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PURPOSE: An analysis of data from the Advanced Glaucoma Intervention Study (AGIS) has found eyes reported to have partial optic disc rim notching (not to the edge) at baseline to have less risk of subsequent visual field loss than eyes with no notching. Because this is counterintuitive and because classification of notching had not been defined in the AGIS protocol, we have assessed AGIS ophthalmologists interobserver and intraobserver agreement on notching. METHODS: Fourteen glaucoma subspecialists classified notching in 26 pairs of stereoscopic disc photographs of eyes with mild to severe glaucomatous optic neuropathy. They classified images as showing either no notching, notching not to the edge, or notching to the edge. Several hours later, 10 of them classified the same images a second time. RESULTS: In an analysis of interobserver agreement, of 26 stereoscopic images, a plurality of ophthalmologists classified notching as absent in 9 (35%), as present but not to the edge in 7 (27%), and as present and not to the edge in 10 (38%). All 14 ophthalmologists (100%) agreed on the classification of 7 (27%) of the images, and 13 of the 14 ophthalmologists (93%) agreed on the classification of 4 additional images (15%). Of these 11 images with at least 93% agreement, notching was reported as absent in 3 (27%) and to the edge in 8 (73%). In the remaining 15 images, there was substantial disagreement about whether notching was present and, if so, whether it was to the edge. In an analysis of intraobserver agreement, none of the 10 ophthalmologists who completed the viewing a second time classified all eyes exactly the same as the first time, though 5 ophthalmologists made 4 or fewer reclassifications. Overall, 80% of the original classifications were reproduced on second reading. Of the initial classifications that were not reproduced, slightly more than half were first classified as having notching not to the edge. CONCLUSION: Without definitions or examples of optic disc rim notching, the glaucoma subspecialists had relatively high intraobserver agreement but were likely to disagree with each other in characterizing the degree of disc rim notching. We recommend development of a standard photographic classification of disc rim notching. The classification should be tested for inter- and intra-observer agreement.

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BACKGROUND: Both annual testing for fecal occult blood and biennial testing significantly reduce mortality from colorectal cancer. However, the effect of screening on the incidence of colorectal cancer remains uncertain, despite the diagnosis and removal of precancerous lesions in many persons who undergo screening. METHODS: We followed the participants in the Minnesota Colon Cancer Control Study for 18 years. A total of 46,551 people, most of whom were 50 to 80 years old, were enrolled between 1975 and 1978 and randomly assigned to annual screening, biennial screening, or usual care (the control group). Those assigned to the screening groups were asked to prepare and submit two samples from each of three consecutive stools for guaiac-based testing. Those with at least one positive slide in the set of six were offered a diagnostic examination that included colonoscopy. Screening was conducted between 1976 and 1982 and again between 1986 and 1992. Study participants have been followed with respect to newly diagnosed cases of colorectal cancer and deaths. Follow-up has been more than 90 percent complete. RESULTS: During the 18-year follow-up period, we identified 1359 new cases of colorectal cancer: 417 in the annual-screening group, 435 in the biennial-screening group, and 507 in the control group. The cumulative incidence ratios for colorectal cancer in the screening groups as compared with the control group were 0.80 (95 percent confidence interval, 0.70 to 0.90) and 0.83 (95 percent confidence interval, 0.73 to 0.94) for the annual-screening and biennial-screening groups, respectively. For both screening groups, the number of positive slides was associated with the positive predictive value both for colorectal cancer and for adenomatous polyps at least 1 cm in diameter. CONCLUSIONS: The use of either annual or biennial fecal occult-blood testing significantly reduces the incidence of colorectal cancer.

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For deaths during the first 13 years of follow-up of the Minnesota Colon Cancer Control Study, an expert committee using numerous medical documents, and a nosologist using only the death certificate independently determined whether colorectal cancer caused the death and, if not, whether the disease was present at death. Deaths due to colorectal cancer numbered 318 according to the nosologist and 323 according to the committee, a discrepancy of 1.5%, which is similar in magnitude to that in three previous studies. The nosologist and committee agreed that colorectal cancer caused the death in each of 290 individual cases; they disagreed widely on the number of deaths from other causes but with colorectal cancer. If it is important to know only the gross number of deaths from colorectal cancer, then the death certificate alone appears to be sufficiently accurate; if it is important to know the cause of death of individual subjects or the number dying from other causes but with colorectal cancer, then the expert committee method provides more accurate information.

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BACKGROUND: In 1993, a randomized controlled trial in Minnesota showed, after 13 years of follow-up, that annual fecal occult blood testing was effective in reducing colorectal cancer mortality by at least 33%. Biennial screening (i.e., every 2 years) resulted in only a 6% mortality reduction. Two European trials (in England and in Denmark) subsequently showed statistically significant 15% and 18% mortality reductions with biennial screening. Herein, we provide updated results-through 18 years of follow-up--from the Minnesota trial that address the apparent inconsistent findings among the trials regarding biennial screening. METHODS: From 1976 through 1977, a total of 46551 study subjects, aged 50-80 years, were recruited and randomly assigned to an annual screen, a biennial screen, or a control group. A screen consisted of six guaiac-impregnated fecal occult blood tests (Hemoccult) prepared in pairs from each of three consecutive fecal samples. Participants with at least one of the six tests that were positive were invited for a diagnostic examination that included colonoscopy. All participants were followed annually to ascertain incident colorectal cancers and deaths. RESULTS: The numbers of deaths from all causes were similar among the three study groups. Cumulative 18-year colorectal cancer mortality was 33% lower in the annual group than in the control group (rate ratio, 0.67; 95% confidence interval [CI] = 0.51-0.83). The biennial group had a 21% lower colorectal cancer mortality rate than the control group (rate ratio, 0.79; 95% CI = 0.62-0.97). A marked reduction was also noted in the incidence of Dukes' stage D cancers in both screened groups in comparison with the control group. CONCLUSION: The results from this study, together with the other two published randomized trials of fecal occult blood screening, are consistent in demonstrating a substantial, statistically significant reduction in colorectal cancer mortality from biennial screening.

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PURPOSE: To compare the incidence of encapsulated bleb after trabeculectomy in eyes with and without previous argon laser trabeculoplasty and to assess other risk factors for encapsulated bleb development. METHODS: After medical treatment failure, eyes enrolled in the Advanced Glaucoma Intervention Study (AGIS) were randomly assigned to sequences of interventions starting with either argon laser trabeculoplasty or trabeculectomy. In the present study we compared the clinical course for 1 year after trabeculectomy in 119 eyes with failed argon laser trabeculoplasty with that of 379 eyes without previous argon laser trabeculoplasty. Data on bleb encapsulation were collected at the time that the encapsulation was diagnosed, and 3 and 6 months later. RESULTS: Of multiple factors examined in the AGIS data for the risk of developing encapsulated bleb, only male gender and high school graduation without further formal education were statistically significant. Encapsulation occurred in 18.5% of eyes with previous argon laser trabeculoplasty failure and 14.5% of eyes without previous argon laser trabeculoplasty (unadjusted relative risk, 1.27; 95% confidence limits = 0.81, 2.00; P = .23). After adjusting for age, gender, educational achievement, prescribed systemic beta-blockers, diabetes, visual field score, and years since glaucoma diagnosis, this difference remains statistically not significant. Four weeks after trabeculectomy, mean intraocular pressure was 7.5 mm Hg higher in eyes with (22.5 mm Hg) than without (15.0 mm Hg) encapsulated bleb; at 1 year after trabeculectomy and the resumption of medical therapy when needed, this excess was reduced to 1.4 mm Hg. CONCLUSIONS: This study, as did two previous studies, found male gender to be a risk factor for bleb encapsulation. Four studies, including the present study, have reported a higher rate of encapsulation in eyes with previous argon laser trabeculoplasty; in two of the studies, one of which was the present study, the rate was not statistically significantly higher; in the other two studies the rate was significantly higher. The 4-week postoperative mean intraocular pressure was higher in eyes with than without encapsulated bleb; with the resumption of medical treatment the two means converged after 1 year.

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We developed a Dry Eye Screening Questionnaire for the Dry Eye Epidemiology Projects (DEEP), a proposed large epidemiologic study. All persons who screen positive and a small sample of those who screen negative are to be invited for a diagnostic examination. Containing 19 questions, of which only 14 were used in the analysis, the questionnaire takes only a few minutes to administer on the telephone. To construct a discriminator function and thus a ROC curve, we used stepwise multiple regression on screening responses from a clinic series of 77 cases and 79 controls. Stepwise regression may incorporate into the predictor equation variables whose relation to the predicted is only accidental. Further, misclassification rates are underestimated by the resubstitution method, in which the proportion misclassified is obtained from the same dataset in which the discriminator function was fitted. To counter these problems, we randomly divided the data in half. We chose as predictors only those variables (Dry and Irritated) selected by stepwise regression in both data halves. We estimated unbiased misclassification rates using the unbiased test set method, in which the discriminator is fitted in one data half, and misclassification rates are calculated in the other half. Comparison of ROC curves arising from resubstitution and test set estimates indicates that resubstitution bias in misclassification rate estimation is negligible in our data. A resubstitution estimate made on the entire data is thus preferred. The resulting sensitivity/specificity values are reasonably high (e.g., 60%/94%), suggesting that the questionnaire will be a useful screening tool in the DEEP study. A second discriminator using the sum of all 14 responses is similar in its misclassification characteristics to the first discriminator. A second potentially significant error, arising from applying results from a clinical series to a general population, will be investigated as survey results in DEEP become available.

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BACKGROUND: In the Minnesota Colon Cancer Control Study, annual fecal occult blood testing reduced mortality from colorectal cancer by at least 33.4%. Some attribute a large part of this reduction to chance detection of cancers by colonoscopies; rehydration of guaiac test slides greatly increased positivity and consequently the number of colonoscopies performed. This study was conducted to determine how much of the reduction resulted from chance detection. METHODS: We used a mathematical model developed by Lang and Ransohoff to estimate the proportion of the 33.4% mortality attainable by chance alone. Applying the model requires the specification of five parameters: duration of follow-up, rate of compliance with fecal occult blood testing, rate of compliance with colonoscopy, positivity rate, and efficacy of colonoscopy in reducing colorectal cancer mortality. We took values for four of the five parameters directly from the Minnesota study. For the fifth parameter, efficacy of colonoscopy, we selected a value of 60%, based on the conclusions of another study. Whereas the Lang-Ransohoff model selects persons for colonoscopy by chance alone, those with bleeding cancers would also be selected by sensitive fecal occult blood testing. We therefore adjusted the result of the Lang-Ransohoff model for this dual detectability. RESULTS: We found that 16%-25% of the reduction in colorectal cancer deaths effected by fecal occult blood testing in the Minnesota study was due to chance detection; the remainder was due to sensitive detection. CONCLUSION: Chance played a minor role in the detection of colorectal cancers by fecal occult blood testing in the Minnesota study.

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BACKGROUND: In the Minnesota Colon Cancer Control Study, which used guaiac slides to annually screen stool samples for blood, mortality from colorectal cancer was reduced by 33.4%. The reported sensitivity of this test for colorectal cancer was about 90%. However, results from another study estimated the sensitivity to be 25%-33%; other investigators have reported intermediate values. Given these contradictions, we examined screening sensitivity for colorectal cancer in the Minnesota study by several direct and indirect methods. METHODS: In this reanalysis of data from the Minnesota study, we distinguished between sensitivity for colorectal cancer of the screening test (composed of six slides) and of the screening program (a series of such tests). We estimated screen sensitivity by adjusting the crude estimate from the final tests in each screening phase for colorectal cancer incidence in 5 years of follow-up, by modeling guaiac slide results at each screen as a function of the presence of occult blood, and by incorporating sensitive detection into a modification of a mathematical model developed by Lang and Ransohoff. Program sensitivity was estimated from the fraction of screen-detected cancers among all cancers diagnosed in screened individuals. RESULTS: The crude estimate of program sensitivity was 89.4%, whereas the modified Lang-Ransohoff model estimates screen sensitivities at 94.1%-96.2%, consistent with the estimates from the other methods. Indirect measures, such as the association between the number of positive slides among the six slides in each set and the positive predictivity for colorectal cancer, are consistent with these estimates. CONCLUSIONS: The Minnesota study reduced mortality from colorectal cancer through use of a screening test with average screen and program sensitivities of about 90%.

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Medical therapy has been the standard initial treatment for open-angle glaucoma. When some visual field has been lost and maximum tolerated and effective medical therapy does not succeed in controlling the disease, the patient is considered to have advanced glaucoma, and the first of a potential sequence of surgical treatments is usually indicated. Little is known about the long-term course and prognosis of advanced glaucoma or about the long-term effectiveness of sequential surgical treatments in controlling the disease and preventing vision loss and blindness. The Advanced Glaucoma Intervention Study was designed to study, in advanced glaucoma, the long-term clinical course and prognosis, and, in a randomized trial, the comparative outcomes of two sequences of surgical treatments. Toward these goals, 789 eyes in 591 patients were enrolled at 11 clinical centers between 1988 and 1992. Follow-up will continue until 1996. Eyes were randomly assigned to one of two sequences of surgical treatments. One sequence begins with argon laser trabeculoplasty (ALT), is followed by trabeculectomy, an incisional surgical filtering procedure, should ALT fail to control the disease, and by a second trabeculectomy should the first trabeculectomy fail. The other sequence begins with trabeculectomy, is followed by ALT should the trabeculectomy fail, and by a second trabeculectomy should ALT fail. The main outcome of interest is visual function (visual field and visual acuity). Other important outcomes are intraocular pressure, complications of surgery, time to treatment failure, and extent of need for additional medical therapy. We present in this paper the rationale, objectives, design and methods of the study, and the baseline characteristics of study patients and eyes.

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BACKGROUND: Although tests for occult blood in the feces are widely used to screen for colorectal cancers, there is no conclusive evidence that they reduce mortality from this cause. We evaluated a fecal occult-blood test in a randomized trial and documented its effectiveness. METHODS: We randomly assigned 46,551 participants 50 to 80 years of age to screening for colorectal cancer once a year, to screening every two years, or to a control group. Participants who were screened submitted six guaiac-impregnated paper slides with two smears from each of three consecutive stools. About 83 percent of the slides were rehydrated. Participants who tested positive underwent a diagnostic evaluation that included colonoscopy. Vital status was ascertained for all study participants during 13 years of follow-up. A committee determined causes of death. A single pathologist determined the stage of each tissue specimen. Differences in mortality from colorectal cancer, the primary study end point, were monitored with the sequential log-rank statistic. RESULTS: The 13-year cumulative mortality per 1000 from colorectal cancer was 5.88 in the annually screened group (95 percent confidence interval, 4.61 to 7.15), 8.33 in the biennially screened group (95 percent confidence interval, 6.82 to 9.84), and 8.83 in the control group (95 percent confidence interval, 7.26 to 10.40). The rate in the annually screened group, but not in the biennially screened group, was significantly lower than that in the control group. Reduced mortality in the annually screened group was accompanied by improved survival in those with colorectal cancer and a shift to detection at an earlier stage of cancer. CONCLUSIONS: Annual fecal occult-blood testing with rehydration of the samples decreased the 13-year cumulative mortality from colorectal cancer by 33 percent.

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Planners of several large prevention trials have overestimated the expected incidence of events in the control group, largely because they failed either to recognize or to adequately correct for various effects of population selection. Consequently, the studies have been too small in size or too short in duration to achieve their stated objectives. The selection effects include those engendered by the choice of the target population, the self-selection of volunteers, and protocol exclusions. This paper presents a taxonomy of these effects and the likely direction of their influence on the incidence of events and on mortality rates from other causes. Little information is available to help sample-size planners in adjusting for these effects. A few studies have provided information on the extent to which control group incidence rates have fallen short of expectations. In particular, researchers from the University of Minnesota's Colon Cancer Control Study have provided a detailed comparison of event incidence and all-cause mortality rates with general population rates. (AM J Epidemiol 1993;137:797-810). Other studies should publish similarly detailed information to assist sample-size planners of prevention trials. Until more information is published, this paper provides preliminary guidelines for prevention trial sample-size planning.

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The authors present a method of estimating the duration of ongoing prevention trials, showing how the method was applied to the Colon Cancer Control Study, a University of Minnesota study of occult blood testing undertaken to screen for colorectal cancer in older Minnesotans. In that study, begun in 1975 and ongoing, as in several other recent large prevention trials, it was necessary, after the start of the study, to revise upward the initial estimates of study duration derived from general population experience. The underestimates arose because the planners had not adequately taken various population selection factors into account in estimating the expected number of events in the control group. In this paper, the authors outline a method for estimating control group event rates and study duration requirements (and, in some circumstances, also sample size requirements) of prevention studies, via models of disease-specific and all-cause standardized mortality ratios which adjust for various selection effects. The authors also validate the model for disease-specific standardized mortality ratios by means of independent estimates of disease incidence and case survival.

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Data are presented on the sensitivity, specificity, and positive predictivity of the Hemoccult test based on the experience of the Minnesota Colon Cancer Control Study, a randomized clinical trial to determine whether the use of the Hemoccult test can reduce mortality from colorectal cancer. Rehydrating the slides with a drop of water before processing resulted in an increase in positivity (2.4% to 9.8%), and sensitivity (80.8% to 92.2%) but a decrease in specificity (97.7% to 90.4%) and positive predictivity (5.6% to 2.2%). The effects of age and sex were also evaluated. The test was less specific for men than women (p = 0.03). Specificity was highest for those less than 60 yr of age and decreased with increasing age (p = 0.05). The positive predictivity increased with age from 1.6% for those under 60 yr to 3.6% for those over 70 yr (p = 0.0004).

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Data from the 1971-1972 National Health and Nutrition Examination Survey were used to examine the associations between specific cataract types and age, race, sex, number of years spent in school, diabetes, systolic blood pressure, urban versus rural residence, and average daily ultraviolet spectrum B (UV-B) radiation counts at the site of examination. Separate comparisons were made of persons with no lens changes (n = 1,299) and persons with cortical (n = 55), nuclear (n = 104), and posterior subcapsular cataracts (n = 18). Persons with more than one type of cataract were excluded from the analysis. Cortical cataracts were associated with age (relative risk (RR) = 11.4 for age 70 years vs. age 50 years), race (RR = 3.5 for blacks vs. whites), sex (RR = 3.0 for women vs. men), educational achievement (RR = 1.8 for less than nine years of schooling vs. college), and UV-B count (RR = 3.6 for 6.0 X 10(3) counts vs. (2.6 X 10(3) counts). Nuclear cataracts were associated with age (RR = 38.6 for age 70 years vs. age 50 years), race (RR = 1.8 for black vs. white), and residence (RR = 1.6 for rural vs. urban). Posterior subcapsular cataracts were associated with diabetes (RR = 6.6 for diabetes present vs. diabetes absent) and systolic blood pressure (RR = 2.2 for 160 mmHg vs. 120 mmHg). Cortical cataracts were more common in women and more often found in locations with increased UV-B radiation counts than either nuclear or posterior subcapsular cataracts. In diabetics, the risk of posterior subcapsular cataracts was greater than the risk of nuclear cataracts (p less than 0.05) and also appeared to be greater than the risk of cortical cataracts (p = 0.06).

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The Visual Acuity Impairment Survey (VAIS) pilot study was carried out in three large metropolitan areas of the United States to determine whether it would be feasible to conduct a large two-stage survey of the prevalence of visual acuity impairment and its causes. The study was conducted in conjunction with the Health Interview Survey (HIS), performed by the National Center for Health Statistics and the Census Bureau. In the first stage, a simple vision screening test was administered to 1,868 adults in their homes by specially trained Census Bureau interviewers. All those who failed the test, and a sample of those who passed it, were invited to a local clinic for a check on the accuracy of the screen and a detailed eye examination to establish the cause of the impairment. About 89 per cent of the HIS interviewees took the vision screening test in the home and agreed to have the results released, making it possible for the clinic to invite them for an examination. The principal obstacle to the success of the feasibility study was a low rate (less than 50 per cent) of participation in the clinic examination by the target population. Such low participation would leave the survey open to a serious question about its representativeness. The methods and findings of the pilot study are presented because the lessons may be of value to those attempting similar studies in the future. Suggestions are made for methodological modifications that may enhance the chances for success.

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