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Sinai Health, BGI to Run RNA Sequencing Trials to Develop Better Diagnostics for Preterm Birth

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SAN FRANCISCO (GenomeWeb) – The Lunenfeld-Tanenbaum Research Institute, which is part of the Sinai Health System in Toronto, is collaborating with BGI to develop a better preterm birth diagnostic test that is able to distinguish false preterm labor from actual preterm labor.

The researchers received a C$4.6 million ($3.6 million) grant from Genome Canada's Genomic Applications Partnership. It was one of five projects to receive funding as part of a C$24.6 million investment from Genome Canada, provincial governments, nonprofits, and private companies.

The researchers plan to initially run a three-year, 300-patient discovery trial involving RNA sequencing on BGI's BGISEQ-500 instrument to identify a gene expression signature to help doctors determine whether pregnant women undergoing threatened pre-term labor — meaning they are having contractions prior to 37 weeks gestation — are likely to deliver a baby within the next couple of days.

Stephen Lye, senior investigator at the Lunenfeld-Tanenbaum Research Institute, who is leading the study, said that the goal is to improve upon the current gene expression signature. In addition, he said, the team plans to conduct a separate study to see whether they can identify a gene expression signature in women early on in pregnancy that predicts their risk for preterm birth.

Preterm birth is the most common pregnancy complication with around 15 million babies born prematurely annually, according to the World Health Organization. Complications from preterm birth are the leading cause of death of children under five.

Approximately 2 million women in North American come to the hospital with threatened pre-term labor each year; however, less than 20 percent go on to deliver preterm. Women who are likely to give birth prematurely should be admitted to the hospital and treated, but differentiating those women from those who will end up delivering at full term is difficult.

Lye's team previously conducted a microarray-based study analyzing gene expression from whole blood samples of women with threatened pre-term labor and identified a gene expression signature that could classify whether participants would or would not have a pre-term birth within 48 hours. That test, described in PLOS One in 2014, had a sensitivity of 71 percent and specificity of 76 percent.

However, Lye said that he thinks the test can be improved on. Specifically, he said, there is some evidence to suggest that focusing on white blood cells — specifically the monocytes, lymphocytes, and neutrophils — rather than whole blood, will improve the signal-to-noise ratio. In addition, he said, the previous test was developed using microarray technology, but RNA sequencing will enable a broader search of both mRNA and noncoding RNA.

Improving the test's accuracy is critical because women who are suspected to deliver preterm undergo treatment that would be unnecessary and could even have harmful side effects for normal pregnancies, Lye said.

For instance, Lye said that there are two types of drugs given to women who are diagnosed as likely to deliver preterm. One is a drug that attempts to slow down labor. The other is a steroid, which helps mature the fetal lungs. "The biggest problem that premature babies have is oxygenating their bodies," Lye said.

A 24- or 25-week fetus is less than one pound and can often fit in the palm of a hand, Lye said. Their lungs are severely underdeveloped. If a full-term fetus' lungs are like a "big oak tree in the middle of summer with lots of branches and leaves," then a 25-week-old fetus is "like a sapling in spring," with no branching, no air sacs and limited ability to deliver oxygen, he said.

The drug to slow down labor essentially just delays labor for one or two days, just enough time for the steroid to begin to take effect and help open up the lungs' airways.

But, the drugs can have cardiovascular side effects in the mother, and there is some evidence that steroids given to a fetus that develops to full term can end up leading to abnormalities in brain development. So, determining who should and should not be treated for preterm birth is critical.

In the study, the Lunenfeld-Tanenbaum Research Institute team will partner with BGI, which will provide the sequencing technology and some in-kind support, Charles Bao, general manager of BGI Americas said. Bao said the installation of the BGISEQ-500 will be the first installation of its instrument in Canada. In the future, he said that the researchers may also use BGI's MGISEQ-2000, a higher-throughput, faster instrument that BGI announced last month.

Lye said that the researchers will enroll women who present with threatened pre-term labor. From a blood sample, they will isolate white blood cells and perform whole-transcriptome sequencing. In the discovery phase, the researchers aim to sequence samples from 100 women who go on to deliver within 48 hours and 200 women who progress to full term before delivering. The researchers will compare gene expression profiles between the two cohorts and incorporate clinical information to develop a predictive test. Lye said that information such as whether a woman had a previous preterm birth or experienced bleeding during pregnancy can also be risk factors that, combined with gene expression, can improve the test's accuracy.

"Having clinical information can put the biomarker in context that allows it to be more predictive," Lye said.

Once the researchers identify the gene expression signature, they plan to validate the test on different samples from women in both Canada and China in order to validate the test.

Lye said that the premise behind looking at white blood cells, and monocytes in particular, is that there is some data suggesting that monocytes are one of the cell types that target the uterus to trigger the onset of labor. Pregnancy is a "really dynamic remodeling of the uterus," he said. It has to grow from the size of a small orange to be able to hold a full-term baby plus amniotic fluid. It also has to increase its vasculature system to bring more blood to the area, and then after birth, it has to remodel once again to return to its original size.

"There's lots of data to suggest that maternal white blood cells contribute to these remodeling events," Lye said. "And the ones we think are playing a big role are the monocytes, and we're also looking at the lymphocytes and neutrophils," he said.

He anticipated that the researchers would take three years to conduct the study and get a test ready for commercialization. Although RNA sequencing will be used for the discovery work, Lye said that a diagnostic test would likely be based on multiplex PCR "because the critical thing will be speed," he said.

In a separate study that is not part of the Genome Canada grant but for which the Lunenfeld-Tanenbaum Research Institute team will also collaborate with BGI, Lye said the researchers want to study larger numbers of women early in their pregnancy to see whether there are gene expression differences that predict the risk for preterm birth earlier on. For that study, he said the goal is to recruit around 2,000 women. In addition, he said that preliminary research indicates that the gene expression pattern for the early prediction test will be different than that for the threatened pre-term labor diagnostic. "The white blood cells are responding to different signals earlier in pregnancy, and they change their expression in response to those signals."

The larger 2,000-patient study will enable the researchers to look for gene expression signatures of other pregnancy-related complications, like pre-eclampsia, Lye said. "We hypothesize that different signatures will predict different outcomes," he said. 

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