Jennifer P. Craig, MCOptom, PhD, Kelly K. Nichols, OD, PhD, Esen K. Akpek, MD, Barbara Caffery, OD, PhD, Harminder S. Dua, MD, PhD, Choun-Ki Joo, MD, PhD, Zuguo Liu, MD, PhD, J. Daniel Nelson, MD, Jason J. Nichols, OD, PhD, Kazuo Tsubota, MD, PhD, Fiona Stapleton, MCOptom, PhD

ABSTRACT:

The goals of the TFOS DEWS II Definition and Classification Subcommittee were to create an evidence based definition and a contemporary classification system for dry eye disease (DED).

The new definition recognizes the multifactorial nature of dry eye as a disease where loss of homeostasis of the tear film is the central pathophysiological concept. Ocular symptoms, as a broader term that encompasses reportsof discomfort or visual disturbance, feature in the definition and the key etiologies of tear film instability, hyperosmolarity, and ocular surface inflammation and damage were determined to be important for inclusion in the definition. In the light of new data, neurosensory abnormalities were also included in the definition for the first time.

In the classification of DED, recent evidence supports a scheme based on the pathophysiology where aqueous deficient and evaporative dry eye exist as a continuum, such that elements of each are considered in diagnosis and management. Central to the scheme is a positive diagnosis of DED with signs and symptoms, and this is directed towards management to restore homeostasis. The scheme also allows consideration of various related manifestations, such as non-obvious disease involving ocular surface signs without related symptoms, including neurotrophic conditions where dysfunctional sensation exists, and cases where symptoms exist without demonstrable ocular surface signs, including neuropathic pain.

This approach is not intended to override clinical assessment and judgment but should prove helpful in guiding clinical management and research.

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Alan Tomlinson, Santosh Khanal, Kanna Ramaesh, Charles Diaper, and Angus McFadyen

● PURPOSE: To determine new referents, or cutoff levels for tear film hyperosmolarity in the diagnosis of keratoconjunctivitis sicca (KCS) and to assess their effectiveness in independent patient groups.

● METHOD: A meta-analysis was performed on published data for tear osmolarity in samples of normal eyes and various subtypes of dry eye, and pooled estimates of the mean and standard deviations for normal and (all) dry eye subjects were determined. Diagnostic referents were derived from the intercept between the distributions of osmolarity in the two samples and from receiver operator characteristic (ROC) curves. This referent was tested for effectiveness of diagnosis in independent groups with normal and dry eyes.

● RESULTS: An osmolarity referent of 315.6 mOsmol/L was derived from the intercept of the distribution curves, and 316 mOsmol/L from the ROC curve. When applied to independent groups of normal and dry eye subjects a value of 316 mOsmol/L was found to yield sensitivity of 59%, specificity of 94%, and an overall predictive accuracy of 89% for the diagnosis of dry eye syndrome.

● CONCLUSIONS: Tear hyperosmolarity, defined by a referent of 316 mOsmol/L, was superior in overall accuracy to any other single test for dry eye diagnosis (Lactoplate, Schirmer test, and Rose Bengal staining), even when the other test measures were applied to a diagnosis within the sample groups from which they were derived. For overall accuracy in the diagnosis of dry eye, the osmolarity test was found to be comparable with the results of combined (in parallel or series) tests.

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MICHAEL A. LEMP, ANTHONY J. BRON, CHRISTOPHE BAUDOUIN, JOSÉ M. BENÍTEZ DEL CASTILLO, DAVID GEFFEN, JOE TAUBER, GARY N. FOULKS, JAY S. PEPOSE, AND BENJAMIN D. SULLIVAN

● PURPOSE: To evaluate the use of tear osmolarity in the diagnosis of dry eye disease.

● DESIGN: A prospective, observational case series to determine the clinical usefulness of tear osmolarity and commonly used objective tests to diagnose dry eye disease.

● METHODS: A multicenter, 10-site study consisting of 314 consecutive subjects between 18 and 82 years of age. Bilateral tear osmolarity, tear film break-up time (TBUT), corneal staining, conjunctival staining, Schirmer test, and meibomian gland grading were performed. Diagnostic performance was measured against a composite index of objective measurements that classified subjects as having normal, mild or moderate, or severe dry eye. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic curve, and intereye variability.

● RESULTS: Of the 6 tests, tear osmolarity was found to have superior diagnostic performance. The most sensitive threshold between normal and mild or moderate subjects was found to be 308 mOsms/L, whereas the most specific was found at 315 mOsms/L. At a cutoff of 312 mOsms/L, tear hyperosmolarity exhibited 73% sensitivity and 92% specificity. By contrast, the other common tests exhibited either poor sensitivity (corneal staining, 54%; conjunctival staining, 60%; meibomian gland grading, 61%) or poor specificity (tear film break-up time, 45%; Schirmer test, 51%). Tear osmolarity also had the highest area under the receiver operating characteristic curve (0.89). Intereye differences in osmolarity were found to correlate with increasing disease severity (r2 = 0.32).

● CONCLUSIONS: Tear osmolarity is the best single metric both to diagnose and classify dry eye disease. Intereye variability is a characteristic of dry eye not seen in normal subjects.

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Volles DF, McKenney JM, Miller WG, Ruffen D, Zhang D.

ABSTRACT:

Several relatively inexpensive compact analyzers for measuring cholesterol are available for use outside of the clinical laboratory. We evaluated the analytic and clinical performance of total cholesterol assayed with the AccuMeter (ChemTrak) and the LDX (Cholestech). Accuracy of both devices was evaluated by collecting capillary and venous whole blood from 100 subjects and assaying for total cholesterol.

Results were compared with the Centers for Disease Control standardized reference laboratory method. Mean percent bias, mean absolute percent bias, and percentage of subjects with total error above +/- 8.9% were calculated and results were compared with recommendations from National Cholesterol Education Program (NCEP) for total cholesterol measurements. Precision was evaluated by assay of three pooled serum samples with both devices in duplicate in two runs/day for 20 days. The CV for each serum pool for each device was calculated and compared with NCEP recommendations for precision for total cholesterol measurements. Results with the two devices were compared. The total cholesterol mean percent bias for capillary samples was 2.1% for the LDX and -1.0% for the AccuMeter (p<0.01), and for venous samples 1.6 and -2.0%, respectively (p<0.001). The mean absolute percent bias for capillary samples was 5.4 and 5.2%, respectively (p=0.29), and for venous samples was 5.0 and 5.7% (p=0.79). Each device had an excessive number (12-22%) of individual results that exceeded NCEP recommended total error for a single cholesterol measurement (+/- 8.9%).

In the precision analysis the average CV from all three serum pools was 4.0% and 5.3% for the LDX and AccuMeter, respectively (p<0.05). Thus both devices failed to meet the NCEP recommendation for precision of 3% CV. They both provided total cholesterol results that correctly classified individual patients into appropriate risk groups 95% of the time or better if values within +/- 8.9% of NCEP cut points for risk classification were ignored. Both devices met the NCEP +/- 3% requirement for total cholesterol mean percent bias but did not meet the +/- 3% requirement for CV as a measure of precision. Because of the variability in results, both devices had excessive numbers of individual subjects with total cholesterol results greater than the recommended total error limit of +/- 8.9% difference from the standardized method.

Despite variability in some individual results, the rate of clinical misclassifications for coronary heart disease risk was relatively low for both devices if results near the NCEP cut points were repeated.

Kimberly MM, Vesper HW, Caudill SP, Ethridge SF, Archibold E, Porter KH, Myers GL.

ABSTRACT:

● Background: The American Diabetes Association recommends that people with diabetes use self-monitoring to control their blood glucose concentration. To assess the need for standardization, we evaluated the variability among 5 of the most common monitors: MediSense Precision Xtra, Ascencia Dex, Prestige Smart System, OneTouch Ultra, and Accu-Chek Advantage.

● Methods: We took steps to minimize preanalytical variation. We also eliminated user variability by using one trained operator to collect samples and perform all testing. Each monitor was used twice with each participant; one test was performed using an aged strip and the other using a fresh strip. We compared monitors using a separate ANOVA for each concentration range and strip lot.

● Results: The total CVs and the within-strip lot CVs were not statistically different among monitors, ranging from 3.1% to 11.3% and from 2.1% to 8.5%, respectively. There were statistically significant differences among monitors for among-strip lot CVs, which ranged from nearly 0% to 7.5%. The degree of significance increased as the concentration range increased [3.9-5.5 mmol/l: p<0.05; 5.6-7.7 mmol/l: p =0.003; 7.8-11.1 mmol/l: p < 0.001]. The average percent difference between monitor pairs was statistically significant (p < 0.05) in more than half of the paired comparisons, with significant differences ranging from 5.7% to 32.0%.

● Conclusions: Monitor results can vary significantly so that agreement among them is poor. Standardization is necessary to minimize variability and to improve patient care.