For the first time, researchers claim to have used a healthy person's complete genome sequence to predict his or her risk for dozens of diseases and how that person will respond to several common medications.

The risk analysis, from the Stanford University School of Medicine, also incorporates more traditional information such as a patient's age and gender and other clinical measurements. The resulting, easy-to-use, cumulative risk report likely will catapult the use of such data out of the lab and into the waiting room of average physicians within the next decade, say the scientists.

"The $1,000 genome is coming fast," says Dr. Euan Ashley, a cardiologist and assistant professor of medicine, referring to the cost of sequencing individual's entire DNA. "The challenge lies in knowing what to do with all that information. We've focused on establishing priorities that will be most helpful when a patient and a physician are sitting together looking at the computer screen."

Such priorities include whether a certain medication is likely to work for that particular patient, or if it's likely to have adverse side effects. They also include ascertaining how a patient's obesity or smoking habit can combine with his or her inherent genetic risk for—or protection against—heart attack or diabetes. In short, the focus will be on priorities that result in concrete clinical recommendations for patients based on a degree of data that has never existed before, the researchers say.

"We're at the dawn of a new age in genomics," says Stephen Quake, who is the Lee Otterson Professor of Bioengineering. "Information like this will enable doctors to deliver personalized health care like never before. Patients at risk for certain diseases will be able to receive closer monitoring and more frequent testing, while those who are at lower risk will be spared unnecessary tests. This will have important economic benefits as well, because it improves the efficiency of medicine."

But it may also tell patients things they don't want to know.

Quake made national headlines last August when he used a technology he helped invent to sequence and publish his own genome for less than $50,000, and it is his genome that the researchers analyzed in this newest study. Ashley is the lead author of the research, which was published in the May 1 issue of the Lancet, which claims to be the world's leading general medical journal.

An accompanying article about the ethical and practical challenges of such research, authored by a subset of the researchers involved in the first study, was published in an online-only version of the Lancet. Hank Greely, professor and director of Stanford's Center for Law and the Biosciences, was the senior author of the online piece.

"Patients, doctors and geneticists are about to be hit by a tsunami of genome sequence data. The experience with Steve Quake's genome shows we need to start thinking—hard and soon—about how we can deal with that information," says Greely.

"When combined with other sources of information, genomics has the power to predict the diseases a person is most likely to develop and how he or she might respond to certain medicines," says Jeremy Berg, director of the NIH's National Institute of General Medical Sciences, which funded a portion of the work. "This work provides a glimpse of how genomics can play a role in personalizing the medical care of individual patients."

The study began when the 40-year-old, seemingly healthy Quake asked Ashley's opinion about a particular snippet in his genome associated with an inherited disease called hypertrophic cardiomyopathy. People with the condition have enlarged hearts that don't beat effectively and are at risk for sudden cardiac death. Quake was interested because a distant relative had died unexpectedly in his sleep at the age of 19, presumably from some type of heart problem. Ashley, who runs Stanford's Hypertrophic Cardiomyopathy Center, was alarmed.

"Given his family history and the particular genetic variation Steve has, I recommended that he be screened for the condition," says Ashley. Quake agreed, but the conversation got the two to thinking about how to analyze the information in Quake's genome on a more global level.

"Several of us had already been thinking about how you would take someone's genomic profile, and translate what's in the billions of base pairs in that DNA to something that's clinically useful," says Ashley, who headed the group of geneticists, physicians, ethicists, and others involved in the study. "Then we realized, 'Hey, we already have someone's genome.'"

What's more, Dr. Atul Butte, assistant professor in bioinformatics, and his lab members already had done a lot of the necessary leg work: They'd spent the previous 18 months meticulously cataloguing publications that associated particular genetic changes called SNPs (for single nucleotide polymorphisms) with effects on specific diseases. It was the first time anyone had compiled all the information in one database.

"We read thousands of publications," says Butte, "and we made a list of every single spot in the genome where we know that, for example, the letter A raises the risk of a particular disease, or the letter T confers protection. And then came Steve with his genome, and we were ready."

Together the researchers designed an algorithm to overlay the genetic data upon what already was known about Quake's inherent risk—based on his age and gender—for 55 conditions, ranging from obesity and diabetes to schizophrenia and gum disease. For example, as a 40-year-old white male, Quake entered the study with a 16 percent chance of developing prostate cancer in his lifetime. But as the computer, based on Quake's genomic sequence, began to incorporate the data of study after study, his risk moved first lower, and then higher.

In the end, after incorporating information about 18 separate variants from 54 studies, they determined Quake's risk of prostate cancer actually is about 23 percent. The opposite is true for his risk of Alzheimer's disease, which began at 9 percent and ended—due to the presence of several protective variants—at about 1.4 percent. The scariest monsters in the closet, however, were obesity, type-2 diabetes, and coronary-artery disease, each of which Quake has a more than 50 percent chance of developing.

Was it alarming? "It's certainly been interesting," says Quake of the findings. "I was curious to see what would show up. But it's important to recognize that not everyone will want to know the intimate details of their genome, and it's entirely possible that this group will be the majority. There are many ethical, educational, and policy questions that need to be addressed going forward."

Of course, a person's environment—in the form of choices he or she makes about diet, exercise, and habits like smoking and drinking—also can affect disease risk powerfully. But if clinicians know that a patient has a higher-than-normal risk for a certain disease, they may recommend certain lifestyle changes more strongly, the researchers say.

"This opens the door to targeted environmental interventions based on a patient's genomics, says Butte. "People who may want more control over their destiny could choose to exercise more, or eat better, or even avoid pesticides more conscientiously."

There's hope, too, in the promise of more effectively using available drugs to combat or prevent disease. Dr. Russ Altman is the principal investigator of the Stanford-managed Pharmacogenetics and Pharmacogenomics Knowledge Base, or PharmGKB. Quake's genome gave his group some new opportunities.

"With Steve, we thought, 'Let's apply everything we know about the effect of human genetic variation on drug response to his entire genome,'" says Altman, who together with Quake chairs Stanford's bioengineering department. "And we came up with a table of drugs that are likely to work well for him, like statins, and others that he might need lower doses of, like warfarin."

Altman says, "With whole-genome sequencing, you only ever have to do it once. Our understanding of the information will keep evolving, but the core data set doesn't change."

That evolving knowledge base will present a particular challenge, the researchers believe. Keeping people up-to-date on new findings involving genetic variants that they carry will be a tricky business.

But what of Quake? A complete physical pronounced him free of any sign of cardiomyopathy, but turned up somewhat elevated lipoprotein levels. Normally, given Quake's health and age, most physicians would take a watch-and-wait approach before recommending medication. In the face of this new information about Quake's lifetime genetic risk, however, and the likelihood, based on the data, that he would respond positively to statins, Ashley suggested he consider taking the cholesterol-lowering drugs. It's the first time anyone has ever made clinical recommendations based on a cumulative assessment of a patient's entire genome.