Researchers at Sweden’s Karolinska Institutet have been conducting studies on stroke for many years. Among their findings are studies indicating that stroke victims lack a certain antibody, anti-PC, in their immune systems that normally reduces the risk of arteriosclerosis, a thickening of arterial walls that can lead to stroke.

Their most recent study provides the impetus to move ahead with the development of a preventative vaccine.

Image credit: Doylestown Hospital Stroke Resource Center

The study compared 227 persons who had suffered a stroke during a 13-year period with a control group of 445 sex and age-matched volunteers.  Also controlled were other risk factors such as smoking habits, cholesterol levels, diabetes, body mass index, and blood pressure.  The researchers showed that the stroke group had levels of PC antibodies 30 percent below the average of the control group.  In women who had strokes the level of PC antibodies was almost three times lower than that of the control group.

PC antibodies go to work on phosphorycholine (PC), a class of fat molecules that make up the plaque that form on the inside walls of arteries in arteriosclerosis

So the Karolinska group sees an avenue to prevention of arteriosclerosis and its consequences, including stroke, through the immune system. 

We’re now examining the possibility of developing new immunological treatments for arteriosclerosis

and stroke, either in the form of a vaccine to stimulate the immune defence, or immunisation through the injection of antibodies,” said Professor Johan Frostegård, the study’s lead researcher

Reviewed by Brunilda Nazario, MD, October 4, 2010, by Brenda Conaway  —  After a stroke, you probably have a lot of questions and concerns about how — and even if — you will recover. When will you be able to move your affected limbs? Will you ever be able to speak clearly? Is your independent life gone forever?

“It’s difficult to predict precisely how much function a patient will regain after a stroke,” says Randie M. Black-Schaffer, MD, MA. Schaffer is medical director of the Stroke Program at Spaulding Rehabilitation Hospital in Boston. “How quickly a patient recovers in the first few weeks,” she says, “can give us an indication of how much damage occurred, and we can make some educated guesses based on that.”

According to the National Institute of Neurological Disorders and Stroke, how much of your functional ability you recover depends upon the type of stroke you had, how much brain damage occurred from the stroke, your age, and how quickly rehabilitation begins.

Black-Schaffer advises learning all you can about what caused your stroke and what you can do to avoid further health problems. Use the following questions as a guide when you talk with your doctor about what to expect in the months and years ahead.

1. What caused my stroke?

Eighty percent of all strokes occur when blood flow to the brain is suddenly cut off — usually by a blood clot or some other obstruction. This is called an ischemic stroke. A hemorrhagic stroke occurs when a blood vessel ruptures in the brain.

Knowing the type of stroke you had can help your doctor determine the underlying cause. For example, an ischemic stroke may be caused by a blocked artery due to the buildup of plaque — a mixture of cholesterol and other lipids, or blood fats. People with atherosclerosis, or hardening of the arteries from plaque buildup, are more at risk for this type of stroke. High blood pressure is a common culprit in hemorrhagic stroke. Both of these conditions increase the risk of stroke, and managing them can help prevent a second stroke.

2. Am I at risk for a second stroke?

The overall risk of a second stroke is highest right after a stroke. Three percent of survivors have a second stroke in the first 30 days, and one-third will have another within two years.

“However, individual risk factors are highly variable,” Black-Schaffer says. “That’s why it’s vital to talk with your doctor to understand your specific risk factors and develop a plan to minimize them.”

High blood pressure is the number one cause of stroke and the biggest risk factor for stroke. Having heart disease, high blood cholesterol, or diabetes also puts you at risk. Lifestyle factors that put you at risk include smoking cigarettes, obesity, physical inactivity, heavy alcohol consumption, and illicit drug use.


3. What can I do to help lower my risk of future strokes?

Ask your doctor what you can do to control high blood pressure and any other medical conditions you may have. Also, discuss how to make lifestyle changes that can help lower your risk of stroke, including quitting smoking, eating a healthy diet, managing your weight, and getting regular exercise.

Quitting smoking is one of the best things you can do for your health. Your stroke risk decreases significantly two years after quitting and reaches the level of nonsmokers after five years.

4. What is the stroke recovery process?

Although your stroke rehabilitation program will be tailored to your specific needs, most people follow a similar path. You’ll begin to do assisted exercises in the hospital once your medical condition has stabilized. The goal is to help you regain certain basic functions, such as the ability to eat and dress yourself.

From there, you may go to an in-patient rehab facility where you will receive intensive therapy to help you become more independent. Once you are able to return home, you may receive outpatient therapy or home therapy to help you regain as much of your functions as possible.

Formal rehabilitation takes place for about three to six months. But studies have shown that stroke patients who continue to practice the skills they hope to regain continue to see progress long after a stroke has occurred.

5. Who will be on my stroke rehabilitation team?

During your stroke rehabilitation, you will work with a team of specialists to recover as much function as possible and learn ways to compensate for any loses.

  • Physical therapists will help you regain your strength and balance so you can walk and become more independent. 
  • Occupational therapists will work with you on daily living skills such as eating, dressing, and bathing. 
  • Speech and language pathologists help you overcome difficulties with memory, thinking, speaking, and swallowing.

Depending on your needs, you may see other specialists as well. Be sure to check in with your doctor regularly to discuss how your recovery is going and whether you need additional help. 

6. How long will my recovery from stroke take?

Stroke recovery is different for every patient. Although some people with a mild stroke recover quickly, for most stroke survivors, regaining lost skills is a lifelong process.

“While the biggest gains will be made in the first three months after a stroke, patients can continue to recover some function, even years later,” Black-Schaffer says. “The key is to get into a daily pattern of exercise.” 

7. Am I at risk for depression after a stroke?

Becoming depressed after a stroke is very common. So ask your doctor about the symptoms of depression so that you and your caregivers know what to look for. Post-stroke depression is thought to be caused in part by biochemical changes in the brain. It’s also a completely normal reaction to the losses caused by a stroke. Whatever the reason, treatment is essential. Fortunately, depression can be effectively treated with medication and/or counseling. 


8. What medications will I be taking and do they have any side effects?

Strokes are most often caused by blood clots, so your doctor will probably prescribe anticoagulant or antiplatelet medication, commonly known as blood thinners, to help prevent future strokes. You may also need to take medications to help lower high blood pressure or high cholesterol, treat a heart condition, or manage diabetes.

Be sure to talk with your doctor about your medications so that you understand why you are taking them. Ask about potential side effects and possible food and medicine interactions. To help you keep track, you or your caregiver should write down the name and dose of all your medications, including when and how to take them.   

9. When should I call my doctor?

Talk with your doctor about what symptoms or situations may indicate a call. However, if you notice any of the following signs of stroke, call 911 immediately. Don’t delay — minutes count when it comes to preventing damage from stroke.

  • sudden numbness, paralysis, or weakness, especially on only one side of your body
  • sudden dizziness, problems with walking, or loss of balance or coordination
  • sudden changes in vision
  • drooling or slurred speech
  • sudden confusion or difficulty speaking or understanding speech
  • a sudden, severe headache that is different from past headaches or has no known cause 

10. Where can I get support as a stroke survivor?

Getting support from other stroke survivors can help with your recovery. You can contact the American Stroke Association at 1-800-242-87218721 for help in finding a support program in your area or to find out about online support groups. Another resource for finding out about support groups is the National Stroke Association. Their phone number is 1-800-787-6537

Statins reduce the risk of having a stroke by around a fifth, studies show (file picture)  —  Statins reduce the risk of strokes by about a fifth, a review has shown.

It examined the results of 24 separate studies investigating the cholesterol-lowering drugs, and involving more than 165,000 patients.

The researchers found that the risk of having a stroke fell by 21 per cent for each one millimole per litre decrease in the level of ‘bad’ low-density lipoprotein (LDL) cholesterol in the blood.

And they revealed that statins not only lowered the overall risk of stroke, but also slowed the progression of blockages in the carotid arteries carrying blood to the brain.

One study found that using statins reduced the risk of recurrent strokes by up to 16 per cent.

Previous evidence had suggested only an inconsistent or weak connection between cholesterol levels and stroke risk.

Writing in The Lancet Neurology journal, the researchers from Paris-Diderot University in France, concluded: ‘Lipid ( blood fat) lowering with statins is effective in reducing both initial and recurrent stroke.

‘Because this effect seems to be associated with the extent of LDL cholesterol reduction, the next step is to assess the effectiveness and safety of further reductions in LDL cholesterol after a stroke.’

Drug treatments to raise levels of ‘good’ cholesterol, or highdensity lipoprotein (HDL), might also reduce the risk of stroke, the authors suggested.

STROKE: Remember The 1st Three Letters… S.T.R.

My friend sent this to me and encouraged me to post it and spread the word. I agree. If everyone can remember something this simple, we could save some folks. Seriously.. Please read:


During a BBQ, a friend stumbled and took a little fall – she assured everyone that she was fine (they offered to call paramedics) and that she had just tripped over a brick because of her new shoes. They got her cleaned up and got her a new plate of food. While she appeared a bit shaken up, Ingrid went about enjoying herself the rest of the evening. Ingrid’s husband called later telling everyone that his wife had been taken to the hospital – (at 6:00 pm, Ingrid passed away.) She had suffered a stroke at the BBQ. Had they known how to identify the signs of a stroke, perhaps Ingrid would be with us today. Some don’t die. They end up in a helpless, hopeless condition instead. It only takes a minute to read this…

A neurologist says that if he can get to a stroke victim within 3 hours he can totally reverse the effects of a stroke…totally. He said the trick was getting a stroke recognized, diagnosed, and then getting the patient medically cared for within 3 hours, which is tough.


Have the sense to remember the “3” steps, STR. Read and Learn! Sometimes symptoms of a stroke are difficult to identify. Unfortunately, the lack of awareness spells disaster. The stroke victim may suffer severe brain damage when people nearby fail to recognize the symptoms of a stroke. Now doctors say a bystander can recognize a stroke by asking three simple questions:

S Ask the individual to SMILE
T Ask the person to TALK, to SPEAK A SIMPLE SENTENCE
(Coherently) (i.e. . . It is sunny out today)
R Ask him or her to RAISE BOTH ARMS

*NOTE: Another ‘sign’ of a stroke is this:

Ask the person to ‘stick’ out their tongue. If the tongue is ‘crooked’, if it goes to one side or the other, that is also an indication of a stroke. If he or she has trouble with ANY ONE of these tasks, call 911 immediately and describe the symptoms to the dispatcher. 

STROKE: Remember The 1st Three Letters… S.T.R.

My friend sent this to me and encouraged me to post it and spread the word. I agree. If everyone can remember something this simple, we could save some folks. Seriously.. Please read:


During a BBQ, a friend stumbled and took a little fall – she assured everyone that she was fine (they offered to call paramedics) and that she had just tripped over a brick because of her new shoes. They got her cleaned up and got her a new plate of food. While she appeared a bit shaken up, Ingrid went about enjoying herself the rest of the evening. Ingrid’s husband called later telling everyone that his wife had been taken to the hospital – (at 6:00 pm, Ingrid passed away.) She had suffered a stroke at the BBQ. Had they known how to identify the signs of a stroke, perhaps Ingrid would be with us today. Some don’t die. They end up in a helpless, hopeless condition instead. It only takes a minute to read this…

A neurologist says that if he can get to a stroke victim within 3 hours he can totally reverse the effects of a stroke…totally. He said the trick was getting a stroke recognized, diagnosed, and then getting the patient medically cared for within 3 hours, which is tough.


Have the sense to remember the “3” steps, STR. Read and Learn! Sometimes symptoms of a stroke are difficult to identify. Unfortunately, the lack of awareness spells disaster. The stroke victim may suffer severe brain damage when people nearby fail to recognize the symptoms of a stroke. Now doctors say a bystander can recognize a stroke by asking three simple questions:


Ask the individual to SMILE


Ask the person to TALK, to SPEAK A SIMPLE SENTENCE
(Coherently) (i.e. . . It is sunny out today)


Ask him or her to RAISE BOTH ARMS


*NOTE: Another ‘sign’ of a stroke is this:

Ask the person to ‘stick’ out their tongue. If the tongue is ‘crooked’, if it goes to one side or the other, that is also an indication of a stroke. If he or she has trouble with ANY ONE of these tasks, call 911 immediately and describe the symptoms to the dispatcher.

Types of Stroke

  • Ischaemic Stroke
  • Haemorrhagic Stroke


By Beth Anne Piehl, Special Projects Editor  —  Every second, a person in the world suffers a devastating stroke. In the U.S. alone, approximately 700,000 people experience a stroke annually.

The good news: There are 5.7 million stroke survivors in this country, due in part to advanced training of doctors and nurses, improvements in medical technology and medication and awareness in the general public of the signs and symptoms of stroke that allow for immediate treatment.

Elaine Siwiec, neurology nurse clinician at Northern Michigan Regional Hospital, offered insight into the causes of stroke, risk factors and treatment options, in a Q&A with the News-Review.

PNR: How does a person know if they are having a stroke?
Siwiec: You need to be familiar with the signs and symptoms of stroke. (They include) sudden onset of numbness or weakness of the face, arm or leg on one side; confusion, trouble speaking or understanding; trouble seeing in one or both eyes; trouble walking, dizziness, loss of balance or coordination; and severe headache with no known cause.
Because this is a lot to remember, we teach the Quick Check for Stroke:

F = Facial droop — have the person smile

A = Arm drift — have the person extend their arms and look for a drift

S = Speech abnormal — have the person say something and listen for slurred speech, not using the right words or not speaking at all

T = Time to call 9-1-1.

It is important to recognize symptoms of stroke quickly since the brain ages 3.6 years each hour without treatment.
PNR: Who is most likely to be affected by stroke?
Siwiec: Stroke is more prevalent in blacks (6.8 percent) than whites (2.9 percent) or other races (3.9 percent).

A higher percentage of females reported having had a stroke than males, 3.8 percent and 3.1 percent, respectively. (Statistics from the Michigan Department of Community Health, 2008 report.)

To not understate the problem, each year about 700,000 people experience a new or recurrent stroke. Every 53 seconds, or about every minute, someone in the United States experiences a stroke, and every 3.3 minutes, someone dies of a stroke.
PNR: What are the top risk factors? Can a healthy person, too, have a stroke?
Siwiec: High blood pressure is the number one risk factor for both types of stroke (hemorrhagic or bleeding type and ischemic or type caused by a blockage in a blood vessel supplying blood and oxygen to the brain). High blood pressure, also known as hypertension, results in hardening of arteries that supply the body’s organs with oxygen and nutrient-rich blood.
More risk factors:
Cigarette smoking;
Physical inactivity;
Too much alcohol;
High blood cholesterol;
Obesity and being overweight.
Although it is much less likely, yes, occasionally healthy people have strokes.
PNR: If you lose an ability after a stroke — paralysis, speech impairment — is it possible to regain through therapy or will there likely always be a limitation?
Siwiec: Yes, it is very possible to regain function after a stroke. We used to think that all recovery occurred within the first three months after a stroke. We now know that is not true and recovery can take weeks to months to even years. Even so, stroke is the number one cause of long-term disability in the United States.
PNR: Is there any way to predict stroke?
Siwiec: There really is no way to know if a stroke is going to occur before the symptoms start. However, even though there are some risk factors that cannot be modified such as age, race, sex and family history, there are a number of things we can do to reduce our risk of stroke:

If you smoke, quit.

If you drink alcohol, do so in moderation — no more than one alcoholic drink a day. Remember alcohol is a drug and as such can interact with other drugs. If you don’t drink alcohol, don’t start.

Include exercise in your daily routine. Even a little bit of exercise — a brisk walk, bicycle ride, swim or yard work — can make a difference. Adults should engage in moderate-intensity physical activities for at least 30 minutes on five or more days each week, according to the Centers for Disease Control. Before you start a vigorous exercise program, be sure to check with your doctor.

If your blood pressure is high, work with your doctor to control it.
PNR: Explain how the clot-busting drug works, the time frame for its administration and why it is critical. Can it “reverse” a stroke and its damage?
Siwiec: In 1996, the FDA approved the drug t-PA that can reverse the effects of a stroke caused by a blocked blood vessel (ischemic). The drug must be given within three hours of onset.
Many people ignore the symptoms and don’t get to an emergency room in time to receive the medication.

TPA works by dissolving the clot which has blocked the artery causing the stroke and hence blood is re-supplied to the brain before nerve cell death has occurred. It can result in miraculous recoveries in many patients, but not necessarily all.

Although the drug can be given up to three hours after onset of symptoms, the sooner you get it the better your chances for improvement. Also, many tests have to be performed before administering the TPA, so showing up at the ER at three hours would actually be too late.
PNR: How is Northern Michigan Regional Hospital a leader in stroke treatment and patient care?
Siwiec: NMRH earned re-certification or the Gold Seal of Approval from The Joint Commission as a Primary Stroke Center. The Joint Commission’s Certificate of Distinction for Primary Stroke Centers recognizes centers that make exceptional efforts to foster better outcomes for stroke care.

Achievement of certification signifies that the services provided have the critical elements to achieve long-term success in improving outcomes.
PNR: Any final thoughts for people to remember about stroke?
Siwiec: Transient ischemic attack, or TIA, is sometimes referred to as a mini-stroke. You experience the symptoms of a stroke, but the symptoms last a few minutes to no longer than 24 hours. It is a warning that you are at high risk for a stroke, so:

T = Take

I = Immediate

A = Action

Don’t ignore your symptoms.

Stroke defined

A stroke is sometimes thought of as a “brain attack.” A stroke occurs when a blood vessel or vessels that carry oxygen and other nutrients to a specific area of the brain become blocked or suddenly burst. This interrupts blood flow to the brain and prevents oxygen from getting to where it’s needed. When the oxygen supply is cut off, brain cells begin to die resulting in change or loss of abilities or functions controlled by those cells in the brain.

There are two types of stroke — ischemic (iz-KEE-mik) and hemorrhagic.
About 87 percent of all strokes are ischemic, caused by too little blood supply because of a blood clot in an artery leading to the brain.
The other 13 percent are hemorrhagic, caused by bleeding in the brain when a blood vessel bursts.

Source: Second Chances Study of stroke survivors,

Click on the links below to view select portions of the Second Chances event and panel discussion or watch the entire event.

Groups of clinicians, academics, and some savvy software companies are crafting the tools and ecosystem to make medical sense of the sequence. 

By Kevin Davies, October 6, 2010 | It is doubtful that the scientists and physicians who first started talking about the $1,000 genome in 2001 could have imagined that we would be on the verge of that achievement within the decade. As the cost of sequencing continues to freefall, the challenge of solving the data analysis and storage problems becomes more pressing. But those issues are nothing compared to the challenge facing the clinical community who are seeking to mine the genome for clinically actionable information—what one respected clinical geneticist calls “the $1 million interpretation.” From the first handful of published human genome sequences, the size of that task is immense.

Although early days, a number of groups are making progress in creating new pipelines and educational programs to prepare a medical ecosystem that is ill-equipped to cope with the imminent flood of personal genome sequencing.

Pathologists’ Clearing House

The pathology department at one of Boston’s most storied hospitals isn’t necessarily the place where one might expect to find the stirrings of a medical genomics revolution, but that’s what’s happening at Beth Israel Deaconess Medical Center (BIDMC) under the auspices of department chairman Jeffrey Saffitz.

“I see this as ground-breaking change in pathology and in medicine,” he says.

Together with Mark Boguski and colleagues, Saffitz has introduced a genomic medicine module for his residents (see “Training Day”). And under the stewardship of applied mathematician Peter Tonellato, he is building an open-source genome annotation pipeline that might pave the way for routine medical inspection once whole-genome sequencing crosses the $1,000 genome threshold.

All well and good: but why pathology? “We are the stewards of tissue and we perform all the clinical laboratory testing. This has been our function historically for many years. But we have a sense that the landscape is changing,” says Saffitz. Genetic testing, he argues, must be conducted under the same type of quality assessment, regulatory oversight, and CLIA certification as provided by the College of American Pathologists (CAP), “and should be done by physicians who are specifically trained to do this. That’s us!”

“The brilliance of that,” says Boguski, a pathologist by training, “is that it removes a lot of the mysticism surrounding genomics and makes it just another laboratory test.” There’s really nothing magical or different about DNA, insists Saffitz. “We regard a file of sequence data as a specimen that you send to the lab, just like a urine specimen!”

BIDMC is a medium-sized hospital that conducts 7 million tests a year. Arriving in Boston five years ago, Saffitz began recruiting visionaries to shape “the future of molecular diagnostics” and help the discipline of pathology become a clearinghouse for genomic medicine in a way that is “going to revolutionize the way we do medicine.”

Boguski is best known as a bioinformatician who spent a decade at the National Center for Biotechnology Information (NCBI). He sums up the genomic medicine informatics challenge thus: “You have 3 billion pieces of information that have to be reduced to six bytes of clinically actionable information. That’s what pathologists do! They take in samples—body fluids and tissues—and we give either a yes/no answer or a very small range of values that allow those clinicians to make a decision.”

Increasingly, he says, pathology will become a discipline that depends on high-performance computing to extract clinically actionable information from genome data. That frightens many physicians, but Boguski cites a precedent. “Modern imaging technology would not be possible were it not for high-performance computing, but it’s built into the machine!” he says. “Most practicing radiologists don’t think about the algorithms for reconstructing images from the X-rays. Most pathologists in the future won’t think about that stuff either—it will just be part and parcel of their trade. Nevertheless, we have to invent those technologies.”

Math Lab

Mathematician Peter Tonellato has a deep interest in software systems for the clinic, and formulated the idea of a whole-genome clinical clearinghouse within pathology. “We have to start thinking about genetics as just another component of data information and knowledge that has to be integrated into the electronic health record. Stop labeling genetics as something different and new and completely outside the mainstream medical establishment and move it back into the fundamental foundational effort of medical activity.”

Come the $1,000 genome, it will simply make sense to sequence everyone’s tumor, he says. Just as pathologists study tissue biopsies under a microscope, “we’re going to be sequencing it in parallel and figuring out which pathways and targets are pertinent to that person’s condition.” Simply doing more specialized tests isn’t the solution. “How many tens of millions of dollars and how many years has it taken to validate [the warfarin] test?” asks Boguski. “Multiply that by 10,000 other genes and it simply doesn’t scale. We’re going to have to look at this in a whole new way.”

Tonellato has been funded by Siemens and Partners HealthCare to construct an open-source, whole-genome analysis pipeline. Although not commercially released, the pipeline is built and being used for some pilot projects. He is also partnering with companies—including GenomeQuest—who want to do the sequencing analysis in a best-of-breed competition to establish the most refined NGS mapping utilities and annotation tools. The goal is to annotate those variants in a clinically actionable way down to Boguski’s six bytes of information and the drug response recommendation. “We think we’re as far forward in terms of doing that in an innovative and pragmatic way as anyone,” says Tonellato.

Using the cloud (Amazon Web Services), his team has lowered the cost of whole-genome annotation to less than $2,000. “Everybody talks about the $1,000 genome, but they don’t talk about the $2,000 mapping problem behind the $1,000 genome,” he says. It takes Tonellato’s group about one week using five nodes for the resequencing, mapping and variant calling, while the medical annotation takes three people about a month. High-quality computer scientists have to be paid too, he says. “You can’t just talk about the sequencing costs.”

Of course, it is most unlikely that hospitals will start running massive NGS and compute centers. “We envision a day where every clinical laboratory in every hospital in this country can do this testing,” says Saffitz. “They’re not going to do the sequencing, but there’ll be a machine where they can basically acquire the data, analyze it, and send a report to the doctor saying, ‘This is what we found, this is what it means, this is what you do.’” Where the sequencing is done isn’t of great concern. “We actually treat sequencing as a black box,” says Boguski. What’s important is that the hospital’s cost requirements and quality standards (and those of the FDA) are met. But Tonellato reckons it would be “very odd to have U.S. samples sent abroad for sequencing to Hong Kong or India… and then sit around and wait for the CLIA-certified, clinically accurate results to come back to us. That may happen in the future, but we have to get our own house in order first.”

Another problem is the current state of the gene variant databases, which Boguski calls “completely inadequate” in terms of clinical grade annotation. Where such a resource belongs is open to debate but Boguski is certain it does not belong with the government. “The government is not a health care delivery organization. Whatever that database is, it needs to operate under the same CLIA standards as the actual tests.”

Pathologists have traditionally interacted with patients when they are sick. “But more and more,” says Saffitz, “we’re going to be analyzing the genomes of people who are well, and I hope assuming a very prominent role in the preservation of health and preempting disease.”

Quake Aftershocks

The most comprehensive clinical genome analysis to date was reported in May 2010 in the Lancet. Stanford cardiologist Euan Ashley and colleagues, including Atul Butte and Russ Altman, Stanford’s chair of bioengineering, appraised the genome of Stephen Quake (see, “A Single Man,” Bio•IT World, Sept 2009). “This really needs to be done for a clinical audience to show them what the future is going to be like,” says Altman, who is also director of the biomedical informatics program and chief architect of the PharmGKB pharmacogenomics knowledgebase. The task of interpreting Quake’s genome involved more than 20 collaborators, including bioethicist Hank Greeley and genetic counselor, Kelly Ormond. When discussions turned to the risk of sudden cardiac arrest (Quake’s family has a history of heart disease), Ormond would invite Quake to leave the room until a consensus was reached.

Altman’s own group was able to predict Quake’s response to about 100 drugs. Some of it was imprecise, but he realized that, “especially for the pharmacogenomics, we are much closer [to clinical relevance] than I realized.” He said he would “bet the house” on the results dealing with statin myopathy, warfarin and clopidogrel dosing. The Stanford team also tried linking environmental and disease risk, but Altman admits that is farther from clinical practice. The Lancet study drew high praise from the BIDMC team. “As good as it gets,” is Tonellato’s verdict. “But go down to some town in the middle of America and say, ‘What are you going to do with this genome dataset for your patient?’… Is medicine ready for genetics yet or not? There is a long way to go.”

Since the publication, Altman has received inquiries from companies interested in doing similar “genomic markups” and licensing his group’s annotations. Altman intends to hire an M.D. curator to complement his Ph.D. curators, someone who can highlight the clinical significance of research data. Altman says he would be happy to have PharmGKB data included “in any and all pipelines. Meanwhile, Ashley is leading a Stanford program to make a computer pipeline to reproduce the Quake analysis on a larger scale.

In a rational world, Altman says, it seems logical to sequence human genomes at birth and put the data in a secure database, querying it only when you know what you’re going to do with the results. That’s in an ideal world. In the United States, he notes dryly, some people do not trust governmental databases. “I could imagine if it’s cheap enough, that people will actually resequence the genome on a need-to-know basis, simply so they don’t have to store it. I think that’s a little bit silly, but in order to get genomic medicine effected, I’m not going to lose the fight over the database.”

Whoever ends up doing clinical genomic sequencing in the future, Altman says they will have to document high-quality data with a rapid turnaround. “We will then put [the data] through the pipeline—hopefully the Stanford pipeline or whatever pipeline seems to be winning—and then we will query it as needed and as requested by the physicians on a need-to-know basis.”

1,500 Mutations

Genome Commons was established by Berkeley computational biologist Steve Brenner to foster the creation of public tools and resources for personal genome interpretation. He wants to build an open access Genome Commons Database and the Genome Commons Navigator. He is also launching a community experiment called CAGI (The Critical Assessment of Genome Interpretation) to evaluate computational methods for predicting phenotypes from genome variation data (

One notable private effort in clinical genome annotation is that of Omicia, a San Francisco-based software company founded by Martin Reese in 2002.

Omicia is taking genome data and extracting clinical meaning, focusing on DNA variation, rather than gene expression or pathways. “We have one of the best systems for interpreting the genome clinically,” claims Reese. He started with Victor McKusick’s classic Mendelian Inheritance in Man catalogue, which now lives online as OMIM, mapping a “golden set” of disease mutations to the reference genome. Omicia is also developing algorithms to predict the effect of protein-coding variants to better understand which mutations are medically relevant.

Reese sums up the goal: “You have 21,000 protein coding mutations compared to the reference genome. 10,000 of them are non-synonymous. We have 3,500 in disease genes. That’s roughly 15%. So 15% of 10,000 is 1,500 protein coding mutations. The goal is to interpret 1,500 mutations.”

For the time being, Omicia is offering its services through collaborations. Reese has a three-year collaboration with Applied Biosystems, and was a co-author on the first NGS human genome paper using the SOLiD platform in 2009. Then there is the Life Alliance, a cancer genome alliance, featuring various medical centers and Life Technologies. “We’re doing their interpretation of these cancer genomes for 100 untreatable cancers,” says Reese.

Presenting the data for a physician is a challenge, says Kiruluta, but not as bad as the scant amount of time a physician has to see a patient. “The reporting is to help a physician make a decision quickly—green light, red light. Then there’s a much more detailed interface behind the scenes,” where other medical professionals can study the patient’s data in more detail.

Reese sees advantages to the commercial approach for genome software compared to academic solutions. “This will be a big play in next few years as people make clinical decisions. So the quality of the software, the QC of the assembly, how transparent you are, the annotation, is critical. It will be a big problem for academia to do that—you know how it is when a postdoc writes something!”

Reese has also been spearheading the effort to develop a new Genome Variation Format with Mark Yandell (University of Utah) and others, which was recently published in Genome Biology.

DNA Partners 

The challenge facing the affable Samuel (Sandy) Aronson, executive director for IT at the Partners HealthCare Center for Personalized Genetic Medicine (PCPGM) and PCPGM’s clinical laboratory director, Heidi Rehm, is to deliver clinically actionable information to physicians in the Partners HealthCare network. “This challenge cannot be entirely solved by a single institution,” Aronson notes. “It takes a network of institutions working together.”

Rehm maintains a knowledge base of 95 genes that are routinely curated by the PCPGM’s Laboratory of Molecular Medicine and supplies information to physicians on the status of those genes in their patients in real time. The PCPGM’s GeneInsight suite, developed by Aronson’s team, has been in use for about seven years. There are two components—one for the laboratory, the other for the clinician. The lab section consists of a knowledgebase—the tests, genes, variants, drug dosing, etc—as well as an infrastructure to generate reports via the Genome Variant Interpretation Engine (GVIE).

On the clinical side is a new entity, the Patient Genome Explorer (PGE), which allows clinicians to receive test results from an affiliated lab and query patient records. “The PGE, without a doubt, is one of its kind,” says Rehm. “There’s no other system out there. There’s a lot of excitement about it. Labs are choosing us for testing because we offer that service.” When an update is made to the PCPGM knowledgebase on a variant that is clinically significant, the PGE proactively notifies the clinicians caring for patients with that variant. If there are 100 clinics with 10 patients each, and Rehm updates the knowledgebase, then 1,000 patient updates are dispatched automatically.

For inherited disease testing, the alert changes the variant from one of five categories to another: 1) pathogenic 2) likely pathogenic 3) unknown 4) likely benign, or 5) benign. The PGE made its debut last summer in the Brigham and Women’s Hospital Department of Cardiology. When the system launched, a dozen “high alerts” (meaning a variant has shifted from one major category to another) were immediately dispatched. The physicians’ response has been really positive, says Aronson. “There’s a significant disconnect between the level of quality of data being used for clinical purposes and the quality of data in the research environment,” says Rehm. “Our hope with the distribution of this infrastructure is to get more data validated for clinical use.”

Core Challenges

The Partners effort is a worthy start, but the larger goal is to build a network where labs with expertise in other genetic disorders such as cystic fibrosis contribute their data, perhaps by offering attribution or a nominal transaction fee. “We can’t maintain data on every gene, but we’re willing to establish nodes of expertise,” says Rehm. As for the IT infrastructure, Aronson hopes to enable organizations to create a node on the network, link to the PGEs, and then operate under their own business models—whatever it takes to make the data accessible. The first external partner that linked to GeneInsight was Intermountain Healthcare (IHC) in Utah. “We believe this is the first transfer of fully structured genetic results between institutions so that they got into IHC’s electronic health record and are now available for decision support,” says Aronson.

Aronson anticipates a day where whole-genome sequencing for patients will be a clinical reality. “It’s very much on our radar,” he says, but doesn’t appear unduly concerned. After all, he says, the PGE is designed to store highly validated clinical information, and he doesn’t expect the millions of variants in a whole genome to contain enough clinically actionable variants to overwhelm the database. The challenge will come in understanding complex/low-penetrance diseases, “where we’re more algorithmically dependent. That will require new infrastructure.”

A bigger problem is facilitating the business models that will solve personalized medicine challenges. “Our goal is to expand networking, adding labs, PGEs and going after a network effect,” says Aronson. “We have a structure that could present an answer to how do you—in a true patient-specific, clinically actionable way that clinicians can use in their workflow—help interpret the data?” •

Training Day

It was in 2009 that Mark Boguski conceived the innovative training program for Beth Israel’s pathology residents, and yet remarkably his boss, Jeffrey Saffitz, thinks every pathology department in North America might have introduced a similar program by 2012. The program offers residents the chance to be personally genotyped. It is, after all, a time-honored tradition in medicine for medical students to draw blood and exam each other, so this is nothing new.

Boguski selected Navigenics for the genotyping service because it focuses on medically actionable conditions and has a built-in genetic counseling component. All but two of the 17 BIDMC residents chose to get tested. Afterwards, Saffitz, Richard Haspel and colleagues published a “call to action” for the pathology community in the American Journal of Clinical Pathology. The response was incredibly positive, and many programs are eagerly signing on.

“We want the residents to see that a typical bioinformatics analysis of a genome — pages and pages of text and references using natural language processing or something — isn’t going to work,” says Saffitz. “We actually use that as a teachable moment to say, ‘this is the state-of-the-art today, but here’s how we have to move it forward.’”

Stanford has introduced a similar course in personal genomics where students could optionally get genotyped and analyze their genome, allowing the students to calculate their disease risks and optimal drug dosage. “It felt somewhat historic, actually,” says Altman. There were divisions among the faculty as to whether it should be offered, but Altman hopes the course will become a staple in the curriculum. K.D.

U.S. Department of Health and Human Services
NIH Office of the Director

For Immediate Release: Wednesday, October 6, 2010


The 2010 Nobel Prize in chemistry has been awarded to National Institutes of Health (NIH) grantee Ei-ichi Negishi, Ph.D., of Purdue University, West Lafayette, Indiana.  Dr. Negishi shares the award with Richard F. Heck, Ph.D., of the University of Delaware in Newark, Delaware and Akira Suzuki, Ph.D., of Hokkaido University, Sapporo, Japan.  The three researchers are honored for developing complementary methods to find more efficient ways of linking carbon atoms together to build complex molecules.

“The methodology developed by these stellar scientists has broad implications for the medical, electronic, and agricultural fields,” said NIH Director Francis S. Collins, M.D., Ph.D.  “It has already allowed chemists to synthesize compounds to fight the herpes virus, HIV, and colon cancer.”

Dr. Negishi has received more than $6.5 million in support from the NIH’s National Institute of General Medical Sciences (NIGMS) since 1979.

“Carbon-carbon bonds are like the frame of a house — you have to get them right for the structure to be functional and useful,” said NIGMS Director Jeremy M. Berg, Ph.D.  “By developing more precise and efficient methods for making these bonds, the scientists selected for the 2010 Nobel Prize in chemistry have created a remarkably powerful tool for synthesizing a wide range of useful chemicals.”

The Office of the Director, the central office at NIH, is responsible for setting policy for NIH, which includes 27 Institutes and Centers. This involves planning, managing, and coordinating the programs and activities of all NIH components. The Office of the Director also includes program offices which are responsible for stimulating specific areas of research throughout NIH. Additional information is available at <>.

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit <>.