Foundation, the Walter and Louise Sutcliffe Foundation and the Imperial Cancer Research Fund. Reprint requests: Peter Zauber, MD, 22 Old Short Hills Rd., Livingston, N J 07039. Copyright 9 1999 by the American Society for Gastrointestinal Endoscopy 0016-5107/99/$8.00 + 0 37/1/100727 VOLUME 50, NO. 5, 1999
tal cancer (HNPCC) syndrome also have an increased risk of bowel cancer. This syndrome is associated with germline m u t a t i o n s in genes responsible for repair of errors in DNA replication. H N P C C probably accounts for 5% of colorectal cancer cases b u t the exact extent is unclear as most studies have relied on family history as a surrogate for inherited predisposition. 2 Aside from these syndromes, the increased risk of bowel neoplasm in relatives is unexplained and is attributed to environmental exposures, genetic factors, and interactions between the two. The remaining cases of colorectal cancer are usually referred to as "sporadic"; we will use this term to indicate cases from families without any evidence of a hereditary syndrome. One of the most notable aspects of bowel cancer epidemiology is the variation in the anatomic distribution of bowel cancer across different geographic regions, 9 which is thought to result from dietary differences. Increased dietary fat has been related to increased risk of proximal cancer, whereas high protein intake and low fiber intake have been associated with an increased risk of distal tumors. 1~ Further, in women, bowel cancer risk decreases with increasing parityJ 1 Finally, in H N P C C families, the neoplasm is more commonly in the right side of the bowel than in the general population. TM It is therefore appropriate to screen first-degree relatives of p a t i e n t s sporadically affected with polyps and]or GASTROINTESTINAL ENDOSCOPY
603
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c a n c e r a n d g u i d e l i n e s h a v e b e e n proposed. 13 We r e a s o n e d t h a t c o n s i s t e n t p a t t e r n s w i t h r e s p e c t to a n a t o m i c location of n e o p l a s i a w i t h i n f a m i l i e s m a y be h e l p f u l in d e t e r m i n i n g t h e etiology in d i f f e r e n t families, and, i m p o r t a n t l y for clinical practice, m a y i n d i c a t e w h e t h e r family-specific s c r e e n i n g protocols have merit. S e v e r a l p r e v i o u s s t u d i e s h a v e a l r e a d y focused on bowel m a l i g n a n c i e s a n d h a v e not f o u n d s i g n i f i c a n t c o r r e l a t i o n s w i t h r e s p e c t to l o c a t i o n w i t h i n f a m i lies.14,15 B e c a u s e t h e m a j o r i t y of a d e n o m a s do n o t develop into m a l i g n a n c i e s , t h i s n e o p l a s m m i g h t be a m o r e s e n s i t i v e m e a s u r e of e n v i r o n m e n t a l e x p o sures. We t h e r e f o r e i n v e s t i g a t e d t h e locations of all bowel n e o p l a s m s w i t h i n a s c e r t a i n e d families, all of w h i c h h a d no i n h e r i t e d p r e d i s p o s i t i o n to bowel neoplasia.
PATIENTS AND METHODS Patients seen at a large suburban hospital over a 2-year period for colonoscopy constituted the study population. Participating physicians were three colorectal surgeons and 12 non-surgeon colonoscopists. The most common indications for colonoscopy included personal or family history of colorectal cancer, positive fecal occult blood test, abdominal pain, and prior colonoscopic polypectomy. The study was reviewed and approved by the hospital review board. The patients were asked to participate in the study at the time of initial interview by the clinic nurse. Ninetytwo percent agreed and constituted the study population of 3055 patients. Each patient was then approached by the project interviewer (G.L.) who explained the details of the study and elicited written permission to obtain a detailed family history of all first and second-degree relatives, including information as to the cause of death, major illnesses, and whether the family members had undergone any intestinal evaluations. If the patient was found to have a colorectal neoplasm and had indicated that a first-degree relative was also affected, the relative, or next of kin of deceased individuals, was contacted by letter and then by telephone or fax follow-up for permission to obtain copies of pathology reports. Information regarding age at diagnosis, gender, relationship to the subject, location of the lesion and type of lesion was recorded. All pathologic diagnoses were verified by obtaining a copy of the original pathology report. If the report was unclear, then original slides or paraffin blocks were obtained for independent review. Patients with only hyperplastic polyps were excluded. Patients were included if their adenomas were tubular, tubulovillous, or villous. Good clinical practice dictates that lesions detected by colonoscopy or b a r i u m e n e m a be removed before microscopic subclassification. Therefore, it is the presence of a visualized lesion, not the subtype, that dictates clinical practice. Individuals were categorized as to whether they had had single or multiple adenomas and according to the 604 GASTROINTESTINAL ENDOSCOPY
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worse pathology of their various lesions: carcinoma worse than villous adenoma, worse than tubular adenoma. The location of the lesions was classified as left sided (rectum to splenic flexure) or right sided (transverse colon to cecum). Localization of lesions within the colon is difficult, but we believe our differentiation into right or left colon was accurate. The splenic flexure is the dividing line and few of the lesions were found in this exact area. In addition, the majority of colonoscopies were performed by a small group of collaborative physicians using the same equipment and practice techniques.
Statistical analysis The outcome of interest for the analysis is the location of the neoplasm and the concordance of location between family members. Because some subjects had multiple neoplasms (either synchronous or metachronous), the location for each individual was designated as "left-sided only" or "any right sided" for this analysis. Neoplasm location is thus a binary variable. Alternating logistic regression (ALR) 16 is a new statistical technique for analyzing binary data within related groups such as families. It provides estimates of the standard odds ratio for the likelihood of an outcome, given a particular circumstance. The estimates of the odds of left-sided disease are obtained as a function of the relative's age and gender in exactly the same manner as logistic regression. The ALR method also yields a modified odds ratio, the "pair-wise odds ratio," for the outcomes of the related individuals which expresses the increased odds in favor of left-sided only disease for a relative of a person with left-sided only disease as compared with the case when the person has right-sided disease. The pair-wise odds ratio was also modeled to assess the within-family association for neoplasia location. This permitted the examination of the degree of association and whether this association was the same for pairs of relatives within the same generation or separated by one generation. We obtained the results of the ALR model from an OSWALD program written by Vincent Carey in Splus. 17 The details of the ALR model are contained within the appendix. Most individuals in this analysis had had at least one complete colonoscopy, thereby ensuring the validity of the assigned numbers of neoplasia. However, 4% of all individuals had had only a surgical colectomy and no known follow-up colonoscopy, although it is likely that they had had a perioperative b a r i u m enema. Nonetheless, this could lead to a deficit of right-sided neoplasia. Therefore, a sensitivity analysis was conducted by repeating the analysis using only those data on individuals with a confirmed colonoscopy; the results (not shown) did not differ substantially.
RESULTS O v e r a 2 - y e a r p e r i o d 146 f a m i l i e s w e r e a s c e r tained, each having at least two family members w i t h colorectal n e o p l a s i a t h a t could be verified. T h e 146 subjects h a d 181 affected f i r s t - d e g r e e r e l a t i v e s . T h e r e w e r e 211 p a i r s of f i r s t - d e g r e e r e l a t i v e s : 88 VOLUME 50, NO. 5, 1999
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Table 1. Number of first-degree relatives with differing neoplasia characteristics by relationship to the subject Subject Number 146 Histology Adenoma 99 (68) Carcinoma 28 (19) Both 19 (13) Multiplicity of neoplasia One 95 (65) Two 25 (17) Three or more 26 (18) Location of neoplasia Any right 74 (51) Left only 72 (49)
Siblings
Parents
Child
p Value
74
93
14
27 (36) 41 (55) 6 (8)
18 (19) 58 (62) 17 (18)
11 (78) <0.001 3 (21) 0 (0)
60 (81) 7 (9) 7 (9)
68 (73) 12 (13) 13 (14)
12 (86) 2 (14) 0 (0)
0.15
28 (38) 46 (62)
41 (44) 52 (56)
5 (36) 9 (64)
0.27
Numbers in parentheses indicate percentages.
pairs of first-degree relatives within the same generation (subject and sibling) and 123 pairs in which the first-degree relatives were of different generations (subject and child, subject and parent, or sibling and parent). The average age at diagnosis was 61 years. There were 172 primary colorectal carcinomas and 372 adenomas, of which 77% were tubular and 23% were tubulovillous or villous. The presence of only an adenoma was more common in the subjects (68%) than in the parents (19%) or siblings (36%) of the subject (Table 1). This finding is consistent with our recruitment strategy of identifying m a n y of the families through asymptomatic individuals undergoing o u t p a t i e n t colonoscopies because of a family history of colorectal cancer. Adenomas are a more common finding than is colorectal carcinoma in such a screened population. Neither multiplicity nor location of neoplasm differed between the first-degree relative types. Leftsided only location was inversely related to increasing age. The odds ratio for left-sided only neoplasia was 0.9 for individuals age 60 to 69 years, compared with an individual less than 60 years; and the odds ratio was 0.48 for an individual 70 years or older. Women were 1.64 times more likely to have left-side location only (p < 0.05). The association of neoplasm location b e t w e e n first-degree relatives was based on the concordance of location for pairs of relatives. Of the 211 firstdegree relative pairs, 111 (52%) were concordant for location. Forty-seven pairs (22%) were concordant for any right-side neoplasia and 64 (30%) were concordant for left-sided only neoplasia; 100 pairs (47%) were discordant. The model-based odds ratio for concordance of neoplasm location within first-degree relatives was 1.20, which was not statistically significant (p = 0.52). This odds ratio means that the VOLUME 50, NO. 5, 1999
Table 2. Odds ratio for concordance of location between pairs of first-degree relatives Pair-wise Confidence Model
odds ratio
interval*
p Value
Overall Unadjusted 1.20 0.69-2.10 Adjustedt 1.21 0.66-2.21 By generation: Unadjusted estimates Same generation 1.87 0.82-4.25 One generation apart 0.88 0.41-1.91 Adjusted estimate* Same generation 1.56 0.68-3.59 One generation apart 1.02 0.46-2.25 " *Confidence intervals were computed using empirical estimates of variance from the ALR model. tFor age and gender.
0.52 0. 54
0.14 0.75 0.29 0.97 (robust)
relative odds of one first-degree relative having only a left-sided neoplasm when the other member of the pair has only a left-sided neoplasm is 1.2 times higher than when the other member has any right-sided lesion. The odds ratio for location association was similar after adjusting for the age and gender of each of the two first-degree relatives (Table 2). The association of location within families was also considered within the same generation and between different generations. For the 88 pairs within the same generation, there were 51 pairs (58%) that were concordant. Twenty-two (25%) pairs were concordant for any right-sided neoplasm, 29 (33%) were concordant for left-sided only neoplasm, and 37 (42%) were discordant for left- and right-sided neoplasm (model-based odds ratio = 1.87, p = 0.14). For the 123 pairs of different generations, there were 60 pairs (48%) that were concordant. Twenty-five pairs (20%) were concordant for any right-sided neoplasm, 35 (28%) were concordant for left-sided only neoplasm, and 63 (51%) pairs were discordant. The discordant pairs were further separated as follows: 33 pairs (27%) discordant with older individual having only left-sided lesions and the younger individual having any right-sided neoplasm; and 30 pairs (24%) discordant with the older individual having any right-sided neoplasm and the younger having leftsided lesions only (model-based odds ratio = 0.88, p = 0.75) (Table 2).
DISCUSSION There are tissue and functional differences b e t w e e n the right and left colon. Proximal colon originates embryologically in the midgut and distal colon in the hindgut. The differing tissue origin and the evidence of differing cancer risks by location suggests that within families there may be correlaGASTROINTESTINAL ENDOSCOPY 605
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tions in t h e location of n e o p l a s i a . O u r r e s u l t s s h o w t h a t left-sided only location of n e o p l a s i a is n o t highly c o n c o r d a n t b e t w e e n p a i r s of f i r s t - d e g r e e r e l a t i v e s w i t h colorectal lesions. K n o w l e d g e of t h e location of a n e o p l a s m in one r e l a t i v e is not p r e d i c t i v e for t h e location in a n o t h e r f i r s t - d e g r e e relative, e v e n w h e n age and gender are taken into account. Our data i n d i c a t e a slight s u g g e s t i o n of g r e a t e r c o n c o r d a n c e for l o c a t i o n for t h o s e f i r s t - d e g r e e r e l a t i v e s of t h e s a m e g e n e r a t i o n , b u t t h e c o n c o r d a n c e is not n e a r l y l a r g e e n o u g h to f o r m t h e b a s i s for r e c o m m e n d a t i o n s for clinical m a n a g e m e n t . O n l y two s t u d i e s h a v e a d d r e s s e d t h e site specificity of colorectal c a n c e r b e t w e e n r e l a t i v e s ; b o t h of t h e s e s t u d i e s w e r e b a s e d on t h e genealogic records of t h e U t a h Mormons.14,15 S l a t t e r y a n d K e r b e r 15 h a v e s h o w n t h a t t h e r i s k for d e v e l o p m e n t of a proxi m a l colon c a n c e r in a f e m a l e i n d e x case w a s h i g h e r if t h e f a m i l y m e m b e r h a d h a d a distal, r a t h e r t h a n a p r o x i m a l cancer. For w o m e n w i t h d i s t a l c a n c e r a n d for m e n w i t h e i t h e r p r o x i m a l or d i s t a l cancer, t h e r e did not a p p e a r to be a n y a s s o c i a t i o n w i t h r e s p e c t to t h e location of t h e c a n c e r in t h e r e l a t i v e . H o w e v e r , n e i t h e r s t u d y a n a l y z e d t h e a s s o c i a t i o n of location b y t y p e of affected relative. E v a l u a t i o n of a n i n d i v i d u a l with an affected first-degree relative therefore r e q u i r e s a c o m p l e t e i n s p e c t i o n of t h e colon, p r e f e r a b l y by colonoscopy. It is possible t h a t we failed to find site specificity b e t w e e n first-degree relatives b e c a u s e of a field defect p r e s e n t t h r o u g h o u t the colon of p a t i e n t s w i t h neoplasia. S e v e r a l s t u d i e s h a v e e v a l u a t e d t h e n o r m a l a p p e a r i n g m u c o s a of colons c o n t a i n i n g a n i s o l a t e d n e o p l a s m b y s t u d y i n g t h e labeling index, iS, 19 proliferation specific genes, 20 h y d r o l a s e activity, 21 a n d DNAm e t h y l t r a n s f e r a s e e n z y m e activity. 22 A c o n s i s t e n t p a t t e r n of h y p e r p r o l i f e r a t i o n a n d i n c r e a s e d e x p r e s sion of p r o l i f e r a t i o n - r e l a t e d genes a n d e n z y m e s h a s b e e n reported. Further, s o m e of t h e s e changes involving t h e n o r m a l m u c o s a h a v e b e e n f o u n d to r e g r e s s a f t e r r e m o v a l of t h e n e o p l a s m . T h i s s u g g e s t s t h a t m a n y of the m e a s u r e d changes m a y be t h e r e s u l t of, or m e d i a t e d by, t h e n e o p l a s m . T h e s e s t u d i e s do not a n s w e r t h e question of w h e t h e r t h e u n d e r l y i n g susceptibility p e r m i t t i n g t h e s e c h a n g e s in t h e n o r m a l a p p e a r i n g m u c o s a is genetic in origin, e n v i r o n m e n t a l , or a combination of both. In t h e aggregate, however, t h e y do s u g g e s t a possible g e n e r a l i z e d m u c o s a l predilection for neoplastic c h a n g e a n d also indicate the need for complete e v a l u a t i o n of the colon of relatives of p a t i e n t s w i t h colorectal neoplasia.
ACKNOWLEDGMENTS We t h a n k the endoscopists taking part in this study and the families for their participation and support. 606 GASTROINTESTINAL ENDOSCOPY
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REFERENCES 1. St. John DJ, McDermott FT, Hopper JL, Debney EA, Johnson WR, Hughes ES. Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 1993;118:785-90. 2. Bishop DT, Hall NR. The genetics of colorectal cancer. Eur J Cancer 1994;30A:1946-56. 3. Burt RW, Bishop DT, Cannon LA, Dowdle MA, Lee RG, Skolnick MH. Dominant inheritance of adenomatous colonic polyps and colorectal cancer. N Engl J Med 1985;312:1540-4. 4. Winawer SJ, Zauber AG, Gerdes H, O'Brien MJ, Gottlieb LS, Sternberg SS, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. N Engl J Med 1996;334: 82-7. 5. Cannon-Albright LA, Skolnick MH, Bishop DT, Lee RG, Butt RW. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med 1988;319:533-7. 6. Cottrell S, Bicknell D, Kaklamanis L, Bodmer WF. Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas. Lancet 1992;340:626-30. 7. Lynch HT, Smyrk T, McGinn T, Lanspa S, Cavalieri J, Lynch J, et al. Attenuated familial adenomatous polyposis (AFAP).A phenotypically and genotypically distinctive variant of FAP. Cancer 1995;76:2427-33. 8. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Poweil SM, et al. The molecular basis of Turcot's syndrome. N Engl J IVied1995;332:839-47. 9. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, editors. Cancer incidence in five continents. Lyon, France: International Agency For Research on Cancer; 1997. 10. West DW, Slattery ML, Rebison LM, Schuman KL, Ford MH, Mahoney AW, et al. Dietary intake and colon cancer: sex- and anatomic site-specific associations. Am J Epidemiol 1989;130:883-94. 11. Slattery ML, Mineau GP, Kerber RA. Reproductive factors and colon cancer: the influences of age, tumor site, and family history on risk (Utah, United States). Cancer Causes Control 1995;6:332-8. 12. Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 1993;104:1535-49. 13. Winawer SJ, Fletcher RH, Miller L, Godlee F, Stolar MH, Mulrow CD, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594-642. 14. Cannon-Albright LA, Thomas TC, Bishop DT, Skolnick MH, Burt RW. Characteristics of familial colon cancer in a large population data base. Cancer 1989;64:1971-5. 15. Slattery ML, Kerber RA. Family history of cancer and colon cancer risk: the Utah Population Database. J Natl Cancer Inst 1994;86:1618-26. 16. Carey V, Zeger SL, Diggle P. Modelling multivariate binary data with alternating logistic regressions. Biometrika 1993;80:517-26. 17. Smith DM, Robertson WH, Diggle PG, editors. OSWALD: Object oriented system for analysis of longitudinal data in S [technical report: M.A. 96/192, Department of Mathematical Statistics]. Lancaster, United Kingdom: Univ. of Lancaster; 1996. 18. Ponz de Leon M, Roncucci L, Di Donato P, Tassi L, Smerieri O, Amorico MG, et al. Pattern of epithelial cell proliferation in colorectal mucosa of normal subjects and of patients with adenomatous polyps or cancer of the large bowel. Cancer Res 1988;48:4121-6. 19. Wilson RG, Smith AN, Bird CC. Immunohistochemical detecVOLUME 50, NO. 5, 1999
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tion of abnormal cell proliferation in colonic mucosa of subjects with polyps. J Clin Pathol 1990;43:744-7. 20. Pandey S, Gordon PH, Wang E. Expression of proliferationspecific genes in the mucosa adjacent to colon carcinoma. Dis Colon Rectum 1995;38:462-7. 21. Gibson PR, Folino M, Rosella O, Finch CF, Moeller I, Alexeyeff M, et al. Neoplasia and hyperplasia of large bowel: focal lesions in an abnormal epithelium. Gastroenterology 1992;103:1452-9. 22. Issa JP, Vertino PM, Wu J, Sazawal S, Celano P, Nelkin BD, et al. Increased cytosine DNA-methyltransferase activity during colon cancer progression. J Natl Cancer Inst 1993;85:1235-40. 23. Zeger SL, Liang K-Y. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986;42:121-30. 24. Rathouz P J, Kasper JD, Zeger SL, Ferrucci L, Bandeen-Roche K, Miglioretti DL, et al. Short-term consistency in self-reported physical functioning among elderly women: the Women's Health and Aging Study. Am J Epidemiol 1998;147:764-73. 25. McCullagh P, Nelder JA. Generalized linear models. 2nd ed. New York: Chapman Hall; 1989. APPENDIX I n a l t e r n a t i n g logistic r e g r e s s i o n (ALR) two g e n e r a l ized e s t i m a t i n g e q u a t i o n s 23 a r e u s e d s i m u l t a n e o u s l y to o b t a i n e s t i m a t e s for t h e coefficients (beta) in a location model a n d t h e coefficients (alpha) in a w i t h i n - f a m i l y association model as follows.16,24 First, in the s a m e m a n n e r as o r d i n a r y logistic regression, 25 A L R fits a model for location of t h e form: logit(prob(Yj = 1)) = Do + ~1 age2j + ~2 age3j + ~3 sexj
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This equation describes t h e log odds for left-sided only location as a function of the individual's age a n d sex. H e r e j indexes t h e family member, Yj = 1 i f t h e n e o p l a s i a location for the j t h family m e m b e r is "left-sided only", 0 i f otherwise a n d age2j, age3j, a n d sexj are indicator v a r i a b l e s for m e m b e r s h i p of t h e j t h r e l a t i v e in t h e second age group (60-69 years) or t h i r d age group (> 70) v e r s u s r e f e r e n t age group (< 60 years), a n d sexj = 1 indicates female gender. Second, i n d e p e n d e n c e b e t w e e n two r e l a t i v e s (j, j') in t h e s a m e f a m i l y is not a s s u m e d ; rather, t h e association a m o n g t h e m is m o d e l e d s i m u l t a n e o u s l y . T h e p a i r - w i s e association for n e o p l a s i a location a m o n g r e l a t i v e s is modeled e i t h e r as a c o n s t a n t log odds ratio or as a function of w h e t h e r the r e l a t i v e s a r e w i t h i n the s a m e g e n e r a t i o n or one g e n e r a t i o n removed. This l a t t e r model t a k e s the form: log odds ratio (Yp Yj,) = a l Zjj, + a 2 (1 -Zjj,) where Z~j,= 1 if (j,j') is a relative p a i r from the same generation a n d 0 otherwise. If a 1 = a2, then the log odds ratio is constant across all pairs of relatives. A n i m p o r t a n t feature of t h e ALR m e t h o d is t h a t t h e association is automatically a d j u s t e d for t h e c o v a r i a t e s age a n d sex in t h e location model. Confidence intervals were derived using the robust v a r i a n c e e s t i m a t o r s as d e s c r i b e d by Carey, Zeger a n d Diggle (equation 9 in reference 16). The ALR method was restricted to only pairs of blood relatives. In four families w h e r e both p a r e n t s h a d h a d a colorectal n e o p l a s m , one p a r e n t was selected at r a n d o m for the analysis. In one family with affected individuals across t h r e e generations, the neoplasm of the g r a n d p a r e n t was excluded.
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Background: Relatives of patients with bowel neoplasia have an increased risk of bowel neoplasia. If there were concordance in location of neoplasia between relatives, then location-specific screening could be used. Such concordance might also assist in the understanding of the etiology of neoplasia within individual families. Methods: We have investigated the concordance in anatomic location of colonic neoplasia between first-degree relatives using a new statistical technique for paired data called alternating logistic regression. Results: A total of 146 families were ascertained, none of which had clinical evidence of a hereditary predisposition to edon neoplasia. Among those with neoplasia, there was an increased risk for right-sided disease with older age (40% for less than age 60 vs. 58% for at least 70 years of age, p = 0.008). As assessed by the odds ratio, we found no significant concordance within families for location of neoplasia (odds ratio = 1.2: CI [0.7, 2.2]), although there was a suggestion that location in family members of the same generation was more strongly associated (odds ratio 1.87: CI [0.82, 4.25]). Conclusions: The lack of concordance within families for location argues against considering family-specific bowel screening protocols and indicates that the most important causes of bowel neoplasia are not sufficiently focused on one anatomic site to facilitate etiologic research. (Gastrointest Endosc 1999;50:603-7.)
Relatives of subjects with colorectal neoplasms, w h e t h e r cancer or adenomatous polyps, have been shown to have an increased risk of neoplasm themselves. Close relatives of patients with colorectal cancer have a twofold increased risk of cancer12 and a similar increased risk of adenomatous polyps. 3 Relatives of patients with adenomatous polyps have an increased risk of colorectal cancer 4 and adenomas. 5 Family aggregation of bowel cancer m a y be seen in two dominantly inherited syndromes. Mutations in the APC gene cause familial adenomatous polyposis (FAP) and several clinically related syndromes6-S; such families are usually identifiable clinically because of the extensive polyposis in the bowel. Individuals with this syndrome account for a small fraction of bowel cancer, p e r h a p s 0.5%. Families with the hereditary non-polyposis colorecReceived October 7, 1998. For revision February 25, 1999. Accepted June 15, 1999. From the Department of Medicine, Saint Barnabas Medical Center, Livingston, New Jersey; Department of Health Studies, University of Chicago, Chicago, Illinois; High Point Regional Hospital, High Point, North Carolina; ICRF Genetic Epidemiology Laboratory, St. James's Hospital, Leeds, United Kingdom. Supported by The Harvey Nussbaum Research Foundation, the Walter and Louise Sutcliffe Foundation and the Imperial Cancer Research Fund. Reprint requests: Peter Zauber, MD, 22 Old Short Hills Rd., Livingston, N J 07039. Copyright 9 1999 by the American Society for Gastrointestinal Endoscopy 0016-5107/99/$8.00 + 0 37/1/100727 VOLUME 50, NO. 5, 1999
tal cancer (HNPCC) syndrome also have an increased risk of bowel cancer. This syndrome is associated with germline m u t a t i o n s in genes responsible for repair of errors in DNA replication. H N P C C probably accounts for 5% of colorectal cancer cases b u t the exact extent is unclear as most studies have relied on family history as a surrogate for inherited predisposition. 2 Aside from these syndromes, the increased risk of bowel neoplasm in relatives is unexplained and is attributed to environmental exposures, genetic factors, and interactions between the two. The remaining cases of colorectal cancer are usually referred to as "sporadic"; we will use this term to indicate cases from families without any evidence of a hereditary syndrome. One of the most notable aspects of bowel cancer epidemiology is the variation in the anatomic distribution of bowel cancer across different geographic regions, 9 which is thought to result from dietary differences. Increased dietary fat has been related to increased risk of proximal cancer, whereas high protein intake and low fiber intake have been associated with an increased risk of distal tumors. 1~ Further, in women, bowel cancer risk decreases with increasing parityJ 1 Finally, in H N P C C families, the neoplasm is more commonly in the right side of the bowel than in the general population. TM It is therefore appropriate to screen first-degree relatives of p a t i e n t s sporadically affected with polyps and]or GASTROINTESTINAL ENDOSCOPY
603
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c a n c e r a n d g u i d e l i n e s h a v e b e e n proposed. 13 We r e a s o n e d t h a t c o n s i s t e n t p a t t e r n s w i t h r e s p e c t to a n a t o m i c location of n e o p l a s i a w i t h i n f a m i l i e s m a y be h e l p f u l in d e t e r m i n i n g t h e etiology in d i f f e r e n t families, and, i m p o r t a n t l y for clinical practice, m a y i n d i c a t e w h e t h e r family-specific s c r e e n i n g protocols have merit. S e v e r a l p r e v i o u s s t u d i e s h a v e a l r e a d y focused on bowel m a l i g n a n c i e s a n d h a v e not f o u n d s i g n i f i c a n t c o r r e l a t i o n s w i t h r e s p e c t to l o c a t i o n w i t h i n f a m i lies.14,15 B e c a u s e t h e m a j o r i t y of a d e n o m a s do n o t develop into m a l i g n a n c i e s , t h i s n e o p l a s m m i g h t be a m o r e s e n s i t i v e m e a s u r e of e n v i r o n m e n t a l e x p o sures. We t h e r e f o r e i n v e s t i g a t e d t h e locations of all bowel n e o p l a s m s w i t h i n a s c e r t a i n e d families, all of w h i c h h a d no i n h e r i t e d p r e d i s p o s i t i o n to bowel neoplasia.
PATIENTS AND METHODS Patients seen at a large suburban hospital over a 2-year period for colonoscopy constituted the study population. Participating physicians were three colorectal surgeons and 12 non-surgeon colonoscopists. The most common indications for colonoscopy included personal or family history of colorectal cancer, positive fecal occult blood test, abdominal pain, and prior colonoscopic polypectomy. The study was reviewed and approved by the hospital review board. The patients were asked to participate in the study at the time of initial interview by the clinic nurse. Ninetytwo percent agreed and constituted the study population of 3055 patients. Each patient was then approached by the project interviewer (G.L.) who explained the details of the study and elicited written permission to obtain a detailed family history of all first and second-degree relatives, including information as to the cause of death, major illnesses, and whether the family members had undergone any intestinal evaluations. If the patient was found to have a colorectal neoplasm and had indicated that a first-degree relative was also affected, the relative, or next of kin of deceased individuals, was contacted by letter and then by telephone or fax follow-up for permission to obtain copies of pathology reports. Information regarding age at diagnosis, gender, relationship to the subject, location of the lesion and type of lesion was recorded. All pathologic diagnoses were verified by obtaining a copy of the original pathology report. If the report was unclear, then original slides or paraffin blocks were obtained for independent review. Patients with only hyperplastic polyps were excluded. Patients were included if their adenomas were tubular, tubulovillous, or villous. Good clinical practice dictates that lesions detected by colonoscopy or b a r i u m e n e m a be removed before microscopic subclassification. Therefore, it is the presence of a visualized lesion, not the subtype, that dictates clinical practice. Individuals were categorized as to whether they had had single or multiple adenomas and according to the 604 GASTROINTESTINAL ENDOSCOPY
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worse pathology of their various lesions: carcinoma worse than villous adenoma, worse than tubular adenoma. The location of the lesions was classified as left sided (rectum to splenic flexure) or right sided (transverse colon to cecum). Localization of lesions within the colon is difficult, but we believe our differentiation into right or left colon was accurate. The splenic flexure is the dividing line and few of the lesions were found in this exact area. In addition, the majority of colonoscopies were performed by a small group of collaborative physicians using the same equipment and practice techniques.
Statistical analysis The outcome of interest for the analysis is the location of the neoplasm and the concordance of location between family members. Because some subjects had multiple neoplasms (either synchronous or metachronous), the location for each individual was designated as "left-sided only" or "any right sided" for this analysis. Neoplasm location is thus a binary variable. Alternating logistic regression (ALR) 16 is a new statistical technique for analyzing binary data within related groups such as families. It provides estimates of the standard odds ratio for the likelihood of an outcome, given a particular circumstance. The estimates of the odds of left-sided disease are obtained as a function of the relative's age and gender in exactly the same manner as logistic regression. The ALR method also yields a modified odds ratio, the "pair-wise odds ratio," for the outcomes of the related individuals which expresses the increased odds in favor of left-sided only disease for a relative of a person with left-sided only disease as compared with the case when the person has right-sided disease. The pair-wise odds ratio was also modeled to assess the within-family association for neoplasia location. This permitted the examination of the degree of association and whether this association was the same for pairs of relatives within the same generation or separated by one generation. We obtained the results of the ALR model from an OSWALD program written by Vincent Carey in Splus. 17 The details of the ALR model are contained within the appendix. Most individuals in this analysis had had at least one complete colonoscopy, thereby ensuring the validity of the assigned numbers of neoplasia. However, 4% of all individuals had had only a surgical colectomy and no known follow-up colonoscopy, although it is likely that they had had a perioperative b a r i u m enema. Nonetheless, this could lead to a deficit of right-sided neoplasia. Therefore, a sensitivity analysis was conducted by repeating the analysis using only those data on individuals with a confirmed colonoscopy; the results (not shown) did not differ substantially.
RESULTS O v e r a 2 - y e a r p e r i o d 146 f a m i l i e s w e r e a s c e r tained, each having at least two family members w i t h colorectal n e o p l a s i a t h a t could be verified. T h e 146 subjects h a d 181 affected f i r s t - d e g r e e r e l a t i v e s . T h e r e w e r e 211 p a i r s of f i r s t - d e g r e e r e l a t i v e s : 88 VOLUME 50, NO. 5, 1999
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Table 1. Number of first-degree relatives with differing neoplasia characteristics by relationship to the subject Subject Number 146 Histology Adenoma 99 (68) Carcinoma 28 (19) Both 19 (13) Multiplicity of neoplasia One 95 (65) Two 25 (17) Three or more 26 (18) Location of neoplasia Any right 74 (51) Left only 72 (49)
Siblings
Parents
Child
p Value
74
93
14
27 (36) 41 (55) 6 (8)
18 (19) 58 (62) 17 (18)
11 (78) <0.001 3 (21) 0 (0)
60 (81) 7 (9) 7 (9)
68 (73) 12 (13) 13 (14)
12 (86) 2 (14) 0 (0)
0.15
28 (38) 46 (62)
41 (44) 52 (56)
5 (36) 9 (64)
0.27
Numbers in parentheses indicate percentages.
pairs of first-degree relatives within the same generation (subject and sibling) and 123 pairs in which the first-degree relatives were of different generations (subject and child, subject and parent, or sibling and parent). The average age at diagnosis was 61 years. There were 172 primary colorectal carcinomas and 372 adenomas, of which 77% were tubular and 23% were tubulovillous or villous. The presence of only an adenoma was more common in the subjects (68%) than in the parents (19%) or siblings (36%) of the subject (Table 1). This finding is consistent with our recruitment strategy of identifying m a n y of the families through asymptomatic individuals undergoing o u t p a t i e n t colonoscopies because of a family history of colorectal cancer. Adenomas are a more common finding than is colorectal carcinoma in such a screened population. Neither multiplicity nor location of neoplasm differed between the first-degree relative types. Leftsided only location was inversely related to increasing age. The odds ratio for left-sided only neoplasia was 0.9 for individuals age 60 to 69 years, compared with an individual less than 60 years; and the odds ratio was 0.48 for an individual 70 years or older. Women were 1.64 times more likely to have left-side location only (p < 0.05). The association of neoplasm location b e t w e e n first-degree relatives was based on the concordance of location for pairs of relatives. Of the 211 firstdegree relative pairs, 111 (52%) were concordant for location. Forty-seven pairs (22%) were concordant for any right-side neoplasia and 64 (30%) were concordant for left-sided only neoplasia; 100 pairs (47%) were discordant. The model-based odds ratio for concordance of neoplasm location within first-degree relatives was 1.20, which was not statistically significant (p = 0.52). This odds ratio means that the VOLUME 50, NO. 5, 1999
Table 2. Odds ratio for concordance of location between pairs of first-degree relatives Pair-wise Confidence Model
odds ratio
interval*
p Value
Overall Unadjusted 1.20 0.69-2.10 Adjustedt 1.21 0.66-2.21 By generation: Unadjusted estimates Same generation 1.87 0.82-4.25 One generation apart 0.88 0.41-1.91 Adjusted estimate* Same generation 1.56 0.68-3.59 One generation apart 1.02 0.46-2.25 " *Confidence intervals were computed using empirical estimates of variance from the ALR model. tFor age and gender.
0.52 0. 54
0.14 0.75 0.29 0.97 (robust)
relative odds of one first-degree relative having only a left-sided neoplasm when the other member of the pair has only a left-sided neoplasm is 1.2 times higher than when the other member has any right-sided lesion. The odds ratio for location association was similar after adjusting for the age and gender of each of the two first-degree relatives (Table 2). The association of location within families was also considered within the same generation and between different generations. For the 88 pairs within the same generation, there were 51 pairs (58%) that were concordant. Twenty-two (25%) pairs were concordant for any right-sided neoplasm, 29 (33%) were concordant for left-sided only neoplasm, and 37 (42%) were discordant for left- and right-sided neoplasm (model-based odds ratio = 1.87, p = 0.14). For the 123 pairs of different generations, there were 60 pairs (48%) that were concordant. Twenty-five pairs (20%) were concordant for any right-sided neoplasm, 35 (28%) were concordant for left-sided only neoplasm, and 63 (51%) pairs were discordant. The discordant pairs were further separated as follows: 33 pairs (27%) discordant with older individual having only left-sided lesions and the younger individual having any right-sided neoplasm; and 30 pairs (24%) discordant with the older individual having any right-sided neoplasm and the younger having leftsided lesions only (model-based odds ratio = 0.88, p = 0.75) (Table 2).
DISCUSSION There are tissue and functional differences b e t w e e n the right and left colon. Proximal colon originates embryologically in the midgut and distal colon in the hindgut. The differing tissue origin and the evidence of differing cancer risks by location suggests that within families there may be correlaGASTROINTESTINAL ENDOSCOPY 605
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tions in t h e location of n e o p l a s i a . O u r r e s u l t s s h o w t h a t left-sided only location of n e o p l a s i a is n o t highly c o n c o r d a n t b e t w e e n p a i r s of f i r s t - d e g r e e r e l a t i v e s w i t h colorectal lesions. K n o w l e d g e of t h e location of a n e o p l a s m in one r e l a t i v e is not p r e d i c t i v e for t h e location in a n o t h e r f i r s t - d e g r e e relative, e v e n w h e n age and gender are taken into account. Our data i n d i c a t e a slight s u g g e s t i o n of g r e a t e r c o n c o r d a n c e for l o c a t i o n for t h o s e f i r s t - d e g r e e r e l a t i v e s of t h e s a m e g e n e r a t i o n , b u t t h e c o n c o r d a n c e is not n e a r l y l a r g e e n o u g h to f o r m t h e b a s i s for r e c o m m e n d a t i o n s for clinical m a n a g e m e n t . O n l y two s t u d i e s h a v e a d d r e s s e d t h e site specificity of colorectal c a n c e r b e t w e e n r e l a t i v e s ; b o t h of t h e s e s t u d i e s w e r e b a s e d on t h e genealogic records of t h e U t a h Mormons.14,15 S l a t t e r y a n d K e r b e r 15 h a v e s h o w n t h a t t h e r i s k for d e v e l o p m e n t of a proxi m a l colon c a n c e r in a f e m a l e i n d e x case w a s h i g h e r if t h e f a m i l y m e m b e r h a d h a d a distal, r a t h e r t h a n a p r o x i m a l cancer. For w o m e n w i t h d i s t a l c a n c e r a n d for m e n w i t h e i t h e r p r o x i m a l or d i s t a l cancer, t h e r e did not a p p e a r to be a n y a s s o c i a t i o n w i t h r e s p e c t to t h e location of t h e c a n c e r in t h e r e l a t i v e . H o w e v e r , n e i t h e r s t u d y a n a l y z e d t h e a s s o c i a t i o n of location b y t y p e of affected relative. E v a l u a t i o n of a n i n d i v i d u a l with an affected first-degree relative therefore r e q u i r e s a c o m p l e t e i n s p e c t i o n of t h e colon, p r e f e r a b l y by colonoscopy. It is possible t h a t we failed to find site specificity b e t w e e n first-degree relatives b e c a u s e of a field defect p r e s e n t t h r o u g h o u t the colon of p a t i e n t s w i t h neoplasia. S e v e r a l s t u d i e s h a v e e v a l u a t e d t h e n o r m a l a p p e a r i n g m u c o s a of colons c o n t a i n i n g a n i s o l a t e d n e o p l a s m b y s t u d y i n g t h e labeling index, iS, 19 proliferation specific genes, 20 h y d r o l a s e activity, 21 a n d DNAm e t h y l t r a n s f e r a s e e n z y m e activity. 22 A c o n s i s t e n t p a t t e r n of h y p e r p r o l i f e r a t i o n a n d i n c r e a s e d e x p r e s sion of p r o l i f e r a t i o n - r e l a t e d genes a n d e n z y m e s h a s b e e n reported. Further, s o m e of t h e s e changes involving t h e n o r m a l m u c o s a h a v e b e e n f o u n d to r e g r e s s a f t e r r e m o v a l of t h e n e o p l a s m . T h i s s u g g e s t s t h a t m a n y of the m e a s u r e d changes m a y be t h e r e s u l t of, or m e d i a t e d by, t h e n e o p l a s m . T h e s e s t u d i e s do not a n s w e r t h e question of w h e t h e r t h e u n d e r l y i n g susceptibility p e r m i t t i n g t h e s e c h a n g e s in t h e n o r m a l a p p e a r i n g m u c o s a is genetic in origin, e n v i r o n m e n t a l , or a combination of both. In t h e aggregate, however, t h e y do s u g g e s t a possible g e n e r a l i z e d m u c o s a l predilection for neoplastic c h a n g e a n d also indicate the need for complete e v a l u a t i o n of the colon of relatives of p a t i e n t s w i t h colorectal neoplasia.
ACKNOWLEDGMENTS We t h a n k the endoscopists taking part in this study and the families for their participation and support. 606 GASTROINTESTINAL ENDOSCOPY
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REFERENCES 1. St. John DJ, McDermott FT, Hopper JL, Debney EA, Johnson WR, Hughes ES. Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 1993;118:785-90. 2. Bishop DT, Hall NR. The genetics of colorectal cancer. Eur J Cancer 1994;30A:1946-56. 3. Burt RW, Bishop DT, Cannon LA, Dowdle MA, Lee RG, Skolnick MH. Dominant inheritance of adenomatous colonic polyps and colorectal cancer. N Engl J Med 1985;312:1540-4. 4. Winawer SJ, Zauber AG, Gerdes H, O'Brien MJ, Gottlieb LS, Sternberg SS, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. N Engl J Med 1996;334: 82-7. 5. Cannon-Albright LA, Skolnick MH, Bishop DT, Lee RG, Butt RW. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers. N Engl J Med 1988;319:533-7. 6. Cottrell S, Bicknell D, Kaklamanis L, Bodmer WF. Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas. Lancet 1992;340:626-30. 7. Lynch HT, Smyrk T, McGinn T, Lanspa S, Cavalieri J, Lynch J, et al. Attenuated familial adenomatous polyposis (AFAP).A phenotypically and genotypically distinctive variant of FAP. Cancer 1995;76:2427-33. 8. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Poweil SM, et al. The molecular basis of Turcot's syndrome. N Engl J IVied1995;332:839-47. 9. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, editors. Cancer incidence in five continents. Lyon, France: International Agency For Research on Cancer; 1997. 10. West DW, Slattery ML, Rebison LM, Schuman KL, Ford MH, Mahoney AW, et al. Dietary intake and colon cancer: sex- and anatomic site-specific associations. Am J Epidemiol 1989;130:883-94. 11. Slattery ML, Mineau GP, Kerber RA. Reproductive factors and colon cancer: the influences of age, tumor site, and family history on risk (Utah, United States). Cancer Causes Control 1995;6:332-8. 12. Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 1993;104:1535-49. 13. Winawer SJ, Fletcher RH, Miller L, Godlee F, Stolar MH, Mulrow CD, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594-642. 14. Cannon-Albright LA, Thomas TC, Bishop DT, Skolnick MH, Burt RW. Characteristics of familial colon cancer in a large population data base. Cancer 1989;64:1971-5. 15. Slattery ML, Kerber RA. Family history of cancer and colon cancer risk: the Utah Population Database. J Natl Cancer Inst 1994;86:1618-26. 16. Carey V, Zeger SL, Diggle P. Modelling multivariate binary data with alternating logistic regressions. Biometrika 1993;80:517-26. 17. Smith DM, Robertson WH, Diggle PG, editors. OSWALD: Object oriented system for analysis of longitudinal data in S [technical report: M.A. 96/192, Department of Mathematical Statistics]. Lancaster, United Kingdom: Univ. of Lancaster; 1996. 18. Ponz de Leon M, Roncucci L, Di Donato P, Tassi L, Smerieri O, Amorico MG, et al. Pattern of epithelial cell proliferation in colorectal mucosa of normal subjects and of patients with adenomatous polyps or cancer of the large bowel. Cancer Res 1988;48:4121-6. 19. Wilson RG, Smith AN, Bird CC. Immunohistochemical detecVOLUME 50, NO. 5, 1999
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tion of abnormal cell proliferation in colonic mucosa of subjects with polyps. J Clin Pathol 1990;43:744-7. 20. Pandey S, Gordon PH, Wang E. Expression of proliferationspecific genes in the mucosa adjacent to colon carcinoma. Dis Colon Rectum 1995;38:462-7. 21. Gibson PR, Folino M, Rosella O, Finch CF, Moeller I, Alexeyeff M, et al. Neoplasia and hyperplasia of large bowel: focal lesions in an abnormal epithelium. Gastroenterology 1992;103:1452-9. 22. Issa JP, Vertino PM, Wu J, Sazawal S, Celano P, Nelkin BD, et al. Increased cytosine DNA-methyltransferase activity during colon cancer progression. J Natl Cancer Inst 1993;85:1235-40. 23. Zeger SL, Liang K-Y. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986;42:121-30. 24. Rathouz P J, Kasper JD, Zeger SL, Ferrucci L, Bandeen-Roche K, Miglioretti DL, et al. Short-term consistency in self-reported physical functioning among elderly women: the Women's Health and Aging Study. Am J Epidemiol 1998;147:764-73. 25. McCullagh P, Nelder JA. Generalized linear models. 2nd ed. New York: Chapman Hall; 1989. APPENDIX I n a l t e r n a t i n g logistic r e g r e s s i o n (ALR) two g e n e r a l ized e s t i m a t i n g e q u a t i o n s 23 a r e u s e d s i m u l t a n e o u s l y to o b t a i n e s t i m a t e s for t h e coefficients (beta) in a location model a n d t h e coefficients (alpha) in a w i t h i n - f a m i l y association model as follows.16,24 First, in the s a m e m a n n e r as o r d i n a r y logistic regression, 25 A L R fits a model for location of t h e form: logit(prob(Yj = 1)) = Do + ~1 age2j + ~2 age3j + ~3 sexj
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This equation describes t h e log odds for left-sided only location as a function of the individual's age a n d sex. H e r e j indexes t h e family member, Yj = 1 i f t h e n e o p l a s i a location for the j t h family m e m b e r is "left-sided only", 0 i f otherwise a n d age2j, age3j, a n d sexj are indicator v a r i a b l e s for m e m b e r s h i p of t h e j t h r e l a t i v e in t h e second age group (60-69 years) or t h i r d age group (> 70) v e r s u s r e f e r e n t age group (< 60 years), a n d sexj = 1 indicates female gender. Second, i n d e p e n d e n c e b e t w e e n two r e l a t i v e s (j, j') in t h e s a m e f a m i l y is not a s s u m e d ; rather, t h e association a m o n g t h e m is m o d e l e d s i m u l t a n e o u s l y . T h e p a i r - w i s e association for n e o p l a s i a location a m o n g r e l a t i v e s is modeled e i t h e r as a c o n s t a n t log odds ratio or as a function of w h e t h e r the r e l a t i v e s a r e w i t h i n the s a m e g e n e r a t i o n or one g e n e r a t i o n removed. This l a t t e r model t a k e s the form: log odds ratio (Yp Yj,) = a l Zjj, + a 2 (1 -Zjj,) where Z~j,= 1 if (j,j') is a relative p a i r from the same generation a n d 0 otherwise. If a 1 = a2, then the log odds ratio is constant across all pairs of relatives. A n i m p o r t a n t feature of t h e ALR m e t h o d is t h a t t h e association is automatically a d j u s t e d for t h e c o v a r i a t e s age a n d sex in t h e location model. Confidence intervals were derived using the robust v a r i a n c e e s t i m a t o r s as d e s c r i b e d by Carey, Zeger a n d Diggle (equation 9 in reference 16). The ALR method was restricted to only pairs of blood relatives. In four families w h e r e both p a r e n t s h a d h a d a colorectal n e o p l a s m , one p a r e n t was selected at r a n d o m for the analysis. In one family with affected individuals across t h r e e generations, the neoplasm of the g r a n d p a r e n t was excluded.
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