Predicting extended wear complications from overnight corneal swelling.

PURPOSE: To examine the hypothesis that the corneal overnight swelling response (ONSR) is a predictor of ocular complications in contact lens extended wear (EW). METHODS: The Berkeley Contact Lens Extended Wear Study (CLEWS) was a randomized, concurrently controlled clinical trial in which more than 200 subjects in EW with rigid gas-permeable (RGP) lenses were observed for 1 year. After adapting to EW, subjects were randomized to either medium or high oxygen-permeable (Dk) RGP lenses and underwent clinical assessments, keratometry, and corneal pachometry at 3-month intervals. RESULTS: The ONSR was directly related to lens Dk (P = 0.01) and exhibited substantial variability across subjects. The probability of remaining free of complications over time was not significantly lower for subjects with a mild ONSR compared with those with greater edema (P = 0.84). The risk of development of keratopathy was not significantly related to the ONSR (relative risk = 1.00). CONCLUSIONS: The corneal ONSR is not a good predictor of ocular complications in 1 year of RGP EW. Lenses that cause little or no corneal edema are not necessarily safer for overnight wear.

The Berkeley Contact Lens Extended Wear Study. Part I : Study design and conduct.

OBJECTIVE: The primary aim of the Berkeley Contact Lens Extended Wear Study (CLEWS) was to test the hypotheses that extended wear of rigid gas-permeable (RGP) contact lenses with greater oxygen permeability (Dk) reduces the incidence of contact lens-associated keratopathy (CLAK) and increases the survival rate in RGP extended wear (EW). In this article we describe the clinical trial design in detail, present the results of subject recruitment and retention, and provide the baseline demographic and ocular characteristics of the CLEWS subjects, whose data will be analyzed to address the study aims in a companion article. DESIGN: A randomized, concurrently controlled clinical trial. INTERVENTION: Subjects were fitted with day wear (DW) high-Dk RGP lenses and then adapted to EW. Subjects who adapted to EW were then randomly assigned to either high- or medium-Dk RGP lenses for 12 months of 6-nights/week EW. MAIN OUTCOME MEASURES: Slit-lamp assessment and grading of 17 possible keratopathies, measurement of refractive error and corneal curvature, and symptoms. Follow-up data were collected every 3 months. RESULTS: From 545 subjects entering the DW adaptation phase, 201 adapted to EW and were randomly assigned to medium- or high-Dk lenses for 12 months of EW. The baseline characteristics of the two study groups were similar and did not differ from the 344 DW subjects who failed to adapt to EW. The distributions of oxygen transmissibility for the two study groups were disjoint, indicating that each group received distinctly different levels of hypoxia. CONCLUSIONS: We show that CLEWS was appropriately designed to address the study hypotheses, was conducted with regard for the safety of the subjects, and adhered to rigorous protocols designed to control for bias and ensure the integrity of study data. We establish the internal validity of between-group statistical comparisons and characterize our study population to permit informed evaluation of the applicability of our results to the contact lens-wearing population in general.

The Berkeley Contact Lens Extended Wear Study. Part II : Clinical results.

OBJECTIVE: To describe the principal clinical outcomes associated with 12 months use of rigid gas-permeable (RGP) extended wear contact lenses and address two primary study questions: (1) does extended wear (EW) of high oxygen transmissibility (Dk/t) RGP lenses reduce the incidence of ocular complications, and (2) does the wearing of high-Dk/t lenses reduce the rate of failure to maintain 6-night RGPEW over 12 months? DESIGN: A randomized, concurrently controlled clinical trial. INTERVENTION: Subjects who adapted to EW with high Dk (oxygen permeability) RGP lenses were randomized to either high Dk or medium-Dk RGP lenses for 12 months of 6-night EW. MAIN OUTCOME MEASURES: Contact lens-associated keratopathies (CLAK), changes in refractive error and corneal curvature, and survival in EW. RESULTS: Two hundred one subjects were randomized to medium or high-Dk lenses for 12 months of EW. Sixty-two percent of the subjects in each group completed 12 months of EW; however, the probability of failure was significantly greater for the medium-Dk group. Although the risk of complications was similar for the two groups, the number of CLAK events that led to termination were 16 versus 5 for the medium-Dk and high-Dk groups, respectively. This suggests that the type of adverse response or the inability to reverse an adverse event was different for the group being exposed to the lower oxygen dose. CONCLUSIONS: The level of oxygen available to the cornea has a significant impact on maintaining successful RGP extended contact lens wear, but not on the initial onset of CLAK. The number of clinical events leading to termination was substantially higher for the medium Dk group, which suggests that corneal hypoxia is an important factor in the development of CLAK. Although overnight contact lens wear should be recommended with caution and carefully monitored for early detection of ocular complications, it appears that high-Dk RGP lenses can be a safe and effective treatment for correction of refractive error for most individuals who can adapt to EW.

Cofactors for HIV disease progression in a cohort of homosexual and bisexual men.

To evaluate cofactors for progression of HIV infection, the authors identified 370 men with well-defined seroconversion dates and cofactor data among participants in the San Francisco City Clinic Cohort (SFCCC). Postseroconversion substance use, sexual behavior, and sexually transmitted diseases were assessed using multivariate proportional hazards models. Weekly use of hallucinogens strongly and independently predicted death (relative hazard [RH], 2.59; 95% confidence interval [CI], 1.56-4.28), as well as diagnosis of AIDS; weekly cocaine use also predicted mortality. Receptive anal intercourse with ejaculation was independently associated with mortality risk (RH, 1.45; 95% CI, 1.02-2.04) and AIDS. The associations of accelerated progression with weekly use of recreational drugs and unprotected receptive anal intercourse need to be confirmed in other prospective cohorts.

Predicting RGP daily wear success.

PURPOSE: While most clinicians agree that fitting of rigid gas permeable (RGP) lenses is the preferred treatment strategy for some types of patients, many patients have difficulty adapting to full-time daily wear of these lenses. The Contact Lens Extended Wear Study (CLEWS) is a randomized, controlled clinical trial in which subjects are first adapted to full-time RGP daily wear prior to randomization to either high or medium oxygen transmissibility (Dk/L) RGP lenses for 12 months of extended wear. The CLEWS pre-randomization data provide an opportunity to examine the reasons some patients fail to adapt to RGP daily wear and to determine whether a patient's demographic, historical, and ocular characteristics can be used to predict RGP daily wear success. METHODS: From 1,809 individuals who expressed interest in RGP lenses, 411 subjects passed the CLEWS screening criteria and were fit with high Dk lenses (mean Dk = 92 x 10(-11) [cm2/sec][mL 02/mL x mmHg]). The fitting strategy included minimum apical alignment, lid attachment, centration, and average lens diameters of 9.2 mm. Success was defined as a minimum of 14 hours per day without adverse ocular responses that would contraindicate either full-day daily wear or extended wear. RESULTS: Of the 411 subjects, 286 (69.6%) were successful with RGP extended wear. Among the 125 failures, 50 were based on clinician findings (e.g., cornea, vision, compliance), while 75 subjects chose to discontinue wear because of unacceptable comfort or poor vision. Multivariate linear logistic regression modeling shows that younger patients with greater corneal curvature (K) and less predicted residual astigmatism have a higher probability of RGP daily wear success. CONCLUSIONS: Our study showed that RGP lenses can be fit with a relatively high rate of success and that many of those patients who elect to discontinue RGP daily wear report unacceptable comfort as the primary reason. We propose a Bayesian statistical method that will assist clinicians in selecting those candidates for RGP daily wear who are most likely to adapt successfully.

The repeatability of automated and clinician refraction.

PURPOSE: Auto-refractors are used as a starting point for clinicians' refractions and in studies of refractive error. We investigated the repeatability of the Hoya AR-570 and clinician refraction. METHODS: Eighty-six subjects, aged 11 to 60 years, were recruited by mailing inquiries to 500 randomly selected patients who had received recent examinations at the University of California Optometric Eye Center. Contact lens wearers, patients with best corrected visual acuity worse than 20/30 in either eye, and patients with a history of diabetes were excluded. Each subject was examined by two clinicians during one visit. The first clinician obtained five auto-refractor readings for each eye (which were later averaged), performed a balanced subjective refraction (with spherical masking lenses in the phoropter), and repeated the automated refractor measurements. This protocol was then repeated by the second clinician. Clinicians were randomized with regard to testing order and masked to automated refractor results, each other's refractions, and previous spectacle prescriptions. RESULTS: To quantify repeatability, we used mixed model analyses of variance to estimate the appropriate variance components while accounting for the correlation among, for example, repeated measurements of the same eye. Astigmatic data were analyzed by converting into Fourier form: two cross-cylinders at axis 0 degrees (J0) and axis 45 degrees (J45). For mean spherical equivalent, the average difference between five averaged automated refractor readings, taken by two different optometrists, was +0.02 D (95% limits of agreement = -0.36 to +0.40 D). The average difference between the two optometrists' subjective refractions was -0.12 D (95% limits of agreement = -0.90 to +0.65 D). The 95% limits of agreement for the automated refractor were about half those of the clinician for both astigmatic terms (J0 and J45) and for all comparisons. CONCLUSIONS: Automated refraction is more repeatable than subjective refraction and therefore more appropriate for studies of myopia progression.

Epithelial permeability reflects subclinical effects of contact lens wear.

AIMS: Recently, it was reported by the authors that a single drop fluorophotometric technique for estimating corneal epithelial permeability (Pde) to fluorescein is not sufficiently precise for monitoring permeability changes in individual patients., but may be useful for evaluating mean differences in Pdc in population based research. To determine whether this technique provides a more sensitive index of epithelial integrity compared with conventional clinical assessments, the effects of mild corneal trauma on Pdc, the slit lamp appearance of the cornea, and corneal thickness (CT) were assessed. METHODS: After baseline slit lamp examinations (SLE) and CT measurements, one randomly chosen eye of each of 32 normal subjects underwent 1 hour of closed eye soft contact lens (CL) wear while the fellow eye served as a control (no CL). After removing the CL, the SLE and CT measurements were repeated. Then, Pdc to fluorescein was assessed using a single drop fluorophotometric method refined to enhance feasibility, precision, and accuracy. RESULTS: The mean (95% confidence interval) difference in natural log (Pdc) between 32 pairs of eyes (CL minus no CL) was 0.341 (0.069, 0.613), p = 0.016. By contrast, none of the 32 subjects exhibited corneal epithelial disruption upon SLE with white light following the closed eye period. Also, no substantial differences were apparent in the corneal swelling response between paired eyes, mean delta CT (95% CI) = -2.31(-7.53, 2.91) microns, p = 0.37. CONCLUSIONS: Pdc measurements, used in studies of modest sample size, appear capable of detecting average differences in corneal barrier function that remain undetectable by SLE or pachymetry.

Optical and structural development of the crystalline lens in childhood.

PURPOSE: To document the development of key optical and structural parameters of the crystalline lens throughout childhood and examine possible mechanisms by which lens power remains coordinated with the growth of the eye to maintain emmetropia. METHODS: Using cycloplegic autorefraction, video-based phakometry, and ultrasonography, the authors measured refractive error and crystalline lens parameters in 994 children in the first through eighth grades, who participated in the Orinda Longitudinal Study of Myopia, between one and five times from 1989 through 1993. Polynomial growth curves were fit to the data by maximum likelihood estimation. The average annual rates of change in each parameter from each subject's longitudinal data were also estimated. RESULTS: The lens radii of curvature flattened throughout childhood, yet decreases in lens equivalent power stopped after 10 years of age. This indicates that the refractive index of the lens increased during later childhood. Lens thinning in early childhood also ceased after 10 years of age. The spherical volume of the lens showed no appreciable net increase, but the axial length of the eye continued to grow throughout childhood. The prevalence of myopia in our data increased sharply at age 10 years, reaching 21.3% by the age of 14 years. CONCLUSIONS: Concurrent thinning and flattening of the crystalline lens imply that the lens is mechanically stretched by the equatorial growth of the eye during childhood. Changes in the patterns of lens development near the age of 10 years, concurrent with the onset of myopia, suggest that forces arise which interfere with equatorial growth. Such forces might diminish the decreases in lens power and amplify axial elongation to promote myopia.

Measurement of corneal epithelial permeability to fluorescein. A repeatability study.

PURPOSE: Permeability (Pdc) to sodium fluorescein (F) is a characteristic of the barrier function of the corneal epithelium. The repeatability of several in vivo fluorophotometric methods used to measure permeability in humans remains largely undocumented. This study examines the repeatability of a method based on topical instillation of a single drop of F for the quantitative assessment of Pdc. METHODS: Nine healthy subjects with no history of ocular disease provided 1 (n = 1), 2 (n = 1), or 3 (n = 7) repeated measurements of each eye at successive visits. After making 3 baseline fluorescence scans centrally through the tear film and cornea, 2 microliters of 0.35% F were instilled and 10 fluorescence scans were obtained at approximately 2-minute intervals immediately after instillation. Subsequently, the eyes were rinsed three times with nonpreserved saline and four additional scans were performed. RESULTS: Pdc was calculated by dividing the baseline-corrected postrinse stromal fluorescence by the time integral of the tear film fluorescence calculated over the 20-minute exposure period. After applying a logarithmic transformation to the Pdc estimates, a mixed-model analysis was used to assess measurement repeatability. On the Pdc scale, there is an estimated 95% chance that a second measurement could be as much as 2.88 times higher or 0.35 times lower than a first measurement. CONCLUSIONS: This substantial variability between repeated measurements indicates that the single-drop procedure is unreliable for monitoring individual patient changes. However, with careful sample size planning, this technique can be used in population-based research to compare differences in treatment effects between groups of subjects.

Prediction of early-onset esotropia from components of the infantile squint syndrome.

PURPOSE: To examine the association between components of the infantile squint syndrome (ISS) and age of onset of esotropia among subjects in the Cooperative Amblyopia Classification Study (CACS). METHODS: Fifty subjects were classified retrospectively as having early-onset esotropia (EOE) and 150 subjects were classified as having late-onset esotropia (EOE), depending on whether symptoms of (or treatment for) strabismus occurred before the first birthday or between the first and ninth birthdays, respectively. The authors compared the degree to which latent nystagmus (LN), dissociated vertical deviation (DVD), monocular asymmetry of optokinetic nystagmus (MOKN), monocular asymmetry of smooth pursuit (MSP), and perceived monocular speed bias (MSB) predicted EOE. RESULTS: Slow-phase velocity of MOKN and MSP were faster in response to nasal than to temporal target motion. In contrast, MSB revealed that targets of equal velocity were perceived as moving faster temporally than nasally. The authors evaluated MOKN, MSP, and MSB as dichotomous and as continuous predictors. Dichotomous analysis showed significant associations between DVD and asymmetries of MOKN in the preferred eye of subjects with EOE. Univariate logistic regression models, based on DVD and LN as well as on continuous measures of MOKN, MSP, and MSB, revealed predictive power for all ISS components except LN. In the preferred eye, MSP asymmetry was the strongest single predictor of EOE; multivariate analysis revealed that prediction of EOE improved with the inclusion of DVD. CONCLUSIONS: Multivariate analysis indicated that dichotomous measures of DVD and continuous measures of MSP were independent predictors of EOE in a population of 8- to 40-year-old subjects with strabismus. In the preferred eye, MOKN asymmetry was predictive of EOE in the absence of information about MSP. Predictive values of all ISS components depended heavily on the baseline prevalence of EOE in the target population.

Development of oral lesions in human immunodeficiency virus-infected transfusion recipients and hemophiliacs.

The authors used multivariate repeated-measures transition models to identify risk factors for two oral lesions related to human immunodeficiency virus (HIV)-candidiasis and hairy leukoplakia-in 152 HIV-infected blood transfusion recipients and hemophiliacs. Subjects were examined for occurrences of these lesions every 6 months from July 1985 through March 1993, yielding 1,076 study visits. It was found that, after adjustment for the CD4:CD8 T-lymphocyte ratio, patients with a history of candidiasis in the previous 18 months were at high risk of lesion recurrence. This risk increased with the number of prior episodes and with the recency of the episode(s). A history of hairy leukoplakia was less predictive of persistence of that lesion after adjustment for significant risk factors (including candidiasis and use of antifungal agents at the current examination, a low CD4:CD8 cell ratio, and age less than 40 years). The authors also found a high coprevalence of candidiasis and hairy leukoplakia in these subjects. These results suggest that HIV-infected patients with oral candidiasis should be carefully monitored for subsequent episodes over the next 12-18 months, and patients with either oral candidiasis or hairy leukoplakia and a low CD4:CD8 cell ratio should be carefully examined for the other type of lesion as well.

A competing risks analysis of presenting AIDS diagnoses trends.

The proportions of gay men presenting with various AIDS diagnoses display temporal trends. In particular, the proportion of initial diagnoses reported as Kaposi's sarcoma (KS) has declined over time. Epidemiologists have hypothesized that (a) KS may require a cofactor, whose prevalence has declined over time, or (b) KS may have a shorter incubation period than other presenting diagnoses. We examine whether this latter hypothesis, considered in a competing risks framework, could account for the observed decline in KS. We nonparametrically estimate the relevant cause-specific hazard functions from the doubly-censored data of the San Francisco City Clinic Cohort by maximizing a roughness penalized likelihood using an EM algorithm. These estimates suggest that differences in the underlying cause-specific hazard functions account for a substantial portion of the observed diagnoses trends.

Quantifying corneal toricity from videokeratography with Fourier analysis.

BACKGROUND: Fourier analysis can be used to quantify corneal toricity from videokeratography data. This study measures the repeatability of Fourier-derived toricity values in normal adult corneas. METHODS: The Topographic Modeling System (TMS) was used to model the corneas of 29 subjects on two occasions, and Fourier analysis applied to the data. Repeatability of Fourier-derived toricity values between sessions was examined, and 95% limits of agreement were established. RESULTS: The 95% limits of agreement between sessions for the Fourier method were -0.02 +/- 0.16 diopters (D) and -0.5 +/- 5.7 degrees for toricity amount and axis, respectively. CONCLUSIONS: The Fourier method yields highly repeatable toricity values and thus provides a sensitive means of detecting longitudinal toricity change in normal corneas.

Accuracy of videokeratography for instantaneous radius in keratoconus.

PURPOSE: Present videokeratographs provide corneal radius of curvature measurements in terms of axial (sagittal) radius and, for some instruments, instantaneous (tangential) radius. The EyeSys videokeratograph allows conversion from axial to instantaneous radius based on an algorithm, which assumes a basic corneal shape of elliptical form. METHOD: We tested the accuracy of the EyeSys instantaneous radius algorithm for 29 keratoconic corneas using the criterion that instantaneous radius of the cone apex could be determined accurately by aligning the cone apex with the optic axis of the videokeratoscope. RESULTS: There was a close relation between the instantaneous values obtained from the regular and apex alignments for the 17 eyes with cone apices below 55 D (95% limits of agreement -0.39 to 1.49 D), but not for the 12 eyes above 55 D (95% limits of agreement -4.87 to 6.61 D). The mean distance of the cone position from the center of the map was 1.16 mm for the instantaneous map and 1.59 mm for the axial map. CONCLUSION: Assuming the criterion for accuracy to be the corneal radii found when the videokeratograph was aligned with the cone apex, the instantaneous map for the EyeSys videokeratograph at regular alignment provided reasonably valid measurements for corneas up to 55 D, but large errors existed for some corneas of higher power.

Longitudinal evidence of crystalline lens thinning in children.

PURPOSE: Most earlier studies indicated that the eye's crystalline lens grows continually throughout life, but cross-sectional results of crystalline lens thinning during childhood have been reported. The authors investigated crystalline lens thickness in childhood using cross-sectional and longitudinal data. METHODS: The Orinda Longitudinal Study of Myopia is a community-based study of normal eye growth and myopia development in school-age children. During a 1-to 3-year period, A-scan ultrasonographic lens thickness measurements of 869 children 6 through 14 years of age were analyzed. RESULTS: On average, between the ages of 6 and 10 years, the crystalline lens thins in its axial dimension by almost 0.2 mm. This thinning can be depicted by a cubic model. In this sample, the children with myopia had thinner crystalline lenses than the children with emmetropia of the same age. CONCLUSIONS: This article provides the first longitudinal evidence that the crystalline lens thins during the period of coordinated ocular growth between the ages of 6 and 10 years. Further, it shows that lens thickness is associated with refractive error. Thinner crystalline lenses in children with myopia may result from one of two underlying mechanisms: Either the crystalline lens exhausts its ability to compensate for axial elongation after undergoing accelerated lens thinning before the onset of myopia, or the crystalline lens in the myopic eye may be thinner throughout childhood, during which it thins at a rate consistent with other refractive errors. If mechanical forces link eye growth to crystalline lens compensation, more complex, visually guided feedback loops may not be needed to explain the normal eye growth that results in emmetropization.

Marker-dependent hazard estimation: an application to AIDS.

The acquired immunodeficiency syndrome (AIDS) results from infection with the human immunodeficiency virus (HIV). The time of infection is generally unknown since transmission usually occurs during the course of repeated sexual contacts or needle sharing. Brookmeyer and Gail describe the biases that may arise in survival analyses using the recruitment time rather than the unknown infection time as the origin in prevalent cohorts of HIV-infected individuals. We apply a non-parametric hazard estimator, introduced by Nielsen, that assumes the hazard of an AIDS diagnosis depends upon the unknown time of infection solely through the value of possibly multidimensional markers of HIV-disease progression such as CD4+ T lymphocyte cell counts. Essentially, we estimate the hazard for a specific marker value y by dividing the number of occurrences among subjects with marker measurements in a neighbourhood of y by the total risk time in that neighbourhood. We present this estimator, which relies upon kernel estimator techniques to produce a smooth estimate, within a counting process framework. We apply this method to marker data from the San Francisco Men's Health Study.

An annotated bibliography of methods for analysing correlated categorical data.

This paper provides an annotated bibliography of over 100 articles concerning methods for analysing correlated categorical response data. Most of the papers listed here concern categorical regression models and estimation, with particular emphasis on binary responses. The papers are classified by several characteristics which group them according to common themes. The bibliography serves as a reference of methods for analysts of correlated categorical data, as well as for persons interested in methodologic work in this active area of statistical research.

Decreased serum dehydroepiandrosterone is associated with an increased progression of human immunodeficiency virus infection in men with CD4 cell counts of 200-499.

Dehydroepiandrosterone (DHEA) and its interconvertible sulfate derivative (DHEA-S) are human androgenic steroids that have been reported to inhibit viral expression and have been associated with a decreased risk of cancer. The relationship between serum DHEA and DHEA-S levels and subsequent progression to AIDS was investigated in a sample of human immunodeficiency virus (HIV)-infected men from the San Francisco Men's Health Study followed prospectively since 1984. Among 108 men seropositive for HIV at study entry and with CD4 lymphocyte counts of 200-499 microliters 24 months later, serum DHEA levels below the lower limit of normal (less than 180 ng/dl) at this later date were predictive of subsequent progression to AIDS (relative hazard = 2.34; 95% confidence interval = 1.18-4.63; P = .01) after controlling for hematocrit, age, and log absolute CD4 cell number in a Cox proportional hazards model. This is the first large prospective cohort in which an endocrinologic variable has been observed to independently predict progression to AIDS. These observations, in addition to recent in vitro data, suggest that DHEA might have a protective effect in HIV infection.

The natural history of HIV-1 infection: staging classifications of disease.

We evaluated and compared four staging classification systems for HIV infection in a population-based cohort: (1) a staging based on prodromal clinical criteria; (2) the Walter Reed Staging Classification (WRSC); (3) the immunologic staging system (ISS), and (4) a simple staging based on oral disease and CD4+ T-cell depletion. The staging systems were applied to 386 HIV-infected men in the San Francisco Men's Health Study cohort who did not have AIDS at the baseline examination. After 48-56 months of follow-up the cumulative incidence of AIDS and the cumulative mortality by stage was determined for each staging. Unlike the other systems, the WRSC could not classify a substantial proportion of HIV-infected men (51.9%). The WRSC and ISS include one or more stages which did not appear to be associated with a prognosis substantially different from that of adjacent stages. The simplified staging system based on CD4+ T-cell depletion and oral disease may be the most effective of the systems studied. A more complete understanding of the pathophysiology during the evolution of HIV infection will be required to define a more detailed staging of this disease.