Tuesday, March 22, 2016

Genetic counseling

Little Kate Summersgill certainly didn’t look like a child with Down syndrome — no upward slanting eyes or telltale flat facial features.

Devon and Mike Summersgill had believed baby Kate was all but certain to be born with the intellect-stunting disorder because of a blood test Devon’s doctor recommended during her 2014 pregnancy. Even after the birth, when their baby looked fine, their genetic counselor, Laura Limone, insisted that the result of the test was not a mistake, Devon says.

Only after the New Jersey couple agonized over Kate’s future and spent almost $2,000 more on another test were they satisfied that Limone was wrong — their baby was fine. And when they learned that Limone had a financial relationship with the company that makes the test, called MaterniT21 PLUS, they wondered whether money had influenced the counselor’s advice.

“My first reaction was just utter confusion followed by anger,” said Devon Summersgill, 33, a special education teacher.

Parents are starting to question the independence of the fast-growing field of genetic counseling as more and more counselors are paid by the companies that make the tests. About 14 percent of the nation’s 4,000 genetic counselors worked directly for testing labs in 2014, up from 9 percent just two years earlier, according to the latest count by their professional society. The balance tend to work for hospitals or doctors’ practices.

“It’s a mass exodus to labs,” where pay tends to be higher and the perks are better, said Cori Feist, a genetic counselor with Oregon Health & Science University...

But the insurance industry and some state regulators are beginning to crack down on the ties between genetic counselors and the testing companies. As of this year, some health plans offered by insurer UnitedHealthcare no longer cover certain genetic tests ordered by counselors that work for labs. Cigna Corp. already has a similar policy.

Concerns are also growing that counselors working in close proximity to patients in doctors’ offices may be over-promoting tests. Pennsylvania and Florida have prohibited lab personnel, including genetic counselors, from working at health-care providers’ sites.

George J. Annas, a bioethicist at Boston University’s School of Public Health, said counselors have an incentive to favor companies that pay them, and that may color what they tell patients, including what to say about a test’s limitations. Whenever a “highly competitive commercial business” gets involved in medical choices, “you’ve got problems,” he said...

All prenatal screening tests have limitations, but counselors don’t always explain them clearly, something Jessica Daviso of Andover, Massachusetts, learned in an alarming way. Daviso said her lab-employed counselor never told her “that my test result was probably wrong.”

Daviso, 33, received a prenatal test result from California-based Counsyl Inc., a lab company, in October that indicated a high likelihood her fetus had Turner syndrome, a condition marked by short stature and infertility in girls, according to emails between her and a Counsyl genetic counselor, Kristen Rauch.

Rauch told Daviso that a recent study showed the “false positive” rate for Turner and similar syndromes was about 1 percent, the emails show, and recommended a second test that would confirm the condition.

Daviso and her husband Eugenio then sought out experts at Tufts Medical Center, where a genetic counselor looked at the test and other factors, including her age and other personal data, and estimated there was only about a 14 percent chance that her fetus had Turner’s – not the near certainty that Daviso said she was led to believe.

That’s because the false positive rate is only one factor in measuring a test’s accuracy. In pregnancy, it represents the percentage of times that women carrying healthy fetuses are given false alarms.

But a pregnant woman who receives a positive result needs to know something more: among the much smaller group of women who test positive, how often is the test right? Many prenatal genetic-test companies do not prominently advertise this rate, known as the positive predictive value, the New England Center for Investigative Reporting has found.

After the Tufts input and ultrasounds that have not indicated a problem, Daviso declined to have the more-definitive test, which carries a risk of miscarriage. She is due in April and says she and her husband believe there’s little chance the baby will have Turner.

“The accuracy of these tests comes directly from the labs that analyze the results and seek to profit most from [their] administration,” said Daviso. “The companies are promoting an inaccurate test.”...

Several studies have found that non-invasive test results indicating a fetus is at high risk for some genetic problems can be wrong more than 50 percent of the time.

Some women appear to have terminated pregnancies based on the screening test alone, according to scientists and an industry-funded study. Officials at Stanford University in California said in 2014 that there have been at least three cases of women aborting healthy fetuses relying on results of a genetic screening test.

“Women are not getting complete information,” said Dr. John Williams III, director of Reproductive Genetics at Cedars-Sinai hospital in Los Angeles. “We have seen several cases in which the NIPT test results were false positives.”...

Devon Summersgill said it was her obstetrician, Dr. Neil Russo, who suggested she give a blood sample for Sequenom’s MaterniT21.

After the positive test result, Summersgill said Russo told her the screening test was 99 percent accurate and referred the couple to New Jersey Perinatal Associates, a high-risk pregnancy practice where Limone works. Limone said she is not paid by Sequenom for New Jersey Perinatal test orders.

Summersgill said Limone told her the test was almost certainly accurate. Limone said that the false positive rate for the test was tiny — 0.2 percent, according to medical records the Summersgills shared with NECIR. The Summersgills say Limone told them an amniocentesis would have to be done to confirm the finding.

Dr. Leon G. Smith, Jr., of New Jersey Perinatal, wrote to Summersgill’s obstetrician, saying she was “counseled” about “the definitive nature of NIPT studies” and said that there was a “very high likelihood that this baby has fetal Down syndrome.”

As a teacher, Summersgill had dealt with children with Down syndrome, and she and her husband had already decided abortion wasn’t an option because “we felt she could live a happy and fulfilling life.” They chose not to risk a confirmatory amniocentesis. The test result, and Limone’s comments felt “pretty definitive,” Summersgill said.

They began telling family and friends, that their daughter was almost certainly going to have the condition.

After Kate’s 2014 birth, another genetic test the couple sought from a hospital seemed to rule out Down, and they began to breathe easier. Then came a follow-up call from the obstetrician, Russo, who ordered the original test. The doctor insisted that he had never heard of a MaterniT21 test being wrong, according to Summersgill, and suggested another call to Limone...

Dr. Wayne LaMorte, who teaches medical-test interpretation in a course at Boston University, calculated that a positive Down screen from Sequenom was correct for someone of Summersgill’s age only about half the time.

The Summersgills said Limone never told them the test could be wrong so often for someone of her age group and did not disclose her association with Sequenom when she counseled them on the test results. They say the experience has left them concerned that women may terminate pregnancies based on test results that are shakier than portrayed.

“We squeezed a life time of worry into six months of pregnancy,” Mike Summersgill said. 
Courtesy of a colleague


  1. Christian Millare had a severe seizure on Jan. 5, 2008, and died. He was two years old.

    His mother Amy Williams is convinced, based on his medical records, the opinions of experts, and the published literature, that her son's life didn't have to come to such a premature end. Eight years later, Williams is suing Quest Diagnostics, one of the largest reference labs in the US, and its subsidiary Athena Diagnostics, which in 2007 tested Christian for mutations in the SCN1A gene.

    I 2007, Christian's doctors sent his blood sample to Athena to gauge if he had mutations in the SCN1A gene, which is involved in the mechanism that controls the flow of sodium ions from neuron to neuron. Defects in SCN1A can throw off this process, creating an imbalance of excitatory and inhibitory electrical impulses in the brain and causing seizures. Mutations in SCN1A are well known in the literature to cause Dravet syndrome, a severe form of epilepsy that impacts one in 21,000 infants. Dravet syndrome babies start having seizures a few months after birth and have developmental delays. The Dravet Syndrome Foundation estimates that 80 percent of patients will have an SCN1A mutation.

    In the complaint, Williams accuses Athena of misclassifying her son's SCN1A mutation as a variant of unknown significance (VUS), meaning that the lab determined there wasn't sufficient evidence in 2007 to link the mutation to epilepsy or determine it was benign. Williams asserts there was enough evidence at the time that her son's mutation was disease-causing. The complaint cites two papers, one published in June 2006 and one published in March 2007, which mention Christian's specific mutation had been studied and seen in another patient who had epileptic encephalopathy.

    One of the authors of the 2007 paper, published in Brain, is Sat Dev Batish, who then was and still is Athena's chief director of genetics. Moreover, a patent that Australian firm Bionomics licensed to Athena for the development of its SCN1A test lists the mutation (1237T>A) that Christian had as one that "disrupts the functioning of an assembled ion channel so as to produce an epilepsy phenotype."(continued)

  2. (continued)Further complicating matters, amid the litany of workups and tests performed on Christian, Williams claims the report that Athena issued in June 2007 with the VUS finding never made its way to her. She learned about it in 2014, while searching for more definitive answers to why Christian passed away. Newly married, Williams was fearfully considering whether she could have a child again. Uncertain if she had passed on a genetic abnormality to Christian, she didn't want to risk it. "My body can't go through it again," Williams told GenomeWeb. "My heart can't go through it."

    Williams was able to obtain the original VUS report from Athena in the fall of 2014, and learned that the company now had classified the SCN1A mutation as disease-causing. Athena issued an amended report in 2015, but the published studies listed in the document as evidence the lab used to make the variant classification are the same as the 2007 report.

    "Athena seemed to make a series of mistakes, according to the complaint. Although the initial mistake, while extremely unfortunate and ultimately tragic, may be chalked up to human error, it does appear that they did not follow their own variant classification scheme," said Girish Putcha, who has directed a number of clinical labs. He reviewed the plaintiff's complaint for this article but is not involved in the case.

    The complaint notes that, based on Athena's own variant classification criteria described in the 2007 report, Christian's mutation should have been deemed an "amino acid change of unknown significance," instead of a VUS. In 2010, Athena launched a program called Athena Insight, which investigates the pathogenicity of variants and categorizes them on a seven-point scale...(continued)

  3. (continued)Further, "upon information and belief, prior to 2015, [Quest and Athena] recognized that a substantial number of patients were affected by similar erroneous SCN1A … sequencing reports," the complaint states.

    If the case goes forward, a jury will have to decide whether there was sufficient evidence in the literature in 2007 for Athena to determine a pathogenic link between Christian's mutation and Dravet. "We can demonstrate that the change was made between the 2007 report and what we received in 2015. We do not know when that change was made by Quest and Athena." Cranshaw told GenomeWeb. "That's why we've brought it to the court and why we think a jury should consider the facts in the case."

    John Conley, a law professor at the University of North Carolina, told GenomeWeb that if this case goes forward it could impact the standard of care provided by a genetic testing lab, but first, plaintiffs will have to prove that if Athena hadn't been negligent, Christian wouldn't have died. "That to me is their biggest challenge," said Conley, an expert in biotech and IP law. "The link between a genetic test and an outcome is so complex and attenuated, that's going to be hard to explain factually and hard to prove."...

    "I often felt like an investigator tracking a serial killer trying to figure out what the triggers were, but eventually gave up because nothing made sense," she said. Christian's immune system was weak, so any illness could set off a seizure. As a precaution, he had his tonsils and adenoids removed. Still, nothing seemed to help. Sometimes he'd shake. Other times one side of his body would stiffen like during a stroke. He'd seize at the grocery store, when he was overexcited, or too tired. The visits to the hospital grew more frequent, and there were endless tests and workups.

    One of these evaluations was to see if a mitochondrial disorder could be causing his seizures. The results suggested this might be the case, so Christian was treated with increasing doses of the sodium channel-blocking drugs carbamazepine and lamotrigine, which are standard treatments for epileptic seizures when they are not due to Dravet syndrome. (continued)

  4. Also, in answers to written questions (or interrogatories) from the plaintiff, Quest and Athena said that the doctors treating Williams' deceased son "may be liable in whole or in part to the plaintiff or to the defendants."...

    In response to the plaintiff's questions, Quest and Athena said that Christian's doctors may be liable because, based on the 2007 SCN1A VUS result from Athena, Christian's doctors failed to test his parents in order to rule out Dravet Syndrome and continued to treat him with sodium channel blocking medications "when they apparently had no beneficial effect on [his] symptoms."

    In her complaint, Williams identifies Timothy Livingston, then employed at University of South Carolina Medical School, as Christian's treating neurologist who prescribed sodium channel blocking agents. The SCN1A genetic test was ordered "at the direction of" Christian's clinical geneticists John Shoffner and Frances Kendall in January 2007, while they were at Horizon Molecular Medicine in Atlanta, according to the complaint. Shoffner has managed patients with mitochondrial disorder for nearly 30 years and identified some of the first gene mutations that cause such diseases. Christian's SCN1A test report indicates Athena should have issued the report to Shoffner...

    While Williams' lawyers have set out to prove that Athena was negligent and that negligence caused Christian's death, it wasn't unexpected that Quest and Athena would turn their attention to Christian's doctors. "Look for the defendant down the road to lay off blame on the doctor," John Conley, a law professor at the University of North Carolina and an IP and biotech law expert, told GenomeWeb last week.

    Williams previously told GenomeWeb that she hopes the lawsuit results in a change in the regulations so labs are held more accountable for the results they report. Many experts in the genomics field agree. Russ Altman, director of the biomedical informatics program at Stanford University Medical School, said there needs to be a robust infrastructure for tracking the latest information on variants, as well as standards for determining when a variant is actionable, interpretable, or truly of unknown significance.