BGI Releases Non-Invasive Prenatal Testing Results

January 29, 2015 | BGI published the results of its non-invasive prenatal test, the NIFTY, this month in Ultrasound Obstetrics and Gynecology (DOI: 10.1002/uog.14792). The study tracked the clinical performance of the test, in nearly 147,000 pregnancies. The results showed high sensitivity and specificity and no significant difference between high-risk and low-risk pregnant women.

In the paper, the authors estimate that more than 500,000 NIPT have been done worldwide, though population-level data of the test’s performance is still lacking. The study reported the results of tests on 146,958 samples from 508 medical centers in mainland China, which were offered to women at 9 weeks gestation and beyond as either primary or secondary screening. Test results were collected between early 2012 and mid-2013. The published study reports findings for trisomy 21, 18, and 13.

NIFTY is a low-coverage, whole genome sequencing test of plasma cell-free DNA. Cell-free DNA (cfDNA) sequencing was done at “low coverage” on HiSeq2000 platforms.

NIFTY has been available to pregnant women in China since 2010. As of 2014, the NIFTY tests have been offered by more than 2,000 healthcare providers in more than 60 countries including England, Australia, Spain, Singapore, Israel, Czech Republic, Turkey, and Thailand. BGI estimates than nearly 440,000 test samples have been processed so far. Last July, the Chinese Food and Drug Administration approved the NIFTY test in conjunction with BGI's two sequencers: BGISEQ-1000 and BGISEQ-100 for high risk women. BGI contends that the new study results suggest that the test is appropriate for widespread use. 

According to the study’s results, NIFTY identified 1,578 trisomy-positive and 145,380 negative samples. Comparing the results with follow-up confirmatory invasive testing, or by tracking patients' eventual pregnancy outcomes, the study team then calculated the false positive (FPR) and false negative rate (FNR) for each tested trisomy, and the overall sensitivity, specificity, and positive predictive value (PPV).

Interestingly, to incentivize reporting of the pregnancy’s outcome, specifically false negatives, the study paid approximately $32,000 each to nine cases of confirmed NIPT false negative result.

Overall, the study showed the sensitivity of NIFTY as 99.1%, 98.2%, and 100% in trisomies 21, 18, and 13 respectively. Specificity was 99.95%, 99.95% and 99.96% respectively. For T21, the FPR was 0.05 percent, and the PPV was 92.19 percent. For T18, the FPR was also 0.05 percent, and the PPV was 76.6 percent. FPR and PPV for T13 were 0.04 percent and 32.84 percent, respectively.

The study confirms the performance metrics of earlier smaller studies of NIPT from both NIFTY and other providers, in a significantly expanded sample range. The data also shows that the NIFTY test’s performance did not differ substantially among higher- and lower-risk women.

The study identified “high risk” women as those with any risk factor: advanced maternal age (over the age of 35); abnormal sonographic markers; family history of aneuploidy; or previous trisomic fetus.

“In this paper, we showed the first-hand information of NIPT performance in a very large population, and consistency with the accuracy shown in small studies,” corresponding author Wang Wei commented in a press release. “The results also suggested that high quality of NIPT service can be achieved at NGS-based clinical labs with strict protocols and standards.”

Importantly, the study authors noted in the press release that most confirmed false positives and false negatives in the study could be traced to noticeable biological factors, such as maternal copy number variation or mosaicism. Wang said that the group was somewhat surprised to find that low fetal fraction was not a major contributor to NIPT misdiagnoses in their cohort, considering that the importance of fetal fraction has been "overwhelmingly emphasized in the past few years, and low fetal fraction is believed to be a major risk of causing NIPT false results."

Because maternal genetic background played an important role in false positive and false negative results, the authors said, NIPT should be interpreted with those data in mind. The study design called for pre- and post-test genetic counseling, a course that the authors recommend for general testing.

On the whole, the authors believe that their findings suggest that, “it is suitable to offer NIPT as a routine screening test for fetal T21, T18, and T13 in the general population.”