Collecting a 50 nanoliter sample of tear fluid, a quantity that is not readily visible to the naked eye, is controlled and monitored by the Test Card lab-on-a-chip technology and the TearLab Pen. Data submitted to the FDA for CLIA Waiver categorization demonstrates that by following the simple user instructions, tear collection will not affect the osmolarity reading. Refer to the TearLab Tear Collection Guide for more details.
TearLab recommends that tears be collected from the inferior lateral tear meniscus. Keep in mind that the tear fluid in a dry eye patient has lost homeostatic control and is unstable, with the potential to change from blink to blink. Collecting in the lower lateral cul-de-sac allows the tear fluid to re-mix between blinks and represents the best overall indication of the osmotic state of the tear fluid at the time of collection. In addition, using the higher of either the OD or OS reading, mitigates the unstable effect in a dry eye subject and will provide the correct result with nearly a 90% confidence rate.
The single-use Test Card contains a microfluidic channel that is gently placed on the tear lake (meniscus) in the corner of the eye on the inner lower lid margin, and via passive capillary action, less than 50-nanoliters of tear sample is instantly and automatically collected when it comes in contact with tear fluid. A sample smaller than the period at the end of this sentence.
It is a calibration code that needs to be entered into the Reader after the sample has been collected and the Pen is docked into the Reader. Although every Test Card in a box will have the same calibration code, this number can vary from 1-20 and may vary from box to box. You should take care when opening a new box of Test Cards to ensure that you are entering the correct number when performing a test. Entering the incorrect code will result in an inaccurate test result.
The solutes and biological components from the previous tear fluid sample will remain in the microfluidic channel and will result in an inaccurate measurement if used more than once. Due to the small size of the microfluidic channel, the Test Card cannot be cleaned after use.
The TearLab Test Card is a highly precise component, and even the smallest trace of residual salts will affect subsequent measurements. You should never collect tears with a used Test Card.
The Pen detects whether there is fluid within a Test Card, and if it detects fluid the green light will not illuminate to protect against re-use. If a Test Card is allowed to completely dry out, a used Test Card may illuminate the Pen; however, the Test Card will retain solutes and biological components from the previous tear fluid collection and result in an inaccurate measurement if used more than once. You should never collect tears with a used Test Card. A Test Card that is outside of its foil wrapper that does not have a protective cover on it should be considered used, even if the Pen's green light illuminates. The rule of thumb is to never place a Test Card without a plastic cover on a Pen. A Test Card without a plastic cover should not be used to collect tears. Test Cards should be discarded immediately following use to avoid their accidental reuse.
CV (Coefficient of Variation) is an industry standard measurement of precision equal to the standard deviation divided by the mean of a set of measurements. The smaller the CV the more precise and accurate the test. The TearLab has a CV of less than 2%, which is considered excellent and comparable to the most sophisticated laboratory technologies. In addition, such a "tight" CV indicates that the TearLab instrument is capable of measuring osmolarity with little or no variability between consecutive measurements of a single fluid sample, and any variability seen in patient measurements is related to the instability of the tear film due to loss of homeostatic control in the dry eye disease state. Thus, the variability between measurements in a normal, healthy lacrimal system will not exceed the TearLab CV of 2% in patient measurements. The TearLab instrument has thus allowed us to identify and quantify instability as a hallmark of the disease, and this variability in homeostatic control can now be used as a confirming clinical indication of disease and if correctly understood, should not confound the clinician who encounters variability of measurements. Any difference between OD and OS measurements greater than 8 mOsm/L is a classic indication of loss of homeostatic control and is a confirming indicator of dry eye disease.
Sensitivity is the ability to diagnose persons who actually have the disease.
Specificity is the ability to diagnose persons who do not have the disease.
Positive Predictive Value is the percent of people with a positive test who have the disease.
Negative Predictive Value is the percent of people with a negative test who do not have the disease.
In laboratory medicine the reliability of a binary or dichotomic (yes/no; healthy/sick) test is generally evaluated in terms of sensitivity and specificity, while in non-binary tests (where there is a severity scale - such as in dry eye, ie., normal, mild, moderate, severe), these terms are less relevant. The most important measure in a diagnostic method is the Positive Predictive Value, as it reflects the probability that a positive test reflects the underlying condition being tested. In clinical studies, tear osmolarity consistently demonstrates a high PPV (98.4% by Versura et al; Curr Eye Res. 2010 Jul;35(7):553-64).
The TearLab Osmolarity System has demonstrated performance equivalent to existing laboratory osmometers. The historical performance of osmolarity in published literature is compared to published data on TearLab performance. What is significant is that TearLab, for the first time, provides a clinical tool that meets this performance criteria outside of the laboratory environment, at the point-of-care in the hands of the doctor office staff.
(ref: BD Sullivan et al. "Diagnostic performance of osmolarity combined with subset markers of dry eye disease in an unstratified patient population," ARVO 2010.).
|Historical Performance of Osmolarity||TearLab Osmolarity System|
|Laboratory Staff||Doctor Office Staff|
The place of tear osmolarity measurement in the diagnosis of dry eye disease is “well-established” in guidelines and physician-authored, peer-reviewed literature published over many years: (Methodologies to diagnose and monitor dry eye disease: Report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop. The Ocular Surface 2007;5:108-123.)
Normal tear film is in homeostasis with blood osmolarity at a reference value of 290 mOsm/L, with a normal "homeostatic range" for tear osmolarity defined as 275-307 mOsm/L. It is important to note that both clinical and sub-clinical hyperosmolar stress to the ocular surface, above the normal homeostatic range, has been related to:
These factors contribute to a progressive pathogenesis commonly referred to as Dry Eye Disease (DED).
Normal osmolarities are typically found at a mean value of 302 mOsms/L, mild/moderate osmolarity (Dry Eye) at a mean of 315 mOsms/L and severe osmolarity (Dry Eye) at a mean of 336 mOsms/L. Osmolarity values in the low end of the abnormal range should be considered together with symptoms for a definitive dry eye diagnosis. Values in the upper range of normal (for the general population) in the presence of symptoms should suggest early/mild DED.
In DED, it is known that symptoms correlate poorly with objective signs. It is important to note that in the absence of symptoms the presence of hyperosmolarity above the normal homeostatic range (275 - 307 mOsm/L) is still evidence of DED. Hyperosmolarity in the absence of symptoms should be considered an abnormality in the body's homeostatic osmoregulation and a sign of DED.
The osmolarity value will be a composite of the combined effects of either dysfunction (aqueous deficiency or evaporative) and should be used in a global assessment of dry eye disease. The ultimate endpoint of disease progression is a hyperosmolar state.
Hyperosmolarity plays a role in the physical destabilization of the tear film, damage to the ocular surface and contributes to the progression of the disease. It is recognized as both a sign of the disease and the central causative mechanism in the disease pathogenesis.
There is no known relationship between the osmolarity of other body fluids and tear fluid. However, studies are currently ongoing to better define this relationship.
The TearLab Osmolarity System is intended to measure the osmolarity of human tears to aid in the diagnosis of dry eye disease in patients suspected of having dry eye disease, in conjunction with other methods of clinical evaluation.
Osmolarity may differ from left and right eye (and this is particularly characteristic in patients with DED). Each eye should be tested and the higher osmolarity should be considered the relevant value; look for other signs of DED with other methods of clinical evaluation. (Ref: B.D. Sullivan et al., "Diagnostic performance of osmolarity combined with subset markers of dry eye disease in an unstratified patient population", ARVO 2010).
> 308 mOsms/L in either eye
|Consider treating for dry eye disease|
< 308 mOsms/L in both eyes
|Consider other pathologies or other methods of clinical evaluation|
The ability to mitigate environmental stress via compensatory mechanisms will vary from eye to eye within the same patient, thus resulting in variations in the osmolarity readings. As dry eye disease progresses, osmolarity readings may vary from eye to eye, with at least one eye in the abnormal range.
Patients with dry eye disease (hyperosmolarity) have a dysfunctional tear film, combined with poor homeostatic osmoregulatory capability. As such, stress on the tear film causes instability that is not seen in normal tear film. The TearLab instrument allows us to quantify eye-to-eye variability and can be used as a confirming clinical indication of disease and, if correctly understood, should not confound the clinician who encounters variability in measurements. Any difference between OD and OS measurements greater than 8 mOsm/L is a classic indication of loss of homeostatic control and is a confirming indicator of dry eye disease.
This is demonstrated in the table below, in which four consecutive TearLab osmolarity measurements are made one-minute apart over three days in both a dry eye and normal patient.
* As seen below, the dry eye patient has wide fluctuations in tear osmolarity, eye-to-eye, test-to-test and day-to-day, attributed to the pathological instability of the tear film, while the normal patient shows no variability beyond the expected analytical variability of the instrument itself.
|Mild/Moderate Dry Eye||Normal Patient|
|OSDI = 22.92||OSDI = 4.17|
|Right Eye||Left Eye||Right Eye||Left Eye|
No. Just as other physiological indicators, such as intra-ocular pressure or blood pressure, vary day-to-day and measurement-to-measurement, tear film osmolarity will also vary. In the demonstration chart above, diagnosed dry eye patients were tracked over a three-day period and tested. As indicated previously, the dry eye patient has wide fluctuations in osmolarity while the normal subject had basically no biological variability.
Currently there is no data to support diurnal variations. Studies are ongoing to address this question.
TearLab is not currently aware of any factors that affect how osmolarity should be evaluated within different demographic groups.
Hyperosmolarity (> 308 mOsms/L) defines dry eye disease in conjunction with clinical evaluation and a single measurement can result in a treatment decision. In which case, a mean is not necessary to establish diagnosis. Test both eyes and take the higher of the two readings, regardless of which eye, for the clinical assessment of that patient at that time point.
Osmolarity should be considered in conjunction with other methods of clinical evaluation.
In the presence of other signs and symptoms of DED such as pronounced corneal staining, or short breakup times, consider that the patient may be exhibiting an osmolarity at the low end of the abnormal range. Also ensure that the patient is not using eye drops within one hour of testing, and also consider that if the patient is being treated, that the treatment may be reducing the tear osmolarity.
In the absence of other signs, if a patient exhibits consistently low osmolarity over time, consider pathologies other than dry eye disease.
TearLab osmolarity is intended to diagnose DED in patients suspected of having Dry Eye Disease in conjunction with other methods of clinical evaluation. Literature suggests that pre-treating patients diagnosed with DED prior to LASIK surgery results in better refractive outcomes following LASIK surgery.
Numerous systemic medications may result in side effects. Some systemic medications may change the make up of the tear film, which may increase ocular dryness, possibly resulting in a higher osmolarity. TearLab currently makes no claims for the affect of medication on osmolarity.