Posted on by Dr. Francis Collins
Back in April 2003, when the international Human Genome Project successfully completed the first reference sequence of the human DNA blueprint, we were thrilled to have achieved that feat in just 13 years. Sure, the U.S. contribution to that first human reference sequence cost an estimated $400 million, but we knew (or at least we hoped) that the costs would come down quickly, and the speed would accelerate. How far we’ve come since then! A new study shows that whole genome sequencing—combined with artificial intelligence (AI)—can now be used to diagnose genetic diseases in seriously ill babies in less than 24 hours.
Take a moment to absorb this. I would submit that there is no other technology in the history of planet Earth that has experienced this degree of progress in speed and affordability. And, at the same time, DNA sequence technology has achieved spectacularly high levels of accuracy. The time-honored adage that you can only get two out of three for “faster, better, and cheaper” has been broken—all three have been dramatically enhanced by the advances of the last 16 years.
Rapid diagnosis is critical for infants born with mysterious conditions because it enables them to receive potentially life-saving interventions as soon as possible after birth. In a study in Science Translational Medicine, NIH-funded researchers describe development of a highly automated, genome-sequencing pipeline that’s capable of routinely delivering a diagnosis to anxious parents and health-care professionals dramatically earlier than typically has been possible .
While the cost of rapid DNA sequencing continues to fall, challenges remain in utilizing this valuable tool to make quick diagnostic decisions. In most clinical settings, the wait for whole-genome sequencing results still runs more than two weeks. Attempts to obtain faster results also have been labor intensive, requiring dedicated teams of experts to sift through the data, one sample at a time.
In the new study, a research team led by Stephen Kingsmore, Rady Children’s Institute for Genomic Medicine, San Diego, CA, describes a streamlined approach that accelerates every step in the process, making it possible to obtain whole-genome test results in a median time of about 20 hours and with much less manual labor. They propose that the system could deliver answers for 30 patients per week using a single genome sequencing instrument.
Here’s how it works: Instead of manually preparing blood samples, his team used special microbeads to isolate DNA much more rapidly with very little labor. The approach reduced the time for sample preparation from 10 hours to less than three. Then, using a state-of-the-art DNA sequencer, they sequence those samples to obtain good quality whole genome data in just 15.5 hours.
The next potentially time-consuming challenge is making sense of all that data. To speed up the analysis, Kingsmore’s team took advantage of a machine-learning system called MOON. The automated platform sifts through all the data using artificial intelligence to search for potentially disease-causing variants.
The researchers paired MOON with a clinical language processing system, which allowed them to extract relevant information from the child’s electronic health records within seconds. Teaming that patient-specific information with data on more than 13,000 known genetic diseases in the scientific literature, the machine-learning system could pick out a likely disease-causing mutation out of 4.5 million potential variants in an impressive 5 minutes or less!
To put the system to the test, the researchers first evaluated its ability to reach a correct diagnosis in a sample of 101 children with 105 previously diagnosed genetic diseases. In nearly every case, the automated diagnosis matched the opinions reached previously via the more lengthy and laborious manual interpretation of experts.
Next, the researchers tested the automated system in assisting diagnosis of seven seriously ill infants in the intensive care unit, and three previously diagnosed infants. They showed that their automated system could reach a diagnosis in less than 20 hours. That’s compared to the fastest manual approach, which typically took about 48 hours. The automated system also required about 90 percent less manpower.
The system nailed a rapid diagnosis for 3 of 7 infants without returning any false-positive results. Those diagnoses were made with an average time savings of more than 22 hours. In each case, the early diagnosis immediately influenced the treatment those children received. That’s key given that, for young children suffering from serious and unexplained symptoms such as seizures, metabolic abnormalities, or immunodeficiencies, time is of the essence.
Of course, artificial intelligence may never replace doctors and other healthcare providers. Kingsmore notes that 106 years after the invention of the autopilot, two pilots are still required to fly a commercial aircraft. Likewise, health care decisions based on genome interpretation also will continue to require the expertise of skilled physicians.
Still, such a rapid automated system will prove incredibly useful. For instance, this system can provide immediate provisional diagnosis, allowing the experts to focus their attention on more difficult unsolved cases or other needs. It may also prove useful in re-evaluating the evidence in the many cases in which manual interpretation by experts fails to provide an answer.
The automated system may also be useful for periodically reanalyzing data in the many cases that remain unsolved. Keeping up with such reanalysis is a particular challenge considering that researchers continue to discover hundreds of disease-associated genes and thousands of variants each and every year. The hope is that in the years ahead, the combination of whole genome sequencing, artificial intelligence, and expert care will make all the difference in the lives of many more seriously ill babies and their families.
 Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation. Clark MM, Hildreth A, Batalov S, Ding Y, Chowdhury S, Watkins K, Ellsworth K, Camp B, Kint CI, Yacoubian C, Farnaes L, Bainbridge MN, Beebe C, Braun JJA, Bray M, Carroll J, Cakici JA, Caylor SA, Clarke C, Creed MP, Friedman J, Frith A, Gain R, Gaughran M, George S, Gilmer S, Gleeson J, Gore J, Grunenwald H, Hovey RL, Janes ML, Lin K, McDonagh PD, McBride K, Mulrooney P, Nahas S, Oh D, Oriol A, Puckett L, Rady Z, Reese MG, Ryu J, Salz L, Sanford E, Stewart L, Sweeney N, Tokita M, Van Der Kraan L, White S, Wigby K, Williams B, Wong T, Wright MS, Yamada C, Schols P, Reynders J, Hall K, Dimmock D, Veeraraghavan N, Defay T, Kingsmore SF. Sci Transl Med. 2019 Apr 24;11(489).
DNA Sequencing Fact Sheet (National Human Genome Research Institute/NIH)
Genomics and Medicine (NHGRI/NIH)
Genetic and Rare Disease Information Center (National Center for Advancing Translational Sciences/NIH)
Stephen Kingsmore (Rady Children’s Institute for Genomic Medicine, San Diego, CA)
NIH Support: National Institute of Child Health and Human Development; National Human Genome Research Institute; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
Credit: Adapted from Nima Mesgarani, Columbia University’s Zuckerman Institute, New York
Computers have learned to do some amazing things, from beating the world’s ranking chess masters to providing the equivalent of feeling in prosthetic limbs. Now, as heard in this brief audio clip counting from zero to nine, an NIH-supported team has combined innovative speech synthesis technology and artificial intelligence to teach a computer to read a person’s thoughts and translate them into intelligible speech.
Turning brain waves into speech isn’t just fascinating science. It might also prove life changing for people who have lost the ability to speak from conditions such as amyotrophic lateral sclerosis (ALS) or a debilitating stroke.
When people speak or even think about talking, their brains fire off distinctive, but previously poorly decoded, patterns of neural activity. Nima Mesgarani and his team at Columbia University’s Zuckerman Institute, New York, wanted to learn how to decode this neural activity.
Mesgarani and his team started out with a vocoder, a voice synthesizer that produces sounds based on an analysis of speech. It’s the very same technology used by Amazon’s Alexa, Apple’s Siri, or other similar devices to listen and respond appropriately to everyday commands.
As reported in Scientific Reports, the first task was to train a vocoder to produce synthesized sounds in response to brain waves instead of speech . To do it, Mesgarani teamed up with neurosurgeon Ashesh Mehta, Hofstra Northwell School of Medicine, Manhasset, NY, who frequently performs brain mapping in people with epilepsy to pinpoint the sources of seizures before performing surgery to remove them.
In five patients already undergoing brain mapping, the researchers monitored activity in the auditory cortex, where the brain processes sound. The patients listened to recordings of short stories read by four speakers. In the first test, eight different sentences were repeated multiple times. In the next test, participants heard four new speakers repeat numbers from zero to nine.
From these exercises, the researchers reconstructed the words that people heard from their brain activity alone. Then the researchers tried various methods to reproduce intelligible speech from the recorded brain activity. They found it worked best to combine the vocoder technology with a form of computer artificial intelligence known as deep learning.
Deep learning is inspired by how our own brain’s neural networks process information, learning to focus on some details but not others. In deep learning, computers look for patterns in data. As they begin to “see” complex relationships, some connections in the network are strengthened while others are weakened.
In this case, the researchers used the deep learning networks to interpret the sounds produced by the vocoder in response to the brain activity patterns. When the vocoder-produced sounds were processed and “cleaned up” by those neural networks, it made the reconstructed sounds easier for a listener to understand as recognizable words, though this first attempt still sounds pretty robotic.
The researchers will continue testing their system with more complicated words and sentences. They also want to run the same tests on brain activity, comparing what happens when a person speaks or just imagines speaking. They ultimately envision an implant, similar to those already worn by some patients with epilepsy, that will translate a person’s thoughts into spoken words. That might open up all sorts of awkward moments if some of those thoughts weren’t intended for transmission!
Along with recently highlighted new ways to catch irregular heartbeats and cervical cancers, it’s yet another remarkable example of the many ways in which computers and artificial intelligence promise to transform the future of medicine.
 Towards reconstructing intelligible speech from the human auditory cortex. Akbari H, Khalighinejad B, Herrero JL, Mehta AD, Mesgarani N. Sci Rep. 2019 Jan 29;9(1):874.
Advances in Neuroprosthetic Learning and Control. Carmena JM. PLoS Biol. 2013;11(5):e1001561.
Nima Mesgarani (Columbia University, New York)
NIH Support: National Institute on Deafness and Other Communication Disorders; National Institute of Mental Health
Posted on by Dr. Francis Collins
My last post highlighted the use of artificial intelligence (AI) to create an algorithm capable of detecting 10 different kinds of irregular heart rhythms. But that’s just one of the many potential medical uses of AI. In this post, I’ll tell you how NIH researchers are pairing AI analysis with smartphone cameras to help more women avoid cervical cancer.
In work described in the Journal of the National Cancer Institute , researchers used a high-performance computer to analyze thousands of cervical photographs, obtained more than 20 years ago from volunteers in a cancer screening study. The computer learned to recognize specific patterns associated with pre-cancerous and cancerous changes of the cervix, and that information was used to develop an algorithm for reliably detecting such changes in the collection of images. In fact, the AI-generated algorithm outperformed human expert reviewers and all standard screening tests in detecting pre-cancerous changes.
Nearly all cervical cancers are caused by the human papillomavirus (HPV). Cervical cancer screening—first with Pap smears and now also using HPV testing—have greatly reduced deaths from cervical cancer. But this cancer still claims the lives of more than 4,000 U.S. women each year, with higher frequency among women who are black or older . Around the world, more than a quarter-million women die of this preventable disease, mostly in poor and remote areas .
These troubling numbers have kept researchers on the lookout for low cost, but easy-to-use, tools that could be highly effective at detecting HPV infections most likely to advance to cervical cancer. Such tools would also need to work well in areas with limited resources for sample preparation and lab analysis. That’s what led to this collaboration involving researchers from NIH’s National Cancer Institute (NCI) and Global Good, Bellevue, WA, which is an Intellectual Ventures collaboration with Bill Gates to invent life-changing technologies for the developing world.
Global Good researchers contacted NCI experts hoping to apply AI to a large dataset of cervical images. The NCI experts suggested an 18-year cervical cancer screening study in Costa Rica. The NCI-supported project, completed in the 1990s, generated nearly 60,000 cervical images, later digitized by NIH’s National Library of Medicine and stored away safely.
The researchers agreed that all these images, obtained in a highly standardized way, would serve as perfect training material for a computer to develop a detection algorithm for cervical cancer. This type of AI, called machine learning, involves feeding tens of thousands of images into a computer equipped with one or more high-powered graphics processing units (GPUs), similar to something you’d find in an Xbox or PlayStation. The GPUs allow the computer to crunch large sets of visual data in the images and devise a set of rules, or algorithms, that allow it to learn to “see” physical features.
Here’s how they did it. First, the researchers got the computer to create a convolutional neural network. That’s a fancy way of saying that they trained it to read images, filter out the millions of non-essential bytes, and retain the few hundred bytes in the photo that make it uniquely identifiable. They fed 1.28 million color images covering hundreds of common objects into the computer to create layers of processing ability that, like the human visual system, can distinguish objects and their qualities.
Once the convolutional neural network was formed, the researchers took the next big step: training the system to see the physical properties of a healthy cervix, a cervix with worrisome cellular changes, or a cervix with pre-cancer. That’s where the thousands of cervical images from the Costa Rican screening trial literally entered the picture.
When all these layers of processing ability were formed, the researchers had created the “automated visual evaluation” algorithm. It went on to identify with remarkable accuracy the images associated with the Costa Rican study’s 241 known precancers and 38 known cancers. The algorithm’s few minor hiccups came mainly from suboptimal images with faded colors or slightly blurred focus.
These minor glitches have the researchers now working hard to optimize the process, including determining how health workers can capture good quality photos of the cervix with a smartphone during a routine pelvic exam and how to outfit smartphones with the necessary software to analyze cervical photos quickly in real-world settings. The goal is to enable health workers to use a smartphone or similar device to provide women with cervical screening and treatment during a single visit.
In fact, the researchers are already field testing their AI-inspired approach on smartphones in the United States and abroad. If all goes well, this low-cost, mobile approach could provide a valuable new tool to help reduce the burden of cervical cancer among underserved populations.
The day that cervical cancer no longer steals the lives of hundreds of thousands of women a year worldwide will be a joyful moment for cancer researchers, as well as a major victory for women’s health.
 An observational study of Deep Learning and automated evaluation of cervical images for cancer screening. Hu L, Bell D, Antani S, Xue Z, Yu K, Horning MP, Gachuhi N, Wilson B, Jaiswal MS, Befano B, Long LR, Herrero R, Einstein MH, Burk RD, Demarco M, Gage JC, Rodriguez AC, Wentzensen N, Schiffman M. J Natl Cancer Inst. 2019 Jan 10. [Epub ahead of print]
 “Study: Death Rate from Cervical Cancer Higher Than Thought,” American Cancer Society, Jan. 25, 2017.
 “World Cancer Day,” World Health Organization, Feb. 2, 2017.
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