Validity of a Personal and Family History of Cataract and Cataract Surgery in Genetic Studies

Abstract

purpose. To determine the accuracy of a history of cataract and cataract surgery (self-report and for a sibling), and to determine which demographic, cognitive, and medical factors are predictive of an accurate history.

methods. All participants in the Salisbury Eye Evaluation (SEE) project and their locally resident siblings were questioned about a personal and family history of cataract or cataract surgery. Lens grading at the slit lamp, using standardized photographs and a grading system, was performed for both SEE participants (probands) and their siblings. Cognitive testing and a history of systemic comorbidities were also obtained for all probands.

results. Sensitivity of a history of cataract provided on behalf of a sibling was 32%, specificity 98%. The performance was better for a history of cataract surgery: sensitivity 90%, specificity 89%. For self-report of cataract, sensitivity was also low at 55%, with specificity at 77%. Self-report of cataract surgery gave a much better performance: sensitivity 94%, specificity 100%. Different cutoffs in the definition of cataract had little impact. Factors predicting a correct history of cataract included high school or greater education in the proband (odds ratio [OR] = 1.13, 95% confidence interval [CI]1.02–1.25) and younger sibling (but not proband) age (OR = 0.94 for each year of age, 95% CI 0.90–0.99). Gender, race and Mini-Mental Status Examination (MMSE) result were not predictive.

conclusions. Whereas accurate self and family histories for cataract surgery may be obtainable, it is difficult to ascertain cataract status accurately from history alone.

Age-related cataract is the leading cause of blindness in the world today, ¹ and its surgical treatment is the most commonly performed procedure under Medicare, at an annual cost of $3.4 billion. ² At present, the underlying mechanisms of cataract are not well understood, and few if any effective strategies exist to prevent or delay its onset. ³ New evidence suggests that genetics may play an important role in determining who will be affected by age-related cataract, ^{4 5} and it is hoped that genetic studies may elucidate biochemical pathways that will lead eventually to new prevention strategies. As genetic investigations of other diseases of aging become more common and successful, ⁶ there is naturally much interest in studying multiple age-related diseases among the same set of individuals to maximize efficient use of resources. 

Age-related cataract is a sufficiently prevalent condition ⁷ that studies involving large groups of older persons not specifically selected for the cataract phenotype might still be expected to have significant power. The cataract phenotype can be characterized as a continuous variable, allowing even unaffected individuals to contribute useful information. Recent large epidemiologic studies of cataract have generally relied on specialized photographic equipment and highly trained observers to ascertain phenotype. ^{8 9} Large genetic studies of age-related cataract have generally taken a similar approach. ^{4 5 10} Clinical assessment of the lens without photographic documentation ¹¹ may be a less expensive option, but still requires specialized equipment and highly trained personnel. These approaches to defining the cataract phenotype, while insuring a high degree of reliability, are resource-intensive and may not be practical for studies of other age-related diseases that might seek to incorporate information on cataract. The question arises as to whether such rigorous direct ascertainment of phenotype is necessary for accurate genetic studies of cataract and whether an oral history of cataract might be of use. 

The present study focuses on a group of persons aged 72 years and more recruited for genetic studies of age-related cataract from an ongoing population-based study of aging and visual disabilities. ¹² Subjects were asked about a history of cataract and cataract surgery in themselves and in their locally resident siblings. These self-reports and family histories were then validated against lens grades. A number of demographic, cognitive, and medical factors were also studied as potential predictors of an accurate history. To the best of our knowledge, this is the first study to attempt to validate an oral history of cataract and cataract surgery in this fashion. 

Materials and Methods

The Salisbury Eye Evaluation (SEE) is a population-based study of the effects of aging on vision and visual disabilities, performed on the Eastern Shore of Maryland. ¹² As part of an on-going study of the genetics of age-related cataract, all participants in the SEE study, now aged 72 years and above, were administered a genetic history questionnaire at their most recent follow-up examination. Information was obtained regarding any siblings residing within 100 miles of either Salisbury, or Baltimore, Maryland. All SEE participants having one or more such siblings were then asked if the sibling had ever had cataract or cataract surgery in either eye. Details regarding personal history of cataract and cataract history of the family member were also obtained. The SEE participants then underwent examination at the slit lamp (model SL-5; Topcon America Corp., Paramus, NJ), with grading of the lens after pharmacologic dilation. The lenses were graded by a single experienced observer using photographic standards and the Wilmer Lens Grading System, which has been described. ⁸ Briefly, nuclear cataract was graded on a decimal scale from 0.0 to 4.0, with respect to four photographic standards. Cortical cataract was graded according to the portion of the lens involved in units of 1/16, and posterior subcapsular cataract (PSC) as present or absent. Blood samples were obtained for later genetic analysis, and permission was sought to contact locally resident siblings. 

Those siblings for whom permission was obtained to make contact were sent a letter describing the study, and a stamped, self-addressed postcard which they were to return to the study center if they did not wish to be contacted further. Those siblings from whom no postcard was received within 2 weeks were contacted by telephone, and a brief questionnaire administered to confirm their relationship to the SEE participant who had identified them as a sibling. The siblings were then invited to a central site in either Baltimore or Salisbury, where lens grades, a personal history of cataract and cataract surgery, and blood for genetic analysis as detailed earlier were obtained. Siblings were not asked about the cataract or cataract surgery history of the SEE participant (i.e., proband) to whom they were related. 

The specific text of the questions regarding cataract and cataract surgery follows: 

Probands.

“Has your sibling ever been diagnosed with cataract? Has your sibling ever had surgery for cataract?” (This question was asked separately for each sibling.) 

Probands and Siblings.

“Have you ever been told you have cataract? Have you ever had eye surgery? If yes, what type of surgery?” 

In addition to this information, the following data were obtained for both SEE participants and their siblings: age, race, gender, and number of current medications. Additional information obtained for SEE participants only included: medical history (including specific comorbidities and an overall comorbidity score), Mini-Mental State Examination ¹³ (MMSE) and educational history. A MMSE score of 18 or more had been a requirement for entry into the SEE study at baseline, 7 years earlier. Additional information for siblings included only a determination of their relationship to the SEE participant who had identified them (full sibling related by blood, half sibling, or not biologically related). 

The primary definition of cataract used in this study required the presence of one or more of the following in either eye: nuclear cataract grade 2 or higher (of a possible 4); cortical cataract 2/16 or higher; presence of any posterior subcapsular cataract (PSC), pseudophakia, or aphakia. A subject was determined to have had previous cataract surgery if either pseudophakia or aphakia was detected on slit lamp examination in either eye. The impact of different definitions of cataract was also examined (detailed later). 

Informed consent was obtained from all subjects before participation in any phase of this investigation. The protocol for this study adhered to the tenets of the Declaration of Helsinki and was approved by the Joint Committee for Clinical Investigation of the Johns Hopkins University School of Medicine before enrollment of any subjects. 

Statistical Methods

The t-test and χ² test were performed to determine significance of observed differences involving continuous and categorical variables, respectively. The logistic regression and generalized estimating equation (GEE) ¹⁴ model was used to evaluate the associations between demographic characteristics/clinical factors and the accuracy of recollection for cataract status. The level established for statistical significance was a two-tailed P < 0.05. Data process and analyses were performed on computer (SAS ver.8.2; SAS Institute, Inc., Cary, NC). 

Results

Figure 1 details enrollment and eligibility results for the ongoing study of cataract genetics on which the current report is based. Note that among the 436 SEE participants with one or more eligible siblings, 20 (5%) participants were excluded because the missing information on cataract. Therefore, this report is on a 416 persons in 159 sibships. The size distribution of these sibships is outlined in Table 1 . 

SEE participants were, on average, 5 years older than their siblings. Approximately 60% of both SEE participants and their siblings were female, and 23% of these sibships were black (Table 2) . Table 2 also outlines the educational, cognitive, and health status of the SEE participants. The majority (94.1%) of siblings indicated that they were full sibs to the SEE participant who had identified them, whereas 5.9% described themselves as half siblings. 

With regard to a history of cataract, neither a self report nor history on behalf of a sibling showed good validity when compared to lens grading. Self-report showed sensitivity of 55%, specificity of 77%, and a positive predictive value of 76%, whereas the corresponding figures for a sibling history were: sensitivity 32%, specificity 98%, and positive predictive value 95%. 

By contrast, a history of cataract surgery, whether provided on behalf of oneself or a sibling, was generally accurate. A self-reported cataract surgical history had a sensitivity of 94%, specificity of 100%, and positive predictive value of 100%. Cataract surgical history on behalf of a sibling performed nearly as well: sensitivity 90%, specificity 89%, and positive predictive value of 95%. 

To ascertain whether a change in the definition of cataract might improve the performance of self or sibling cataract history, we examined two alternative definitions. A more relaxed definition of cataract (nuclear grade, ≥1.5; cortical, ≥1/16, any PSC) lowered the sensitivity of a sibling history of cataract to 20%, while dropping specificity to 94%. The effect on validity of a self-reported history of cataract was similar. A more stringent cataract definition (nuclear grade ≥3.0, cortical ≥4/16, any PSC) raised the sensitivity of a sibling history to 49%, while lowering specificity to 96%. Again, the effect on self-reported history of cataract was similar. It appears that no change in the definition of cataract would significantly improve the validity of an oral cataract history with respect to direct examination of the lens. 

To determine which factors might be predictive of an accurate cataract or cataract surgical history, separate logistic regression and GEE models were created with a correct self or sibling history as an outcome variable respectively, and several demographic, cognitive, and medical factors as outlined in the Methods section as potential predictors. SEE participants with a high school or greater education were significantly more likely to provide an accurate cataract history on behalf of a sibling (odds ratio [OR]1.13, 95% confidence interval [CI] 1.02–1.25). The number of medications taken by a SEE participant was also predictive of a more accurate history on behalf of a sibling, although with borderline significance (OR of 1.11 for each additional medicine, 95% CI 1.00–1.23). 

Although a younger sibling age was predictive of a more accurate cataract history as obtained from the SEE participant (OR 0.94 for each year of age, 95% CI 0.90–0.99), the age of the SEE participant him- or herself was not significantly predictive. Other factors that were determined not to be predictive of an accurate history of cataract in behalf of self or sibling included: gender, race, presenting or best corrected visual acuity, systemic comorbidity score of the SEE participant, having visited an eye care professional within the past year; specific comorbidities including diabetes, hypertension, stroke, and Parkinson’s disease; and SEE participant’s score on the MMSE. 

Discussion

Oral histories have been validated as accurate and inexpensive tools in a number of areas of medicine, including screening for night blindness in vitamin A deficiency ¹⁵ and ascertaining cause of death in the so-called verbal autopsy. ¹⁶ The present study suggests that, in the area of cataract, an oral history has clear limitations. Although a history of previous cataract surgery related in behalf of oneself or a sibling is reliable, the validity of a personal or family history of cataract is questionable, whatever definition of cataract is used. This suggests that genetic studies among older persons that plan to include some assessment of cataract phenotype without investing the resources for slit lamp or photographic lens grading ought to rely on a personal and/or family history of cataract surgery. 

The main practical difficulty with such an approach would be the resultant impact on the study’s power. The prevalence of previous cataract surgery within a given population course depends on access to cataract surgical services and the age of the population. A recent meta-analysis ⁷ has estimated the prevalence of previous cataract surgery among U.S. residents older than 40 years as 5.1% in 2000, compared with an estimated prevalence of significant cataract in the same group of 17.2%. The proportion with previous cataract surgery is estimated to increase to 14.6% among persons aged 75 to 79 years and 29.2% for those aged 80 years and more. 

It appears that knowledge about the presence of cataract is not precise, even among this group of persons who are participating in an eye study and have regular contact, for the most part, with eye care providers. There may be several reasons for this: in contradistinction to night blindness, for example, cataract may or may not be symptomatic, depending on the degree of opacity and the particular visual needs of the subject. Moreover, even among eye care providers, the definition of cataract depends on imposing arbitrary cutoffs on an essentially continuous process, lens opacity. Finally, cataract is a slowly progressive condition, so that even persons with significant decrement in visual acuity may be less likely to notice the gradual change. 

The finding that higher educational attainment is predictive of a more accurate cataract history on behalf of a sibling is not unexpected. Younger age of a sibling was also correlated with a greater likelihood of an accurate cataract family history as provided by the SEE participant, perhaps because a diagnosis of cataract in a younger person would be more striking or memorable. It is more difficult to understand why the number of medications used by SEE participants would be predictive of an accurate cataract family history. The number of medications may perhaps best be understood as an index of the SEE participants’ accuracy of recollection, in the sense that subjects who were able to manage and recall more medications perhaps had a better grasp of medical details. 

It is also somewhat surprising that neither the SEE participants’ mental status nor their overall comorbidity score was predictive of the accuracy of their cataract history. This is probably in part because persons with significant dementia were excluded from the study at baseline, thus decreasing the chances that an association between mental status and accuracy of history would be observed. Similarly, this group of participants, all of whom have maintained sufficient mobility to participate in a longitudinal study over 7 years, may in fact be somewhat less likely to reveal associations between the burden of medical comorbidity and ability to provide an accurate history. Finally, the same may be true of visual acuity: only 6.8% of probands had best corrected visual acuity of less than 20/40. It may be that studies including more participants with significant cognitive, physical, and visual disabilities would be more likely to reveal such associations. 

 Supported by National Institute of Aging Grant AG16294 (NGC); a National Institutes of Health Career Development Award K-23 EY00388 (NGC), and a Research to Prevent Blindness Career Development Award (NGC).

 Submitted for publication October 14, 2002; revised March 3, 2003; accepted March 5, 2003.

 Disclosure: H. Bowie, None; N.G. Congdon, None; H. Lai, None; S.K. West, None

 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.

 

Figure 1.

 

Flow chart showing the recruitment of subjects for the SEE study of cataract genetics.

Table 1.

 

Sibship Sizes for Families Participating in the Current Study

Sibship size	Sibships (n)	Subjects (n)
Two	94	188
Three	42	126
Four	17	68
Five	4	20
Six	0	0
Seven	2	14
Total	159	416

Table 2.

 

Characteristics of SEE Participants and Their Siblings

Characteristic	SEE Participants	Siblings	P *
Age (y± SD)	76.8±3.8	71.7±7.7	<0.001
Gender (% female)	60.6%	60.6%	1.0
Race (% black)	22.7%	22.7%	1.0
Education (y± SD)	10.9±3.4	, †	—
MMSE score (± SD)	26.5±28	, †	—
Number of comorbidities (Median)	3	, †	—
Eye care visit in the past year?	72.7%	, †	—