"Noninvasive Prenatal Genetic Testing" and Its Flagship Company Are Under Fire. How Many Problems Are Tangled Up Here?

No technology can predict risk with 100% certainty — and in this case, the risk came from how it was sold.

On the evening of Friday, July 13, BGI Genomics published an announcement responding to a report circulating online, BGI's Malignant Turn (《华大癌变》). The report said that a year earlier, a pregnant woman tested by BGI Genomics and told she was "low risk" gave birth to a baby with multiple defects — and that hers was not the only such case. In three pages, BGI Genomics piled up scientific evidence and government reports, trying to win back confidence in the technology called "noninvasive prenatal genetic testing," and in the company itself.

The effort collapsed on Monday. BGI Genomics's share price fell 10% on July 16, its daily limit, closing at 92.3 yuan a share. The company had listed on the ChiNext board of the Shenzhen Stock Exchange a year earlier, on July 14, 2017, and Monday also happened to be the day 200 million of its shares came off lock-up.

That same day, BGI Genomics followed up with a "Letter to Expectant Mothers", written in a plainer, warmer voice: "The clinical diagnosis a doctor gives, based on a combination of tests, is extremely important. Expectant mothers, please listen carefully to your doctor's advice."

If you want to read up on noninvasive prenatal genetic testing on BGI Genomics's official website, you again get a choice between an "expert version" and a "general public version." China's largest genetic testing company began as the Institute of Genomics under the Chinese Academy of Sciences. After a spell of controversy over partners "running public and private business side by side," it became a model of industry, academia, and research combined. In the consumer market, BGI Genomics's 2017 revenue topped 2 billion yuan, more than 1.136 billion of it from reproductive health products.

In Friday's announcement, BGI Genomics said that as of May 31, 2018, "BGI Genomics has provided noninvasive prenatal genetic testing to more than 3.13 million expectant mothers worldwide."

The same announcement explained where the company's claim of 99.99% screening accuracy comes from: among 2.48 million samples from babies already born, 70 cases have been confirmed so far in which a baby with an abnormal chromosome count was born anyway, for one reason or another — about one in every 35,000 tests. That is a number drawn from BGI Genomics's own samples, not a probability describing how accurate the technology is.

"The more data you accumulate, the more precise it gets," said Yin Ye, CEO of BGI Genomics, on an audio program about genetics that the company produces itself. The episode, Noninvasive Prenatal Testing: The Choice of a Million People (《无创产前检测，百万人的选择》), aired just before Down Syndrome Day on March 21, 2017. On it, Yin Ye claimed that whether you looked at "end-user acceptance" or "technological maturity," noninvasive prenatal genetic testing had already become the "first-choice service" for doctors and pregnant women screening for Down syndrome.

Figures Yin Ye gave on the program showed that uptake was indeed rising, and fast. He said BGI had provided roughly as many noninvasive prenatal genetic tests in its first six years combined as it had in the previous 12 months alone — close to 1 million.

Getting Approved Was Once a Problem

For the two or three years around 2013, BGI Genomics and its peers were in an awkward spot. According to a report in Southern Weekly in April 2013, someone reported BGI Genomics to the authorities in January 2012 for importing unregistered gene sequencers and their reagents to run prenatal healthy-birth screening at several Shenzhen hospitals.

Noninvasive prenatal genetic testing had not been approved at the time, yet companies and institutions everywhere were offering it. That is where the complaint came from, and the argument never really stopped. Even people who believed in the technology were pessimistic back then, saying that getting it approved any time soon "was a nearly impossible task."

Still, the technology had already shown its pull. It tests for the risk that a fetus has Down syndrome (Trisomy 21), and also for Edwards syndrome (Trisomy 18) and Patau syndrome (Trisomy 13). For Down syndrome it is more accurate than ordinary "Down syndrome screening" (maternal serum screening), which is 65%-80% accurate. It falls short of amniocentesis, which is close to 100% accurate, but it drops amniocentesis's risk of miscarriage. It is a noninvasive method of high-throughput sequencing of cell-free fetal DNA in the mother's blood: all it takes is a little of the pregnant woman's blood, because the fetus's DNA is already in it.

People in the industry keep stressing that this is a screening technology, not a diagnostic one. But often enough, experts qualified in genetic counseling have called it "a prenatal screening technology that approaches the level of a diagnosis."

In those years, testing firms spent most of their effort building ties with hospitals. Even without regulation, people trusted a testing recommendation from a geneticist more than one from a private testing outfit that had appeared out of nowhere.

From May 2010 to noon on April 2, 2013 — nearly three years — BGI Genomics completed only 109,582 test samples. But Yin Ye, then chief operating officer, told a Southern Weekly reporter that BGI Genomics already worked with five or six hundred hospitals. Berry Genomics, another of the largest genetic testing institutions at the time, gave a figure of more than three hundred.

Hospitals are still the most important channel. BGI Genomics's 2017 annual report says the company signed comprehensive cooperation agreements with hospitals including the International Peace Maternity and Child Health Hospital affiliated with Shanghai Jiao Tong University School of Medicine and the First Hospital of Shanxi Medical University, and newly won the backing of several local governments. That backing secures revenue, and investor confidence with it.

Local governments have supported noninvasive prenatal genetic testing for years, even before it was approved. At the end of 2011, the Guangdong Provincial Health Department and the Guangdong Provincial Price Bureau agreed to add noninvasive Trisomy 21 testing to the province's list of priced medical services.

The Southern Weekly report cited above argues that this came out of local governments' hunger to cut birth defects. According to the Report on the Prevention and Treatment of Birth Defects in China (《中国出生缺陷防治报告》), released by the former Ministry of Health in the second half of 2012, the lifetime economic burden of the babies born with Down syndrome in China each year comes to more than 10 billion yuan.

Shenzhen's Support

A year after the complaint, the government of the city where BGI Genomics is based began openly backing the company's push into noninvasive prenatal screening. In January 2013, BGI Genomics received the Guangdong Provincial Health Department's approval for its noninvasive test for fetal chromosomal aneuploidy.

On a later audio program, Yin Ye said that they had talked it over with the Shenzhen government, from the very beginning, about how a technology like this should be positioned. He also said that by 2017, half of all pregnant women in Shenzhen were choosing it.

In the same month the approval came through, the Shenzhen municipal government held a meeting on how to support BGI Genomics's test. Minutes obtained by a Southern Weekly reporter at the time showed that the meeting decided the city's special industrial development fund would back BGI Genomics's noninvasive prenatal testing technology for three years, from 2013 to 2015, with total funding over those three years capped at 30 million yuan. It also asked the Shenzhen Municipal Health and Family Planning Commission to pick several larger municipal public hospitals with well-run procedures to prepare for the technology and settle health-insurance reimbursement. All of it was done in the name of industrializing frontier biological science.

From May 21, 2013, every pregnant woman who took BGI Health's noninvasive prenatal genetic test got a 600-yuan special government subsidy. BGI Health would also screen for fetal Trisomy 18 and Trisomy 13 free of charge. On top of that, a woman tested at one of four municipal pilot hospitals in Shenzhen had another 400 yuan paid on her behalf by the maternity insurance fund. That made noninvasive prenatal testing cheaper in Shenzhen than anywhere else. Yin Ye put the price at about 450 yuan.

At this year's Two Sessions, Yuan Yafei, a member of the National Committee of the Chinese People's Political Consultative Conference and chairman of Sanpower Group, proposed speeding up the rollout of noninvasive prenatal screening, and held up Shenzhen as the example to follow.

Outside Shenzhen, the Hunan Provincial Health Department approved Hunan Jiahui Genetics Specialist Hospital in 2011 to use noninvasive prenatal genetic testing as a diagnostic technique, not merely a screening one. One of the three largest noninvasive prenatal testing institutions before that, the Prenatal Diagnosis Center of Xiangya Hospital, Central South University, was in Changsha too.

Only 340 Medical Institutions Can Diagnose?

The National Health and Family Planning Commission finally accepted this genetic testing technology, which had spread before it was ever approved, and in 2015 tried to bring it under rules. The Commission's Department of Maternal and Child Health Services issued the Notice on Pilot Clinical Applications of High-Throughput Gene Sequencing for Prenatal Screening and Diagnosis at Prenatal Diagnosis Institutions (《关于产前诊断机构开展高通量基因测序产前筛查与诊断临床应用试点工作的通知》), naming 109 medical institutions as clinical pilot sites.

When the pilot ended in 2016, the Commission's new notice said that, in principle, any hospital or medical laboratory qualified to do prenatal testing could carry out noninvasive DNA prenatal screening and diagnosis. That meant the institutions offering the screening could also deliver the final diagnosis.

The loose mood did not last. A list the Commission released on May 17, 2018 showed that, as of December 31, 2017, only 340 medical institutions had been approved to perform prenatal diagnostic techniques. That is fewer than the number of hospitals BGI Genomics worked with before the technology was approved at all.

According to that list, the Wangcheng District Maternal and Child Health Hospital in Changsha, Hunan — the one named in BGI's Malignant Turn — is not approved to perform prenatal diagnostic techniques. Neither is the Jianghan District Maternal and Child Health Hospital in Wuhan, which since last September has offered older expectant mothers in the city free noninvasive prenatal genetic testing and diagnosis.

An operator on the Wuhan mayor's hotline said the free service, which runs through August this year, has not been affected by the controversy. The technology, the operator said, never could guarantee 100% accuracy.

The Argument About Probability

Dennis Lo told The Paper this month that medical bodies need to set guiding principles — spelling out, for instance, the minimum number of DNA strands a testing company must sequence, and the fetal DNA concentration required.

For a noninvasive prenatal genetic test to be as accurate as possible, fetal DNA has to make up more than 4% of the DNA in the pregnant woman's blood. Past 10 weeks of pregnancy, though, 98% of women are already above that 4%. No rule sets the concentration directly, but hospitals generally advise doing noninvasive prenatal screening after week 12.

Dennis Lo's team invented the technology. It published the NIPT technique in 2008 and ran the world's first large clinical trial of it. From 753 cases completed over three years, the team arrived at a detection rate of 99%. The clinical results were published in January 2011. NIPT launched in the United States in October 2011, at first only as a screen for Down syndrome, later extended to Trisomy 18 (Edwards syndrome), Trisomy 13 (Patau syndrome), and other chromosomal disorders.

In 2012, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) jointly said they recommended noninvasive prenatal genetic testing for mothers over 35, women who had already borne a child with a trisomy condition, and women whose ultrasound results pointed to a high risk of aneuploidy.

One risk in how the technology is used, Dennis Lo believes, is that "not all companies and not all labs actually do NIPT the same way, and I think a lot of pregnant women, or doctors, don't understand that," he told The Paper.

On accuracy, Dennis Lo said NIPT detects Down syndrome in 99.3%-99.5% of cases, and that its detection rates for Trisomy 13 and Trisomy 18 are lower.

At the same time, figures Dennis Lo provided showed that at some hospitals in Europe and the United States, amniocentesis is now used half as often. Because doctors are no longer as practiced at it as they once were, he argues, amniocentesis's miscarriage rate of under 0.5% may be an underestimate.

Because the sale of intellectual property is involved, though, Dennis Lo may have an interest in the question. The Chinese University of Hong Kong, where his team works, filed a patent on the technology and has licensed it to companies that sell genetic testing.

Misleading Marketing Can Work on Doctors and Pregnant Women at Once

On one occasion after another, remarks by BGI Genomics chairman Wang Jian have made the technology sound seamless.

On May 28 this year, Wang Jian told the China International Big Data Industry Expo in Guizhou that BGI Genomics had laid down three rules of discipline for its staff, one of them being that employees' newborns must not have birth defects. If one did, it would be a "disgrace," proof "that we're fooling society."

Another BGI Genomics product carries the name "whole genome." The "whole genome" test claims to screen for Trisomy 21, Trisomy 18 and Trisomy 13, and "may also detect information on other chromosomal abnormalities and on partial chromosomal deletions and duplications" — but it does not cover sex chromosome abnormalities. "Whole genome" in fact refers to whole-genome mapping, which sequences the entire genome in the plasma in a random but representative way, as opposed to the usually cheaper targeted sequencing, which reads only specific chromosomes.

Pregnant women generally do not know the difference. They think they have bought a foolproof medical service that screens every chromosome.

Worse, doctors' knowledge has not kept up with the speed at which new products reach the market — and the policy encouraging second children will only speed it up further. Since these tests require a doctor's prescription, misleading marketing can work on doctors and pregnant women at the same time.

"In practice, some of the medical workers who deal directly with pregnant women do not understand the indications for NIPT well enough themselves, or fail to explain them accurately. Add to that the pregnant women and family members who do not read the informed consent form carefully, and you get a skewed understanding of NIPT's limits," said Ma Duan, deputy director of the Birth Defects Research Center at Fudan University in Shanghai, in an interview with a Southern Weekly reporter this month.

In its "Letter to Expectant Mothers" of July 16, BGI Genomics noted that the case described in BGI's Malignant Turn fell outside what "noninvasive prenatal genetic testing" screens for. So it could not be covered, either, by the genetic testing insurance BGI Genomics buys for the women it tests.

BGI Genomics's website says women who buy noninvasive genetic screening usually also receive a testing insurance policy, to cover the risk that a screening technology gets it wrong. Under its terms, if a noninvasive prenatal DNA test comes back low-risk but the live-born baby has one of the covered conditions, the payout is 400,000 yuan.

If the result comes back high-risk, then — as in the Technical Standards for Prenatal Screening and Diagnosis Using Cell-Free Fetal DNA in Maternal Peripheral Blood (《孕妇外周血胎儿游离 DNA 产前筛查与诊断技术规范》), issued in 2016 — the company advises an invasive prenatal diagnostic procedure to confirm.

As of publication, BGI Genomics's shares hit the daily limit down again on July 17, closing at 83.07 yuan.

Cover image from chuttersnap on Unsplash, and Annie Spratt on Unsplash