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This white paper is based on a webinar presentation E\6LYDQ%HUFRYLFL&KLHI7HFKQRORJ\2IƓFHUDW.DULXV and Lisa McFerrin, Genomics Bioinformaticist at $PD]RQ:HE6HUYLFHVLQZKLFKWKH\GLVFXVVHGWKH advantages and challenges of diagnosing infections by analyzing microbial cell-free DNA. Dr. Bercovici began with a case study illustrating the advantages of the Karius Test, a microbial cell- free DNA test. A one-month-old baby was brought into the hospital with a persistent fever, but blood culture tests came back negative. Doctors prescribed broad-spectrum antibiotics, but two weeks later, the baby returned to the hospital with fever and now a swollen shoulder. More tests came back negative, and the doctors switched the antibiotic prescription. "They didn't change their decision based on new data that was presented by a conventional method," Dr. Bercovici pointed out. "Rather, they simply assumed that the previous treatment didn't work." When cultures from the ŴXLG LQ WKH VZROOHQ VKRXOGHU DOVR FDPH EDFN negative, the doctors reached out to Karius. 7KH .DULXV 7HVW SURYLGHG D GHƓQLWLYH DQVZHU within 24 hours: the culprit was Streptococcus agalactiae. "The doctors immediately removed all the ineffective or non-targeted treatment, and prescribed the right drug," said Dr. Bercovici. "And now the baby is doing better." The story highlights several limitations of conventional infectious disease testing, Dr. Bercovici noted. Conventional tests exhibit lower and narrower sensitivity and often require invasive procedures for deep tissue infections. Specialized tests, such as PCR tests, detect the presence or absence of only a handful of pathogens. "You either ordered the right test, or you simply won't see any positive answer," he said. Most conventional tests are qualitative, meaning they can only detect the presence or absence of a microbe, but not the amount. Finally, once a drug has been given, the action of the antibiotic will interfere with the ability of the test to detect the microbe. Patients receive a lot of empiric treatment, Dr. Bercovici said, because of the degree of 1 38 uncertainty doctors face. This leads to an overuse of broad-spectrum antibiotics, and the patient may be subject to unsafe procedures and ineffective treatment. He explained that the Karius Test reduces this uncertainty by providing a broad and accurate detection of more than 1,000 pathogens from a single blood draw, with no biopsy needed. The non-invasive test detects both bloodstream and deep infections, with a faster time-to-diagnosis than traditional pathogen cultures across several indications. Cell-free DNA has gained popularity as a useful biomarker for various conditions, including fetal abnormalities, transplant rejection, and tumor SURƓOLQJLQFDQFHU)LYH\HDUVDJR'U%HUFRYLFL said, "at Stanford University we observed that when a patient has an infection, the infectious microbe sheds cell-free DNA into the bloodstream." "Now, where Karius innovated is in the analysis of microbial cell-free DNA, not human cell-free DNA, and how we leverage this emerging analyte towards improving diagnosis of infectious diseases," said Dr. Bercovici. Although the microbial DNA makes up only one in 100,000 of the circulating cell-free DNA molecules, it's enough to work with. "You get A GENOMEWEB / AWS WHITE PAPER JANUARY 2020 SIVAN BERCOVICI, PhD &KLHI7HFKQRORJ\2IƓFHU Karius LISA MCFERRIN, PhD Genomics Bioinformaticist Amazon Web Services JANUARY 2020