Debating the Value of Genetic Testing

Early accounts of AvaGen’s role in clinical practice stimulate discussion and highlight the need for greater dialog.

Editor’s note: The January/February edition of Review of Cornea & Contact Lenses included a feature on genetic testing in keratoconus that included anecdotal impressions from several optometrists, as well as commentary from representatives of Avellino, makers of the AvaGen test. In one section of the discussion, Brian Chou, OD, reported receiving differing results on repeat testing of the same patient.

Here, representatives of Avellino offer elaboration and Dr. Chou responds to the new information.

Genetic Testing for Keratoconus Will Continue to Evolve, but Patients Can Benefit Now

By Mile Brujic, OD, and Sarvari Panchumarthi, PhD

We want to thank the editorial team for their article, “KCN Genetic Testing: Where Does It Fit In?”

One area optometrists should be devoting an increasing amount of attention and interest to is genetic testing. As with many new technological advancements in eye care, an increasing understanding of how these tests work and how to integrate them in the practice of optometry will be of the utmost importance today and in the next several years. 

AvaGen by Avellino helps detect the genetic risk for keratoconus and the presence of corneal dystrophies. A rather new type of test to enter the field, there are three main aspects to it that are critical to help understand its clinical utility. 

First is understanding the polygenic risk score (PRS) for keratoconus. The AvaGen PRS scale ranges from 0 to 100 and is divided into low-, medium- and high-risk segments. The risk score for a patient broadly falls into one of those three segments/categories. As an example, a polygenic risk score of 9 and a score of 22 are both in the low genetic risk category. 

The PRS is based on the number and types of multitudes of genetic variants found in each tested individual. As long as the PRS remains in the same risk category, the minor differences in the score number are not indicative of significant differences in disease risk. Via next-generation sequencing (the technology used in the AvaGen genetic test), the analytical sensitivity and specificity of the test is 100%.

With respect to Dr. Chou’s testing of AvaGen using the same sample patient’s DNA with three different names, dates of birth and ethnicities, we would like to point out that the difference between a PRS of 9 and 22 (found in the first and second samplings of the patient) is not clinically meaningful. Both scores place the patient’s genetic risk in the same category: low-risk. The genes identified in the risk of keratoconus are always detected, and if a specific variant used in the PRS calculation is ‘dropped out’ due to low quality of read depth, the PRS value would be expected to differ slightly. 

Avellino does quality control by running each patient’s sample in triplicates in its test process for each run. In the third testing of the same patient, which was received in mid-October 2021, the PRS yielded a higher value (61), as the company released an improved version of the PRS analysis in this same month.

Second, understanding how a polygenic risk score is developed for complex genetic diseases is key. 

Complex genetic diseases occur due to the cumulative effect of several single-nucleotide variants (SNVs) of very small effect size. Unlike monogenic diseases (where the presence of a single pathogenic variant yields a more definitive predisposition for the disease), polygenic diseases are more complex in nature. There is always an interplay of genes and environment in the manifestation of a polygenic disease. This makes the prediction of disease risk in polygenic diseases more elusive. 

As genomics knowledge improves for a certain disease, the polygenic risk score’s predictive value can be refined and improved over time. For AvaGen, the PRS was updated in October 2021 with refinements in its calculation due to identification of a fewer number of more prevalent variants (common variants), making the test more refined in the information in generates. Ethnicity differences were also accounted for in variant selection in the new version; therefore, ethnicity details are no longer required to estimate individual polygenic risk score, as they were in the calculation. 

Last, with complex genetic diseases, correlation is not causation. A high PRS for a given disease may never see the disease manifest and vice-versa. This is due to the interplay between genetic risk factors and environment/lifestyle. Likewise, someone with a low PRS may experience a given disease, as their lifestyle and other environmental factors may trigger the disease due to non-genetic causes. 

This is where using our current clinical skill set to detect conditions such as keratoconus—including refractive error analysis, slit lamp examination, keratometry, topography, tomography, as well as the knowledge and skill of the eyecare practitioner (ECP)—play a crucial role in patient care. A genetic test should never be used in isolation or as the stand-alone diagnostic method for monogenic or polygenic diseases. 

A resource for ECPs is the availability of genetic counselors, who can further help interpret results of a patient’s genetic test, including PRS, and provide additional guidance, such as helping determine if it is appropriate to test family members. Avellino provides this service for both ECPs and patients. 

Genetic testing is a valuable data source for the medical community, with the eyecare field being no exception. While we may be in the early stages of this journey, patients can benefit now from our collective expertise and knowledge of the human genome. 

Mile Brujic, OD, is a practicing doctor at Premier Vision Group in Bowling Green, OH. He provides consulting services to Avellino. 

Sarvari Panchumarthi, PhD, is a molecular geneticist with more than 20 years of research experience in various subdisciplines of genetics, in particular the genetics concerning cancer, cardiovascular, neurological and ophthalmological disorders.

Progress Toward Answers is Welcome—But Questions Remain

 By Brian Chou, OD

I offer my thanks to Drs. Brujic and Panchumarthi for their interest in my report. Their explanation about the unusual AvaGen results I received provides insight and also raises new questions.

Still left unanswered: what is the explanation for the same keratoconus subject’s identified risk genes getting reported as different each of the three times AvaGen was run? The revised polygenic scoring implemented in October 2021 may explain the subject’s higher polygenic risk score of 61 vs. the prior PRS values of 9 and 22. However, the KCN-associated gene profiles themselves changed from test to test. Was this also a function of the update to the PRS algorithm? In other words, were the same genetic variants detected in all three tests but reported differently to reflect updates to the PRS algorithm? 

I wonder, too, if other clinicians using AvaGen were notified of the scoring change. I learned of this by reading the companion sidebar Q&A to my own report. Due to the potentially high stakes of medical testing, future modifications to the PRS algorithm should include contemporaneous proactive notice to ECPs, not notice after the fact.

I agree that the test-retest PRS change from 9 to 22 would not have altered clinical decision-making, as both values were within AvaGen’s “low risk” category; even so, how would a clinician interpret a test-retest PRS change of the same increment, if for instance the PRS shifted from 22 to 35, thereby moving into the “moderate” risk category?

Although high analytical validity is requisite and expected for CLIA certification, it does not inform the ECP, nor patient, about the more important clinical validity and utility.

I look forward to Avellino and others elucidating these areas. A pure genetic test for keratoconus that is clinically valid and useful is welcome, even if epigenetics plays a notable role.

Dr. Chou practices at ReVision Optometry, a referral clinic for keratoconus and scleral lenses in San Diego. He is a past recipient of the National Keratoconus Foundation’s Top Doctor award.

Is the Joy in Cataract Surgery Fading?

By Don Stover, OD

Cataract surgery 40 years ago meant two months post-op of branded Pred Forte 1% QID, no NSAID and a week of antibiotics. There were limited cases of cystoid macular edema (CME) because it was an all-surgical procedure with no phacoemulsification. High astigmatism (above three diopters) was common, but patients—typically with 20/20+ corrected acuity—did not complain and strangely did not wear their glasses as much as would be predicted. Their color vision was exceptional for the rest of their lives. 

Then phaco started and best-corrected vision was reduced to 20/25 or 20/30—explained wrongly as corneal edema, but it really was macular damage. Color vision was commonly the same before surgery as afterwards. 

Even though the resultant refractive error was almost devoid of astigmatism, patients were wearing their glasses more, not less. Simultaneously, there were improvements in phaco and pharmaceuticals, such as the addition of NSAIDs, stronger steroids and better injectable drugs for dilation during surgery. Meds that worked just as well once a day became available. Good acuity and improved color vision were now possible again. 

But then the economics of cataract surgery changed. Reimbursement was cut from $1800 to the present-day rate of roughly $550. The post-op treatment course went from two months to no more than three weeks. For 30 years, attempts were made to use intracameral injectable medication to eliminate or at least minimize drop use after surgery. Recently reintroduced, this no-drop cataract surgery still poses some problems, such as visual or anatomic concerns at the one-year follow-up visit, which suggest an insufficient post-op regimen.

An article was published stating that post-op cataract surgery meds could be taken five minutes apart and still would work as well, despite known differences between generic and branded products, such as lower dosages and different corneal penetration rates. Unfortunately, most patients are told now to take post-op drops five minutes apart.

Also, recent changes in the availability of steroid medications have taken place. Inveltys, a higher concentration, better-penetrating form of loteprednol, seems to have overtaken use of high-potency Durezol or generic prednisolone as a popular treatment for the shortened three-week post-op period. There should be less elevated pressure from steroid responders. This isn’t quite true, because loteprednol still causes IOP spikes, as does prednisolone, at three to four weeks in some patients. Durezol almost never has those high pressure spikes in the first two days after surgery if used in BID dosage. I continue to recommend Durezol BID for six weeks and QD for two weeks for cataract surgery patients, and I don’t see CME.

More commonly, what we have now with post-op cataract care is a soft steroid used for three weeks, the NSAID Prolensa perhaps used QD and some kind of antibiotic for a week to 10 days. 

The one-year visit tells the story. The patients with fewer post-op meds want glasses, even though the refractive error is minimal, because they are having trouble seeing. Their color vision did not improve much after surgery; it should have. Those patients that used longer and stronger steroids and BID dosing for Prolensa don’t want glasses at the one-year visit, stating that their color vision is significantly better even if they had pre-existing dry AMD.

Another factor comes into play for optometry practices in rural America. Many of our patients have to travel out of town to get surgery. If they are seen by the surgeon for the one day post-op, that means the patient travels on a bumpy highway for a couple of hours, counting the day of surgery and the one-day follow-up back and forth. We’ve had patients stay overnight in the town where they had surgery and their acuity is always a couple of lines better in the first few days after surgery. 

Also, use of 1% cyclogyl right after surgery resulted in a dilated but 20/20- acuity at the one day post-op. Failure to use cyclogyl for the drive home yielded vision of 20/25 or 20/30 almost always at the one-day post-op. If a surgeon counts seconds of phaco time, they should also count how many miles that patient has to drive in to get surgery and follow-up.

In 2020, the cataract surgeon I used for 14 years retired; it was a sad day. In my small optometry practice, sometimes two patients a day were referred there for cataract surgery.

I think “optometry-referred” cataract surgery patients are different. They often have to travel, and thus need the extra cyclogyl drop and should not travel far again the day after surgery. This is the reason for letting the optometrist see patients the next day instead of the surgeon, but this is hard for most surgeons to appreciate. These patients are most likely more prone to subclinical chronic CME and thus stronger and longer post-op medications in my opinion are recommended. 

 There is a financial component to “optometry-referred” patients for the patient, the surgeon and the OD. Branded drugs are very costly to the patient. Thirty years ago, the pharmaceutical companies gave branded post-op meds to patients if their brand of intraocular implant was used. Now, there are no gift bags anymore and samples are hard to come by. Branded meds can cost over $600 and the surgeon may be out of pocket for some injections used during surgery because Medicare won’t allow a supply fee. Certain generic NSAIDs, when relied upon at the expense of better anti-inflammatories, may even cause CME. 

Then there is the cost of seeing cataract patients for two months. I generally see them for three visits if I see the patient on the first day post-op. I generally don’t make money on post-op visits. Wouldn’t it be nice if cataract surgery was one fee and the post-op care was another fee? This might support better post-op care.

I must say cataract surgery is quite remarkable. Most surgeons do a very good job; if anything, there continue to be improvements in the surgery itself.

All I know is that I miss what cataract surgery was just a few years ago. The patients from those days still come in and can’t believe how good their vision is and what a miracle cataract surgery is. They don’t want glasses and color vision is excellent. The more recent cataract surgery patients now want to buy glasses. I should be happy, but I’m really not. I want to be part of the miracle that cataract surgery was again. 

Dr. Stover, a 1981 graduate of University California Berkeley Optometry School, practices in Porterville, CA.