Cataract extraction with multifocal intraocular lens implantation: clinical, functional, and quality-of-life outcomes. Multicenter clinical trial in Germany and Austria.

PURPOSE: To compare bilateral implantation of a multifocal intraocular lens (IOL) versus a monofocal lens with respect to visual function, patient satisfaction, and quality of life. SETTING: Seven clinical sites in Germany and 1 site in Austria. METHODS: A prospective randomized masked clinical trial included 124 randomly assigned bilateral pseudophakic individuals, 64 of whom had bilateral implantation of an Array(R) foldable multifocal IOL (model SA-40N, Allergan) and 60 of whom had bilateral implantation of an AMO(R)PhacoFlex II(R) silicone monofocal IOL (model SI-40NB). Clinical data included binocular uncorrected and corrected distance and near visual acuities, complications, adverse events, and reports of halos and glare. Quality-of-life data were collected on 3 occasions using the modified Cataract TyPE Specification instrument. The functional status of the 2 groups was compared from baseline to final postoperative interview. RESULTS: Three months after surgery, a higher proportion in the Array group achieved a Jaeger value of J3 (20/40 Snellen) or better uncorrected binocular near visual acuity and 0.5 (20/40) or better distance-corrected binocular near visual acuity than in the monofocal groups (97% versus 68% and 95% versus 59%, respectively; P <.001). A higher proportion in the multifocal group achieved both 0.5 (20/40) and J3 or better uncorrected binocular distance and near visual acuities (97% versus 66%; P <.001). Those in the Array group were more likely than those in the monofocal group to never wear glasses overall (41% versus 12%; P <.001). Multifocal patients rated their vision without glasses better overall, at near and at intermediate distances (P <.05), and demonstrated better visual function for near tasks and social activities. CONCLUSIONS: Those who had bilateral implantation of the Array multifocal IOL obtained better uncorrected and distance-corrected near visual acuities and reported better overall vision, less limitation in visual function, and less spectacle dependency than patients with bilateral monofocal IOLs.

Comparison of the clinical success rates and quality of life effects of brimonidine tartrate 0.2% and betaxolol 0.25% suspension in patients with open-angle glaucoma and ocular hypertension. Brimonidine Outcomes Study Group II.

PURPOSE: To compare the clinical effectiveness and the impact on quality of life of twice-daily brimonidine 0.2% with those of twice-daily betaxolol 0.25% in patients with glaucoma or ocular hypertension. METHODS: A prospective, double-masked, randomized, comparative, multicenter, 4-month "real-life" clinical trial involving 188 patients. Medications were instilled twice daily. Efficacy was determined through measurement of intraocular pressure; safety and tolerability were measured using reports of adverse events, a quality of life survey (Glaucoma Disability Index), heart rate, and blood pressure. Patients with an inadequate response in intraocular pressure after 1 month or those who experienced significant adverse events in the first month were switched to the alternative study arm and remained taking the alternative medication for a total of 4 months or left the study. The main outcome measure was clinical success, as determined by evaluation of the efficacy, safety, and tolerability of drug treatment, and was achieved when the investigator recommended that the patient continue the treatment after completion of the study. RESULTS: As initial therapy, clinical success was achieved in 74% of patients treated with brimonidine, as compared with 57% of patients treated with betaxolol (P = 0.027). The overall mean decrease in intraocular pressure from baseline was 5.9 mm Hg with brimonidine and 3.8 mm Hg with betaxolol. Both treatments were well tolerated, and there were no significant between-group differences in the incidence of adverse events or in the quality of life summary scores. CONCLUSIONS: Twice-daily brimonidine 0.2% and betaxolol 0.25% suspension were safe and effective as first-line therapy for glaucoma and ocular hypertension. In this study, brimonidine showed clinical effectiveness superior to that of betaxolol.

Cataract extraction with multifocal intraocular lens implantation: a multinational clinical trial evaluating clinical, functional, and quality-of-life outcomes.

OBJECTIVE: Two million cataract extractions are performed annually in the United States. The procedure is nearly always accompanied by implantation of a monofocal intraocular lens (IOL), which corrects the patient's distance vision. The authors' objective was to measure visual function and quality-of-life outcomes associated with bilateral implantation of a multifocal IOL, which corrects distance and near vision, and to compare the outcomes with those of the standard therapy. DESIGN: A prospective, randomized, double-masked, clinical trial was conducted at eight sites in the United States, seven sites in Germany, and one site in Austria. PARTICIPANTS: Participants included 245 cataract patients, 127 of whom received the multifocal IOL bilaterally and 118 of whom received a monofocal IOL of nearly identical construction bilaterally. METHODS: Clinical data included visual acuity (VA), complications, and adverse events. Quality-of-life data were collected using a previously validated survey instrument at baseline, after first eye surgery, and after second eye surgery. RESULTS: At 3 months after surgery, patients who had received multifocal IOLs had significantly better uncorrected and distance corrected binocular near VA compared with patients who had received monofocal IOLs (mean uncorrected VA, 20/26 multifocal vs. 20/40 monofocal; mean distance corrected VA, 20/28 multifocal vs. 20/45 monofocal; P < 0.0001). Additionally, 96% of patients who had received multifocal IOLs and 65% of patients who had received monofocal IOLs achieved both 20/40 and J3 (Jaeger) or better uncorrected, binocular distance and near visual acuities (P < 0. 0001). Patients who had received multifocal IOLs were more likely than patients who had received monofocal IOLs to never wear glasses overall (32% multifocal vs. 8% monofocal; P < 0.0001). On a 4-point scale, patients who had received multifocal IOLs on average reported having between "a little bit" and "some" glare or halo, whereas patients who had received monofocal IOLs reported between "none" and "a little bit" of glare or halo (1.57 vs. 0.43; P < 0.001). Patients who had received multifocal IOLs rated their vision without glasses better overall at near and at intermediate distances (P < or = 0.002) and demonstrated better visual function for near tasks and social activities. CONCLUSIONS: Cataract patients who received multifocal IOLs at time of surgery obtained better uncorrected and distance corrected near VA and reported better overall vision, less limitation in visual function, less spectacle dependency, and more glare or halo than those who received traditional monofocal IOLs.

Clinical success and quality of life with brimonidine 0.2% or timolol 0.5% used twice daily in glaucoma or ocular t hypertension: a randomized clinical trial. Brimonidine Outcomes Study Group I.

PURPOSE: To compare the clinical success rates and quality of life impact of brimonidine 0.2% with timolol 0.5% in newly diagnosed patients naive to glaucoma therapy. METHODS: A prospective, multicenter, randomized, double-masked, clinical effectiveness trial in which the clinical outcomes of twice daily brimonidine tartrate 0.2% were compared with those of timolol maleate 0.5% in patients with glaucoma and' ocular hypertension was conducted. Two hundred nineteen patients were enrolled--111 in the brimonidine group and 108 in the timolol group. Patients instilled their study medications twice daily for 4 months. Factors for determining clinical success were reduction of intraocular pressure (IOP), safety, and adverse events. Quality of life effects were assessed with the SF-36 Health Survey and Glaucoma Disability Index questionnaires. RESULTS: Clinical success was 71% (75/106) with brimonidine and 70% (73/105) with timolol as initial treatment. The overall mean decrease in IOP was 6.5 mm Hg with brimonidine and 6.2 mm Hg with timolol. Few patients reported a specific adverse event and, with the exception of a slightly higher rate of ocular burning and stinging in the brimonidine group, there were no significant between-group differences. No significant chronotropic effects on the heart were seen with brimonidine, while small but significant mean decreases in heart rate were seen at months 1 and 4 with timolol. Mean systolic and diastolic blood pressure remained relatively stable in both groups. Quality of life remained stable, with no significant between-group differences. CONCLUSIONS: As a first-line agent for the treatment of glaucoma and ocular hypertension, brimonidine has clinical effectiveness equivalent to timolol, but with less chronotropic effect on the heart. Brimonidine is a viable alternative to timolol for first-line therapy in glaucoma and ocular hypertension.

Preference values for visual states in patients planning to undergo cataract surgery.

To assess how preference values that cataract surgery patients assign to their preoperative visual states relate to visual acuity and problems in specific aspects of daily life, the authors interviewed 47 patients scheduled to have cataract surgery. Using a rating-scale technique with a scale from 0 (death) to 1 (excellent health), the patients had a mean preference value of 0.68 for their preoperative vision. Patients' preference values for their preoperative vision were more closely related to problems in specific aspects of daily life (especially feelings of depression and problems interacting with people) than to visual acuity in the operative eye, better eye, or worse eye, or a weighted average of visual acuities in both eyes. These results provide a rationale for relying more on patients' views about the effects of visual impairment than on measures of visual acuity when assessing the need for cataract surgery.

Racial variations in treatment for glaucoma and cataract among Medicare recipients.

PURPOSE: To identify the location of barriers to treatment for glaucoma and cataract among African-American Medicare beneficiaries. METHODS: We examined the receipt of eye care in general and care for glaucoma and cataract in particular among black and white Medicare beneficiaries using 1991 Medicare physician claims data. Racial differences in treatment for glaucoma and cataract were examined both for the Medicare population as a whole and for identified eye care users. The results were compared to the expected value of black-white difference based on population prevalence data for each specific condition. RESULTS: Thirty percent of black beneficiaries and 45% of white Medicare beneficiaries used eye care services in 1991. After adjusting for the expected difference in prevalence, black beneficiaries were half as likely to be surgically treated for glaucoma compared to white beneficiaries, and 80% as likely for cataract. When the analysis was restricted to those using eye care services, blacks continued to have lower than expected rates of treatment for glaucoma (observed RR = 3.2, 95% confidence interval = 3.1-3.4 vs an expected RR of 4.3, 95% confidence interval = 3.5-5.4), but a higher rate of treatment for cataract (RR = 1.2, 95% confidence interval = 1.2-1.3). Among those with physician-diagnosed glaucoma and cataract, blacks were more likely to undergo surgical treatment for these conditions than whites (RR = 1.5 for glaucoma, 95% confidence interval = 1.4-1.5; RR = 1.2 for cataract, 95% confidence interval = 1.2-1.3). CONCLUSION: Barriers to treatment for glaucoma and cataract among black Medicare beneficiaries involve primarily limitations in access to the eye care system. The undertreatment for glaucoma among black beneficiaries was reduced, but not eliminated, after removing the effect of unequal access to the eye care system.

Model of complications of NIDDM. I. Model construction and assumptions.

OBJECTIVE: To develop a model of NIDDM for analyzing prevention strategies for NIDDM. RESEARCH DESIGN AND METHODS: A Markov type model with Monte Carlo techniques was used. Age, sex, and ethnicity of cohort was based on U.S. data. Incidence rates of complications were also based on community and population studies. RESULTS: Nonproliferative retinopathy, proliferative retinopathy, and macular edema are predicted in 79, 19, and 52%, respectively, of people with NIDDM; 19% are predicted to develop legal blindness. Microalbuminuria, gross proteinuria, and end-stage renal disease related to diabetes are predicted in 53, 40, and 17%, respectively. Symptomatic sensorimotor neuropathy and lower-extremity amputation are predicted in 31 and 17%, respectively. Cardiovascular disease is predicted in 39%. Higher rates of complications (1.1-3.0x) are predicted in minority populations. Predicted average life expectancy is 17 years after diagnosis. CONCLUSIONS: A probabilistic model of NIDDM predicts the vascular complications of NIDDM in a cohort representative of the incident cases of diabetes in the U.S. before age 75 years. Predictions of complications and mortality are consistent with the known epidemiology of NIDDM. The model is suitable for evaluating the effect of preventive interventions on the natural history of NIDDM.

Model of complications of NIDDM. II. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia.

OBJECTIVE: To analyze the health benefits and economics of treating NIDDM with the goal of normoglycemia. RESEARCH DESIGN AND METHODS: Incidence-based simulation model of NIDDM was used. Hazard rates for complications were adjusted for glycemia using risk gradients from the Diabetes Control and Complications Trial. Treatment costs were estimated from national survey data and clinical trials. Incremental costs and benefits were expressed in present value dollars (3% discount rate). Life-years were adjusted for quality of life, yielding quality-adjusted life-years (QALYs). RESULTS: Comprehensive treatment of NIDDM that maintains an HbA1c value of 7.2% is predicted to reduce the cumulative incidence of blindness, end-stage renal disease, and lower-extremity amputation by 72, 87, and 67%, respectively. Cardiovascular disease risk increased by 3% (no effect of treating glycemia is assumed). Life expectancy increased 1.39 years. The cost of treating hyperglycemia increased by almost twofold, which is partially offset by reductions in the cost of complications. The estimated incremental cost/QALY gained is $16,002. Treatment is more cost-effective for those with longer glycemic exposure (earlier onset of diabetes), minorities, and those with higher HbA1c under standard care. CONCLUSIONS: The incremental effectiveness of treating NIDDM with the goal of normoglycemia is estimated to be approximately $16,000/QALY gained, which is in the range of interventions that are generally considered cost-effective.

Outcomes of cataract extraction with multifocal intraocular lens implantation: functional status and quality of life.

OBJECTIVE: The authors measured functional status after bilateral implantation of a multifocal versus a monofocal intraocular lens (IOL). METHODS: A retrospective, case-control study was done on 100 subjects implanted bilaterally with a silicone-optic foldable zonal progressive IOL under United States Food and Drug Administration Investigational Device Exemption protocol and 103 control subjects implanted bilaterally with a monofocal IOL of similar design who were matched on age and postoperative corrected distance acuity. The Cataract TyPE specification, a 17-item functional status instrument, was modified, validated, and administered via telephone interview. The measures of vision, functional status, and quality of life were compared between patients and controls. RESULTS: The instrument was valid (Cronbach's alpha = 0.94) and correlated moderately (Pearson's r= 0.34) with Snellen acuity. Multifocal subjects were more likely than monofocal controls to never wear spectacles (41% vs. 11.7%; P < 0.001). Multifocal subjects rated their vision without spectacles significantly better than those with monofocal IOLs (9.0 vs. 7.9; P < 0.001). The difference was most significant in rating of near vision without spectacles (7.8 vs. 5.0; P < 0.001). Multifocal subjects reported less limitation in specific visual tasks without spectacles (0.3 vs. 0.8; P < 0.001, where 1.0 represents "slightly" limited). This difference was consistently observed in subscales related to distance vision activities (0.1 vs. 0.4; P < 0.001), near vision activities (0.6 vs. 1.4; P < 0.001), and social activities (0.1 vs. 0.6; P < 0.001). CONCLUSIONS: In this study, subjects with bilateral multifocal IOLs reported better overall vision, less limitation in visual function, and less spectacle usage than monofocal controls.

Risk of endophthalmitis after cataract extraction: results from the International Cataract Surgery Outcomes study.

AIM: To estimate risk of infectious endophthalmitis after cataract extraction in Denmark and to compare results with the risk of this complication in the USA. METHODS: In the national Danish administrative hospital register, 19,426 patients were identified who underwent first eye cataract surgery from 1985 to 1987 and who were 50 years of age or older. Of these, 61 patients had postoperative endophthalmitis. RESULTS: A 12 month cumulative risk of rehospitalisation for endophthalmitis was estimated at 0.18% (95% CI 0.09-0.26) after extracapsular cataract extraction with lens implant. Advanced age, male sex, intracapsular cataract extraction, and anterior vitrectomy were all associated independently with an increased risk of postoperative endophthalmitis. When restricting the sample to patients aged 65 years or older, in order to allow comparisons to be made with the US National Study of Cataract Outcomes, a 12 month risk of 0.17% (95% CI 0.08-0.25) was estimated. The previously reported US risk of 0.12% is included in the confidence interval of the risk estimated in the Danish sample. CONCLUSION: Despite considerable differences in the healthcare systems, no statistically significant difference in outcome of surgery as measured by risk of endophthalmitis was shown between Denmark and the USA.

Atherosclerotic disease in patients undergoing cataract extraction. A nationwide case-control study. The Cataract Patient Outcomes Research Team.

OBJECTIVE: To evaluate the association between cataract extraction and atherosclerosis and its complications. DESIGN: A nationwide case-control study. SETTING AND PARTICIPANTS: Using a 5% random sample of all Medicare beneficiaries, we analyzed Medicare claims data on 60803 persons 65 years of age and older who underwent cataract extraction in 1986 or 1987 and a control group of 63765 persons matched to the cases for age, race, sex, ZIP code, and reason for Medicare entitlement. MAIN OUTCOME MEASURE: Atherosclerosis and atherosclerosis-related disease and procedures were defined by International Classification of Diseases, Ninth Revision, Clinical Modification, codes or by Health Care Financing Administration Common Procedure Classification System (Current Procedural Terminology) codes. The strength of evidence for atherosclerotic disease was categorized on the basis of the types of bills in the Medicare claims file. RESULTS: Odds of atherosclerosis-related morbidity and procedures were higher for cases than for controls. The association decreased with patient age and was strongest in beneficiaries aged 65 to 69 years (odds ratio, 1.30; 95% confidence interval, 1.13-1.48). CONCLUSION: Our findings suggest that there is a weak association between a visually significant cataract requiring surgery and atherosclerosis in the younger elderly.

The cause-specific prevalence of visual impairment in an urban population. The Baltimore Eye Survey.

BACKGROUND: Whereas population-based data on the causes of bilateral blindness have been reported, little information is available on the distribution of causes of central vision loss less severe than the criteria used to define legal blindness. This visual impairment is responsible for a high proportion of eye care service use and results in important reductions in functional status. METHODS: Data from the Baltimore Eye Survey were used to estimate the cause-specific prevalence of visual impairment (best-corrected visual acuity worse than 20/40 but better than 20/200) among black and white residents of east Baltimore who were 40 years of age or older. Eligible subjects underwent a screening examination at a neighborhood location and, for those whose best-corrected visual acuity was less than 20/30, a definitive ophthalmologic examination at the Wilmer Eye Institute. RESULTS: The prevalence of visual impairment was 2.7% in whites and 3.3% in blacks; the age-adjusted relative prevalence (B/W) was 1.75 (P = 0.01). The leading causes of visual impaired eyes were cataract (35.8%), age-related macular degeneration (14.2%), diabetic retinopathy (6.6%), glaucoma (4.7%), and other retinal disorders (7.3%). Cataract, diabetic retinopathy, and glaucoma were more common as a cause of visual impairment among blacks, whereas macular degeneration was more frequent among whites. More than 50% of all subjects had the potential for improvement in vision with appropriate surgical intervention. CONCLUSION: Visual impairment is a prevalent condition among inner city adults 40 years of age or older. The distribution of causes suggests that improvements in the visual health of the population could be achieved with more effective delivery of efficacious ophthalmologic care.

Eye care for elderly Americans with diabetes mellitus. Failure to meet current guidelines.

PURPOSE: The purpose of the study is to understand current pattern of eye care use among people with diabetes. METHODS: Study population included 175,015 Medicare beneficiaries who had physician-diagnosed diabetes. The authors estimated overall rate of eye care visits among these beneficiaries in 1992 and 1993 using Medicare physician claims data. In combination of Area Resource File, the authors examined association of eye care use with demographic characteristics, regional socio-economic characteristics, and regional eye care provider supply. RESULTS: Fifty-three percent of the population had at least 1 eye care visit in a 1-year period and 67% in a 2-year period. Younger age (ages < 75 years), male gender, black race, high regional poverty, and fewer ophthalmologist supply were related to lower rate of eye care use. There was no association between eye care use and regional education level and optometrist supply. CONCLUSION: The findings suggest that a large portion of elderly people with diabetes is not obtaining the necessary eye care, especially blacks, men, and those residing in poor areas with fewer ophthalmologists.

Risk factors for retinal detachment after cataract surgery. A population-based case-control study.

PURPOSE: Previous analyses of Medicare claims data, as well as clinical series, have suggested that performance of neodymium:YAG (Nd:YAG) laser posterior capsulotomy after extracapsular cataract surgery increases significantly the risk of retinal detachment. However, methodologic problems with previous research limit the strength of conclusions that can be drawn from these earlier studies. This study was designed to resolve those methodological limitations while using a population-based approach for assessment of the independent association between the performance of Nd:YAG laser posterior capsulotomy and pseudophakic retinal detachment. METHODS: A nested case-control study was conducted. Medicare beneficiaries who had undergone extracapsular cataract extraction from 1988 to 1990 were identified from a 5% sample of Medicare claims data. Within this cohort, people who were diagnosed or treated for retinal detachment during the years 1988 through 1991 (cases) were identified from Medicare records. Four controls were matched to each case of retinal detachment using an incidence density design. Providers of the patients' cataract and retinal surgery were contacted and asked to provide clinical data for all cases and controls that they had treated. RESULTS: Seven hundred six cases of retinal detachment were originally identified from Medicare records. After exclusions due to ineligibility, a total of 291 cases and 870 matched controls were available for analysis. Conditional logistic regression models showed that a number of factors were associated independently with an excess risk of retinal detachment after cataract surgery. These included Nd:YAG laser capsulotomy (odds ratio [OR] = 3.8; 95% confidence interval [CI], 2.4-5.9), a history of retinal detachment (OR = 2.7; 95% CI, 1.2-6.1), a history of lattice degeneration (OR = 6.6; 95% CI, 1.6-27.1), axial length (OR = 1.21/mm; 95% CI, 1.03-1.43), refractive error (OR = 0.92/diopter; 95% CI, 0.88-0.95), and a history of ocular trauma after cataract surgery (OR = 6.1; 95% CI, 4.3-28.2). CONCLUSION: Performance of Nd:YAG laser posterior capsulotomy is associated with a significantly elevated risk of retinal detachment in patients who have undergone extracapsular cataract extraction. Other independent risk factors for retinal detachment include axial length, myopia, posterior capsular rupture during surgery, history of retinal detachment or lattice degeneration, and ocular trauma after cataract surgery.

Postoperative management of cataract surgery patients by ophthalmologists and optometrists.

OBJECTIVES: To assess the frequency and content of post-operative examinations by ophthalmologists and optometrists for cataract surgery patients without operative complications and to assess the referral patterns of optometrists when complications are identified. DESIGN: In 1992 we conducted a survey of randomly selected members of the American Academy of Ophthalmology and American Optometric Association. Responses were obtained from 538 (82%) of 655 eligible ophthalmologists and 130 (84%) of 154 eligible optometrists. RESULTS: Eighty-eight percent of responding ophthalmologists reported that patients had 4 or more visits within 4 months after surgery, 97% of ophthalmologists performed the first postoperative examination on their cataract surgery patients, and 60% of ophthalmologists reported that no other eye professional saw their patients postoperatively. Forty-six percent of responding optometrists participated in postoperative care of cataract surgery patients, and usually performed their first postoperative examination 7 days after surgery; 78% of these optometrists reported that they saw patients 3 or more times after surgery. Postoperatively, 83% of ophthalmologists and 75% of optometrists usually performed at least 1 dilated fundus examination, 87% of ophthalmologists and 47% of optometrists performed 4 or more slit-lamp examinations, 74% of ophthalmologists and 42% of optometrists performed 4 or more tonometry tests, and 83% of both groups performed 2 or more refractions. More than 80% of responding optometrists involved in postoperative care of cataract surgery patients immediately refer a patient to an ophthalmologist if there is evidence of acute glaucoma or an unexplained decrease in vision in the eye that was operated on. For less urgent complications, most optometrists promptly make a referral to an ophthalmologist. CONCLUSIONS: In 1992, a small percentage of ophthalmologists and optometrists were performing fewer follow-up examinations and tests for cataract patients than recommended by the American Academy of Ophthalmology. Not all optometrists immediately refer to an ophthalmologist any acute complication that they identify postoperatively.

Risk of retinal detachment following cataract extraction: results from the International Cataract Surgery Outcomes Study.

AIMS: To estimate the risk of retinal detachment (RD) following cataract extraction in Denmark, and to compare the risk with that following cataract extraction in the USA, and with that in a sample of Danish patients who did not have ocular surgery. METHODS: A sample was created from the administrative Danish Hospital Register and included 19,252 patients who underwent first eye cataract surgery between 1985 and 1987, and who were 50 years of age or older. The patients were then followed for 4-6 years using the register data. The design and definition of events were identical to the US National Study of Cataract Outcomes. RESULTS: In Denmark a 4 year cumulative risk of hospitalisation for RD of 0.93% (95% confidence interval (CI) 0.71-1.16) was observed following an extracapsular cataract extraction with a lens implant. A similar cumulative risk of RD was reported from the US study. Thus, no difference in outcomes concerning risk of RD was shown between Denmark and the USA. In a multivariate analysis younger age, male sex, and intracapsular cataract extraction were all associated with higher risk of postoperative RD. A reference group of 7636 people not undergoing any ocular surgery was created and the incidence of RD in this group was calculated. During the sixth year following cataract surgery, the incidence of RD in the cataract group was still 7.5 (95% CI 1.6-22.0) times higher than that observed in the reference group.