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The recent burst of activity in eye disease epidemiology, occasioned by increases in the number of ophthalmologists with training in epidemiology and of epidemiologists interested in eye diseases, makes this an appropriate time for taking stock of methodological problems in this field. In this review, based largely on the author's personal encounter with five large epidemiologic studies (2, 7, 19, 30, 39) of the four major chronic eye diseases (senile cataract, senile macular degeneration, diabetic retinopathy, and glaucoma), the following methodological areas are discussed: quality assurance; disease definitions and classifications; reproducibility of observations; visual acuity and visual field tests; needed technologic advances; study design of case-control studies and clinical trials; and data analysis (shall we count subjects or eyes?). The chief weakness of blindness registers has been inadequate evaluation of the extent of underregistration and of the variability of underregistration according to socioeconomic and racial subgroups. The Health and Nutrition Examination Survey (HANES), conducted by the United States Public Health Service, is a potentially valuable source of descriptive and analytic epidemiologic information on eye diseases. It is an examination of a large probability sample of the US population and includes various histories, clinical and laboratory examinations, and a nutrition interview. In the early 1970s, HANES included eye examinations, but these were curtailed because of inability to get ophthalmologists as examiners. In future HANES studies, efforts should be made to minimize the involvement of ophthalmologists in the eye examinations and to increase the use of nonophthalmologists (e.g., optometrists, technicians) and instruments (e.g., cameras, densitometers, automated perimeters). The validity and reliability of any new procedures will need to be determined. Studies may need to be limited to certain major eye diseases and conditions. Population glaucoma surveys have tended to omit partially or entirely the time-consuming visual field test. Yet, without this test, the diagnostic examination for glaucoma is incomplete. The automated perimeter, with which visual fields can be more quickly measured, promises to be an important screening tool for glaucoma prevalence and case-finding surveys. It should be field-tested for epidemiologic use. The absence of standardized disease definitions, without which comparisons between studies are uncertain, has been a handicap to epidemiologic research in eye disease. A first constructive step toward the development of disease definitions would be the development of disease classifications.(ABSTRACT TRUNCATED AT 400 WORDS) [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Concepts such as participation and environment may differ across cultures. Consequently, cultural equivalence must be assured when using a measure like the Young Children Participation and Environment Measure (YC-PEM) in other settings than the original English-speaking contexts. This study aimed to cross-culturally translate and adapt the YC-PEM into German as it is used in Germany, Austria, and Switzerland., Methods: Following international guidelines, two translations were compared, and the research and expert team made the first adaptations. Twelve caregivers of children with and without disabilities from three German-speaking countries participated in two rounds of think-aloud interviews. Data were analyzed by content analysis to look for item, semantic, operational, conceptual, and measurement equivalence to reach a cultural equivalence version in German., Results: Adaptations were needed in all fields but prominently in item, operational, and conceptual equivalence. Operational equivalence resulted in graphical adaptations in the instructions and questions to make the German version of YC-PEM, YC-PEM (G), more user-friendly., Conclusion: This study presents a cross-cultural translation and adaptation process to develop a German version of the YC-PEM suitable for Germany, Austria, and Switzerland. A culturally adapted YC-PEM (G) is now available for research, practice, and further validation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Krieger, Ederer, Amann, Morgenthaler, Schulze and Dawal.)

Purpose: To determine the least worsening of a visual field (VF) and the least number of confirming tests needed to identify progression of glaucomatous VF defects., Design: Cohort study of participants in a clinical trial., Participants: Seven hundred fifty-two eyes of 565 patients with advanced glaucoma., Methods: Visual field tests were quantified with the Advanced Glaucoma Intervention Study (AGIS) VF defect score and the Humphrey Field Analyzer mean deviation (MD). Follow-up was 8 to 13 years., Main Outcome Measures: Two measures based on the AGIS VF defect score: (1) sustained decrease of VF (SDVF), a worsening from baseline by 2 (alternatively, 3 or 4) or more units and sustained for 2 (alternatively, 3) consecutive 6-month visits and (2) after the occurrence of SDVF, the average percent of eyes with worsening by 2 (alternatively, 3 or 4) or more units from baseline. Two similar measures based on MD., Results: Based on the original AGIS criteria for SDVF (a worsening of 4 units in the AGIS score sustained during 3 consecutive 6-month visits), 31% of eyes had an SDVF. The percent of eyes with a sustained event increases by approximately 10% when either the minimum number of units of field loss or the minimum number of 6-month visits during which the loss is sustained decreases by 1. During 3 years of follow-up after a sustained event, a worsening of at least 2 units was found in 72% of eyes that had a 2-visit sustained event. The same worsening was found in 84% of eyes that had a 3-visit sustained event. Through the next 10 years after a sustained event, based on worsening of 2, 3, or 4 units at 2 or 3 consecutive tests, the loss reoccurred, on average, in >/=75% of study eyes. Results for MD are similar., Conclusions: In patients with advanced glaucoma, a single confirmatory test 6 months after a VF worsening indicates with at least 72% probability a persistent defect when the worsening is defined by at least 2 units of AGIS score or by at least 2 decibels of MD. When the number of confirmatory tests is increased from 1 to 2, the percentage of eyes that show a persistent defect increases from 72% to 84%.

Objective: To present for black and white patients with medically uncontrolled glaucoma 10-year results of treatment with 1 of 2 randomly assigned surgical intervention sequences., Design: Randomized clinical trial., Participants: Three hundred thirty-two black patients (451 eyes) and 249 white patients (325 eyes). Eyes had glaucoma that could not be controlled with medications alone., Methods: Eyes were randomly assigned to 1 of 2 sequences: argon laser trabeculoplasty (ALT)-trabeculectomy-trabeculectomy (ATT) or trabeculectomy-ALT-trabeculectomy (TAT). Second and third interventions were offered after failure of the preceding intervention. Minimum required intraocular pressure (IOP) for intervention failure ranged upward from 18 mmHg, the value depending on whether recent optic disc or visual field (VF) deterioration occurred, and on the magnitude of the field defect. Patients were observed every 6 months, with total potential follow-up ranging from 8 years, 4 months to 13 years., Main Outcome Measures: The averages over follow-up of (1) the percentage of eyes having moderate loss of VF and (2) the percentage of eyes having moderate loss of visual acuity (VA)., Results: Race-treatment interactions in VF and VA loss are significant for the 2 main outcome measures; therefore, results of treatment sequence differences are presented by race. In black patients the average percent of eyes with VF loss was less in the ATT sequence than in the TAT sequence, a difference that is not statistically significant at any visit. In white patients, conversely, after 18 months the average percent of eyes with VF loss was less in the TAT sequence, a difference that increases and is statistically significant in years 8 to 10. In both black and white patients, the average percent of eyes with VA loss was less in the ATT sequence; this difference is statistically significant throughout 10 follow-up years in black patients and is statistically significant only for the first year in white patients. In both black and white patients, average IOP reductions were greater in the TAT sequence, though the TAT-ATT difference was substantially greater in white patients. In both black and white patients, first-intervention failure rates were substantially lower for trabeculectomy than for trabeculoplasty. Ten-year cumulative incidence of unilateral VF impairment comparable to legal blindness was modest in eyes of black (ATT 11.9%, TAT 18.5%) and white (ATT 9.9%, TAT 7.3%) patients., Conclusions: Although IOP was lowered in both sequences in black and white patients with medically uncontrolled glaucoma, long-term visual function outcomes were better for the ATT sequence in black patients and better for the TAT sequence in white patients.

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.

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.

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.

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.

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%.

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.

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.

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.

Natural history data from the Diabetic Retinopathy Study were examined by multivariate methods to determine which baseline characteristics could predict the occurrence of severe visual loss (SVL) in eyes originally assigned to no treatment. The presence and extent of new blood vessels on the optic disc (NVD) had the strongest association with SVL. Several other ocular characteristics also were strongly associated with visual outcome. In the absence of NVD at baseline, the degree of intraretinal hemorrhages and microaneurysms (HMA) had the strongest association with development of SVL. Macular edema was a factor in determining visual loss to 20/200 but not SVL (less than 5/200). Among systemic characteristics, urinary protein was the best predictor of visual outcome, but none were as good as the major ocular variables.

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).

Suppose a fixed-sample trial in a disease with a long response time shows a statistically significant benefit of the experimental treatment before patients have completed the planned follow-up period. The question may then arise--and did arise in the Diabetic Retinopathy Study (DRS)--whether the observed early benefit of treatment may be offset at some time in the future by the subsequent development of harmful treatment effects. If this question raises serious concerns, then the investigators are faced with a dilemma. If the trial is stopped because of the observed early treatment benefit and the treatment is administered to the untreated control group as well as to patients outside the study, and if the treatment is later found to have deleterious effects, then it may ultimately do more harm than good to patients. Moreover, the fact that the treatment is harmful may never become known. If, on the other hand, the trial is not stopped and the treatment proves to have no deleterious effects, then the control group and patients outside the study would be harmed because the treatment was withheld. We show how, in the DRS, this very problem was formulated and resolved. First a severe, delayed harmful treatment effect was postulated. Projections based on this postulation showed that the early gains were so great that they were unlikely to be offset--ever. Based in part on these projections, the following decisions were made: (a) the study protocol would be changed so as to allow treatment of the untreated control group, and (b) patients would continue to be followed in order to make possible the detection of late, harmful treatment effects, should they develop.

A variety of studies are reviewed in which intraocular pressure (IOP) was determined in defined, general populations. The studies exhibit a remarkably consistent pattern for the frequency distribution of IOP. The distribution conforms well to a normal curve for pressures up to 21 mm Hg, after which a distinct skewness to the right begins to appear. When the data are grouped by age and sex, the degree of right skewness intensifies with age. Mean IOP increases with age. Some studies also show higher mean levels for women than men, but not all do. The arbitrary nature of specifying upper limits of normality is stressed. In addition, the literature is reviewed concerning the arguments for a mixture of two overlapping normal (or lognormal) curves vs a continuum for the distribution of IOP.