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Polygenic Scores Show Potential to Predict Humans’ Susceptibility to a Range of Chronic Diseases; New Clinical Laboratory Genetic Tests Could Result from Latest Research

Access to vast banks of genomic data is powering a new wave of assessments and predictions that could offer a glimpse at how genetic variation might impact everything from Alzheimer’s Disease risk to IQ scores

Anatomic pathology groups and clinical laboratories have become accustomed to performing genetic tests for diagnosing specific chronic diseases in humans. Thanks to significantly lower costs over just a few years ago, whole-genome sequencing and genetic DNA testing are on the path to becoming almost commonplace in America. BRCA 1 and BRCA 2 breast cancer gene screenings are examples of specific genetic testing for specific diseases.

However, a much broader type of testing—called polygenic scoring—has been used to identify certain hereditary traits in animals and plants for years. Also known as a genetic-risk score or a genome-wide score, polygenic scoring is based on thousands of genes, rather than just one.

Now, researchers in Cambridge, Mass., are looking into whether it can be used in humans to predict a person’s predisposition to a range of chronic diseases. This is yet another example of how relatively inexpensive genetic tests are producing data that can be used to identify and predict how individuals get different diseases.

Assessing Heart Disease Risk through Genome-Wide Analysis

Sekar Kathiresan, MD, Co-Director of the Medical and Population Genetics program at Broad Institute of MIT/Harvard and Director of the Center for Genomics Medicine at Massachusetts General Hospital (Mass General); and Amit Khera, MD, Cardiology Fellow at Mass General, told MIT Technology Review “the new scores can now identify as much risk for disease as the rare genetic flaws that have preoccupied physicians until now.”

“Where I see this going is that, at a young age, you’ll basically get a report card,” Khera noted. “And it will say for these 10 diseases, here’s your score. You are in the 90th percentile for heart disease, 50th for breast cancer, and the lowest 10% for diabetes.”

However, as the MIT Technology Review article points out, predictive genetic testing, such as that under development by Khera and Kathiresan, can be performed at any age.

“If you line up a bunch of 18-year-olds, none of them have high cholesterol, none of them have diabetes. It’s a zero in all the columns, and you can’t stratify them by who is most at risk,” Khera noted. “But with a $100 test we can get stratification [at the age of 18] at least as good as when someone is 50, and for a lot of diseases.”

Sekar Kathiresan, MD (left), Co-Director of the Medical and Population Genetics program at Broad Institute at MIT/Harvard and Director of the Center for Genomics Medicine at Massachusetts General Hospital; and Amit Khera, MD (right), Cardiology Fellow at Mass General, are researching ways polygenic scores can be used to predict the chance a patient will be prone to develop specific chronic diseases. Anatomic pathology biomarkers and new clinical laboratory performed genetic tests will likely follow if their research is successful. (Photo copyrights: Twitter.)

Polygenic Scores Show Promise for Cancer Risk Assessment

Khera and Kathiresan are not alone in exploring the potential of polygenic scores. Researchers at the University of Michigan’s School of Public Health looked at the association between polygenic scores and more than 28,000 genotyped patients in predicting squamous cell carcinoma.

“Looking at the data, it was surprising to me how logical the secondary diagnosis associations with the risk score were,” Bhramar Mukherjee, PhD, John D. Kalbfleisch Collegiate Professor of Biostatistics, and Professor of Epidemiology at U-M’s School of Public Health, stated in a press release following the publication of the U-M study, “Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative.”

“It was also striking how results from population-based studies were reproduced using data from electronic health records, a database not ideally designed for specific research questions and [which] is certainly not a population-based sample,” she continued.

Additionally, researchers at the University of California San Diego School of Medicine (UCSD) recently published findings in Molecular Psychiatry on their use of polygenic scores to assess the risk of mild cognitive impairment and Alzheimer’s disease.

The UCSD study highlights one of the unique benefits of polygenic scores. A person’s DNA is established in utero. However, predicting predisposition to specific chronic diseases prior to the onset of symptoms has been a major challenge to developing diagnostics and treatments. Should polygenic risk scores prove accurate, they could provide physicians with a list of their patients’ health risks well in advance, providing greater opportunity for early intervention.

Future Applications of Polygenic Risk Scores

In the January issue of the British Medical Journal (BMJ), researchers from UCSD outlined their development of a polygenic assessment tool to predict the age-of-onset of aggressive prostate cancer. As Dark Daily recently reported, for the first time in the UK, prostate cancer has surpassed breast cancer in numbers of deaths annually and nearly 40% of prostate cancer diagnoses occur in stages three and four. (See, “UK Study Finds Late Diagnosis of Prostate Cancer a Worrisome Trend for UK’s National Health Service,” May 23, 2018.)

An alternative to PSA-based testing, and the ability to differentiate aggressive and non-aggressive prostate cancer types, could improve outcomes and provide healthcare systems with better treatment options to reverse these trends.

While the value of polygenic scores should increase as algorithms and results are honed and verified, they also will most likely add to concerns raised about the impact genetic test results are having on patients, physicians, and genetic counselors.

And, as the genetic testing technology of personalized medicine matures, clinical laboratories will increasingly be required to protect and distribute much of the protected health information (PHI) they generate.

Nevertheless, when the data produced is analyzed and combined with other information—such as anatomic pathology testing results, personal/family health histories, and population health data—polygenic scores could isolate new biomarkers for research and offer big-picture insights into the causes of and potential treatments for a broad spectrum of chronic diseases.

—Jon Stone

Related Information:

Forecasts of Genetic Fate Just Got a Lot More Accurate

Polygenic Scores to Classify Cancer Risk

Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-Wide Study: Results from the Michigan Genomics Initiative

Polygenic Risk Score May Identify Alzheimer’s Risk in Younger Populations

Use of an Alzheimer’s Disease Polygenic Risk Score to Identify Mild Cognitive Impairment in Adults in Their 50s

New Polygenic Hazard Score Predicts When Men Develop Prostate Cancer

Polygenic Hazard Score to Guide Screening for Aggressive Prostate Cancer: Development and Validation in Large Scale Cohorts

UK Study Finds Late Diagnosis of Prostate Cancer a Worrisome Trend for UK’s National Health Service

Naval Medical Center Study Reveals More than One-third of Genetic Tests are Misordered; Clinical Laboratories Critical to Improving Lab Test Utilization

Pathologists and clinical lab managers can help physicians more effectively select appropriate genetic tests and better interpret results to identify the most appropriate therapies for their patients

Clinical laboratories and pathology groups aren’t the only healthcare providers being scrutinized for cost cutting and workflow efficiencies. Physicians ordering genetic tests are now in the spotlight thanks to a study of genetic test misordering by one healthcare institution.

In her award-winning presentation, “Genetic Testing Costs and Compliance with Clinical Best Practices,” given at the 2016 annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists (ACOG), Kathleen Ruzzo, MD, revealed some startling facts to the attendees. Ruzzo is an obstetrics and gynecology (OB-GYN) resident at the Naval Medical Center (NMC) in San Diego. She and a team of NMC researchers had reviewed all genetic tests ordered during a 3-month period. They found that more than one-third of the genetic tests examined were unnecessary and had led to more than $20,000 in additional healthcare expenditures. This got the attention of the ACOG, which awarded her 1st prize.

Critical Importance of Staying Informed on Genetic Tests

The researchers examined 114 charts that contained billing codes for genetic tests. They evaluated the charts for compliance with practice guidelines and completed a cost analysis of the tests. The tests were classified per GeneReviews guidelines and were labeled as:

  • Appropriate;
  • Misordered/Not Indicated;
  • Misordered/False Reassurance; or
  • Misordered/Inadequate.

GeneReviews is an online database focusing on information, diagnosis, management, and counseling of single-gene disorders. It is published by the National Center for Biotechnology Information.

The researchers found that:

  • 44 of the 114 charts examined (39%) were misordered based on the guidelines;
  • 24 of the tests were labeled as misordered/not indicated;
  • Eight tests were classified as misordered/false reassurance; and
  • 12 tests were determined to be misordered/inadequate.

“We know there is an ever-expanding number of genetic tests available for clinicians to order, and there is more direct marketing to the patient,” stated Ruzzo in an Ob. Gyn. News article. “It can be difficult to stay on top of that as we have so many different clinical responsibilities.”

Dr. Monica A. Lutgendorf (left) and Dr. Kathleen Ruzzo

Kathleen Ruzzo, MD (above right) and Monica Lutgendorf, MD (above left) of the Naval Medical Center in San Diego, reviewed 114 genetic tests ordered during a three-month period. They discovered that 39% of the tests were misordered according to guidelines, costing a total of $75,000. (Photo copyright: Naval Medical Center.)

The actual testing was performed by Laboratory Corporation of America and occurred over a three-month period. The seven common genetic tests that were reviewed were tests for:

The cost analysis of the tests revealed that $20,000 could have been saved by following the GeneReviews guidelines. The total costs affiliated with the 114 tests reached $75,000. Potential savings were thus 26.6% of the total cost of the genetic tests involved in this study. In many clinical settings, if pathologists and medical laboratory managers could help physicians better utilize genetic tests while reducing the cost of such testing by almost 27%, that would be a major contribution. Plus, patients would be getting better care.

Ordering the Right Genetic Test Saves Money and Protects Patients

According to the National Institutes of Health (NIH), costs affiliated with genetic tests can range from less than $100 to more than $2,000 depending on the type and intricacy of the test. The NIH notes that many insurance companies will pay for genetic testing if ordered by a physician.

Ruzzo also shared that many of her cohorts were surprised at the results of the research.

“I think it opened a lot of people’s eyes … to be more meticulous about [genetic] testing and to ask for help when you need help,” she stated in the Ob. Gyn. News article. “Having trained individuals, reviewing genetic tests could save money in the healthcare system more broadly. We could also approve the appropriate testing for the patient.”

Ruzzo did admit there were limitations to the study; the researchers only looked at small amounts of tests for a short period and they did not concentrate on the consequences of the misordering to the patients.

Monica Lutgendorf, MD, Maternal Fetal Medicine Physician at the Naval Medical Center, was one of the coauthors of the paper. In the Ob. Gyn. News article, she described the findings as “a call to action in general for ob-gyns to get additional training and resources to handle the ever-expanding number of [genetic] tests.”

“I don’t think that this is unique to any specific institution. I think this is part of the new environment of practice that we’re in,” Lutgendorf concluded.

Due to the costs of genetic testing and the fact that so many physicians have not been able to keep up with all the latest advances in genetic medicine and testing, misordering will, most likely, continue to be a problem. Nevertheless, pathologists and clinical laboratory managers can serve a crucial role in helping physicians be more effective at selecting the correct genetic tests and assisting them in interpreting results to choose the most appropriate therapies for their patients.

Meanwhile, for those pathologists and medical laboratory professionals interested in developing effective utilization management programs for lab tests, Dark Daily is presenting a special webinar, titled, “Simple, Swift Approaches to Lab Test Utilization Management: Proven Ways for Your Clinical Laboratory to Use Data and Collaborations to Add Value.” It will take place on Thursday, June 29, 2017 at 1PM EDT.

For information about this high-value webinar and to register, use this link (or copy this URL and paste into your browser:

—JP Schlingman

Related Information:

More Than One-Third of Genetic Tests Misordered, Study Finds

Genetic Tests Often Overused and Misinterpreted, Sometimes with Tragic Consequences

Webinar: Simple, Swift Approaches to Lab Test Utilization Management: Proven Ways for Your Clinical Laboratory to Use Data and Collaborations to Add Value

Research Awards Announced for ACOG 2017 Annual Meeting

Unnecessary Genetic Tests Wastes $500 Million Annually

To Help Physicians and Patients, Medical Laboratories with BRCA Breast Cancer Tests Are Posting Mutation Data into ClinVar’s BRCA Database

Innovative use of crowdsourcing allows pathologists and genetic scientists to create a sizeable database of BRCA mutations that is accessible to clinicians and patients

There’s a new development in the longstanding battle over proprietary healthcare data versus public sharing of such information. Pathologists and clinical laboratory managers will be interested to learn that, when it comes to genetic testing of the BRCA mutation involved in breast cancer, a public data base of mutations is growing so rapidly that it may become the world’s largest repository of such information.

It was last year when the Supreme Court ruled in the gene patent case of Association of Molecular Pathology versus Myriad Genetics that human genes were not patentable. Following that decision, some financial analysts stated that Myriad Genetics, Inc. (NASDAQ:MYGN) retained a competitive advantage over other medical laboratories due to its huge database of mutations in the BRCA genes. (See Dark Daily, “Supreme Court Strikes down Myriad Gene Patents in Unanimous Vote; Decision Is Expected to Benefit Clinical Pathology Laboratories,”  July 1, 2013.) (more…)