Accurate detection and genotyping of SNPs utilizing population sequencing data.

Next generation sequencing technologies have made it possible to sequence targeted regions of the human genome in hundreds of individuals. Deep sequencing represents a powerful approach for the discovery of the complete spectrum of DNA sequence variants in functionally important genomic intervals. Current methods for SNP detection are designed to detect SNPs from single individual sequence datasets. Here we describe a novel method SNIP-Seq (Single Nucleotide polymorphism Identification from Population Sequence data) that leverages sequence data from a population of individuals to detect SNPs and assign genotypes to individuals. To evaluate our method, we utilized sequence data from a 200 kilobase region on chromosome 9p21 of the human genome. This region was sequenced in 48 individuals (5 sequenced in duplicate) using the Illumina GA platform. Using this dataset, we demonstrate that our method is highly accurate for detecting variants and can filter out false SNPs that are attributable to sequencing errors. The concordance of sequencing based genotype assignments between duplicate samples was 98.8%. The 200 kb region was independently sequenced to a high depth of coverage using two sequence pools containing the 48 individuals. Many of the novel SNPs identified by SNIP-Seq from the individual sequencing were validated by the pooled sequencing data and were subsequently confirmed by Sanger sequencing. We estimate that SNIP-Seq achieves a low false positive rate of ~2% improving upon the higher false positive rate for existing methods that do not utilize population sequence data. Collectively, these results suggest that analysis of population sequencing data is a powerful approach for the accurate detection of SNPs and the assignment of genotypes to individual samples.

from The Scripps Institute

MarketWatch: Sequencing Companies Dominate Investment

$400 the approximate cost of genetic testing to predict a patient’s response to the commonly prescribed blood thinner warfarin.

MIT Technology Review, March/April 2010, by Lauren Gravitz – The market for personalized medicine is growing: according to PricewaterhouseCoopers, the core market will reach $42 billion by 2015. However, that growth is not uniform. Some areas, such as genomic sequencing, are surging ahead; others, such as translating genetic data into clinically useful information, languish.

In this environment, startups developing sequencing technologies, such as Pacific Biosciences, Illumina, and Complete Genomics, have attracted sustained investor interest as they race to create ever cheaper ways to decode DNA (see “Faster Tools to Scrutinize the Genome“). In their most recent rounds of venture funding last summer, Pacific Biosciences and Complete Genomics received $68 million and $45 million, respectively.

Diagnostic technologies, too, are moving at a rapid pace. Startups from Boston to Silicon Valley have been pinning down disease-related genetic markers and creating many new tests that are already in the clinic or on their way. As these companies grow and bring more tests to market, large diagnostics companies are likely to acquire them, says venture capitalist Brook Byers of Kleiner Perkins Caufield and Byers.

One of the biggest undeveloped areas in personalized medicine, however, is the information technology needed to analyze and store the huge quantity of genetic data that is starting to pour forth (see “Drowning in Data“). Of the few bioinformatics companies working to digest the data, Proventys, based in Newton, MA, is among the furthest along. Its technology combines biomarkers and other information to make risk predictions about diseases.

Meanwhile, pharmaceutical companies are responding to the nascent market for personalized therapeutics in different ways. Pfizer, for example, is collaborating with existing biotech companies to develop drugs and diagnostics based on genetic testing. AstraZeneca recently announced a partnership with the Danish diagnostics company Dako, the first of many alliances it plans in a strategy for bringing genetic tests to market. Novartis is taking a different tack, dedicating a large portion of its own resources to developing personalized medicine.

In the United States, benefit management companies, which act as middlemen between patients and insurers or employers, are aggressively moving into the market. One of the largest, Medco, has established a personalized-medicine group to recommend which genetic tests insurers should pay for. In February it acquired DNA Direct, a firm that specializes in analyzing genetic diagnostics, to aid in this effort. One of its largest competitors, CVS Caremark, increased its stake in a similar company, Generation Health, last December. Because such companies serve millions of people, they will play a critical role in making genetic tests broadly available and educating doctors about the benefits of offering such tests to their patients.

A machine for DNA sequencing was invented by Leroy Hood and his colleagues at Caltech. In 1992, Hood and several others were granted U.S. patent 5,171,534 for an “Automated DNA Sequencing Technique.” Replacing slow and expensive manual methods, this is one of the most important pieces of intellectual property in biotechnology; explore this interactive analysis by IPVision of the patent’s impact on the innovation landscape.http://www.technologyreview.com/biomedicine/24593/page2/

Cheap DNA sequencing will drive a revolution in health care

The dream of personalized medicine was one of the driving forces behind the 13-year, $3 billion Human Genome Project. Researchers hoped that once the genetic blueprint was revealed, they could create DNA tests to gauge individuals' risk for conditions like diabetes and cancer, allowing for targeted screening or preëmptive intervention. Genetic information would help doctors select the right drugs to treat disease in a given patient. Such advances would dramatically improve medicine and simultaneously lower costs by eliminating pointless treatments and reducing adverse drug reactions.

Delivering on these promises has been an uphill struggle. Some diseases, like Huntington's, are caused by mutations in a single gene. But for the most part, when our risk of developing a given condition depends on multiple genes, identifying them is difficult. Even when the genes linked to a condition are identified, using that knowledge to select treatments has proved tough (see "Drowning in Data"). We now have the 1.0 version of personalized medicine, in which relatively simple genetic tests can provide information on whether one patient will benefit from a certain cancer drug or how big a dose of blood thinner another should receive. But there are signs that personalized medicine will soon get more sophisticated. Ever cheaper genetic sequencing means that researchers are getting more and more genomic information, from which they can tease out subtle genetic variations that explain why two otherwise similar people can have very different medical destinies. Within the next few years, it will become cheaper to have your genome sequenced than to get an MRI (see "A Moore's Law for Genetics"). Figuring out how to use that information to improve your medical care is personalized medicine's next great challenge.

Pharmacogenomics: Personalized Medicine at the Corner Drugstore

MayoClinic.com, GoogleNews.com, February 24, 2010, by Carrie A. Zabel – Personalized medicine offered at your local drugstore?

Two large prescription drug companies have announced plans to offer genetic testing as part of the prescription-filling process. The testing will center on an emerging science, pharmacogenomics, which studies drug response based upon an individual’s genetic make-up. Pharmacogenomic testing is already used for some commonly prescribed drugs such as Tamoxifen and Warfarin.

The process would use a pharmacy benefits management company that would contract with large drugstore chains. When certain prescriptions come in, the company would contact the physician to let them know a genetic test is available, which may help them to more appropriately prescribe that medication. The individual may then be offered the genetic testing, but it wouldn’t be required.

Supporters say this will improve patient safety, health outcomes and decrease overall health care costs by using the right medications in the right patients. It may also provide an opportunity to advance the field of pharmacogenomics by collecting data on genetic testing results and drug effectiveness.

Others are concerned about the privacy of genetic testing information and say the science of pharmacogenomics is premature. Drug metabolism isn’t only based on our genetic make-up, but is affected by many additional factors, such as body size and age. And, since pharmacogenomics is a relatively new science, insurance companies may not reimburse for the cost of genetic testing.

Carrie A. Zabel, M.S., C.G.C., Genetic Counselor

Can a Genomics Platform Model Work in Diagnostics?

Start-Up -- deCODE Genetics has emerged from bankruptcy with a streamlined, diagnostics-oriented business model. In the near term, the privately held firm expects to offer its genomics discovery capabilities on a service basis, echoing the original genomics platform specialists of the late 1990s, including deCODE itself, which did largely unsuccessful technology deals focused on using genetic insight to generate therapies. The difference? It is now using genetic information to assess disease risk and better manage patient health, a strategy it thinks will succeed as the field of personalized medicine diagnostics continues to gain traction.

By Mark L. Ratner

Elsevier Business Intellingence

Medco Acquires DNA Direct: A Great Step for Personalized Medicine

Combined capabilities will deliver precision health services designed to improve

clinical and financial outcomes

FRANKLIN LAKES, N.J. and SAN FRANCISCO, Feb. 2, 2010 –– Committed to being at the forefront

of translating personalized medicine from the science to its daily practice in healthcare, Medco Health

Solutions, Inc (NYSE:MHS) today announced the acquisition of DNA Direct, Inc., a leader in providing

guidance and decision support for genomic medicine to patients, providers, payors and employees.

Financial details of the acquisition were not released.

“DNA Direct has been a recognized pioneer in assimilating knowledge about molecular diagnostic testing

and deploying certified genetics professionals to help rationalize the opportunities and implications faced

by many in this new and rapidly evolving field,” said David B. Snow Jr., Medco chairman and chief

executive officer.

By integrating DNA Direct’s physician, client and patient support services and capabilities with Medco’s

growing portfolio of personalized medicine capabilities and extensive customer base, Medco intends to

deliver a broader suite of precision health services, ranging from consumer education to clinical decision

support.

“Medco is simply the most innovative and forward thinking healthcare company in the industry today,”

said Ryan Phelan, DNA Direct founder and CEO. “Having spent the past 25 years as an entrepreneur

translating healthcare information to patients, I can’t think of a better partner to take personalized

medicine to the next level.”

DNA Direct is the first genomics-focused company offering URAC-accredited utilization management

programs to help payors ensure the appropriate use of the more than 2,000 genetic and molecular tests

available today. URAC is a Washington D.C.-based health care accrediting organization that establishes

quality standards for the health care industry. DNA Direct’s national call center of genetic experts,

complemented by online decision support services help physicians and patients determine if genetic tests

are appropriate and how to use genetic test results to guide clinical decisions. Medco’s existing

personalized medicine approach encompasses a robust pipeline of important pharmacogenetic research,

turnkey testing programs for drugs like tamoxifen and warfarin, and warnings on over 50 drug-gene

interactions, which are used by Medco's specialist pharmacists to inform physicians and patients about

potential therapy adjustments to ensure the safety and efficacy of the treatment.

“When a Fortune 50 company like Medco makes a commitment to personalized medicine with an

acquisition like this, it’s proof positive that we are at a turning point in the healthcare industry,” said

Sharon Terry, president and chief executive officer of Genetic Alliance. “Integrating Medco’s

phenomenal capacity to respond to its members, with the innovative and creative patient-focused services

of DNA Direct is a win for all consumers.”

The DNA Direct purchase builds upon Medco’s commitment to advancing pharmacogenomics (PGx), a

cornerstone of which is the company’s Personalized Medicine Research Center. The research center is

dedicated to furthering the understanding of the impact of genetics on patient medication response and

applying that science to clinical practice. As knowledge is gained through the research, applications will

be rolled out to the broader client base within Medco’s precision health services.

“By integrating proven state-of-the-art science into every day care, we are providing patients and

providers with actionable information that drives more personalized care to achieve higher efficacy or

improved safety,” said Dr. Robert Epstein, Medco’s chief medical officer. “We have already started this

today with our existing Personalized Medicine programs. DNA Direct will serve to accelerate our speedto-

market implementation capabilities, transforming research into actionable services to meet the

demands of our clients and patients.”

About Medco

Medco Health Solutions, Inc. (NYSE: MHS) is pioneering the world’s most advanced pharmacy® and its

clinical research and innovations are part of Medco making medicine smarter™ for more than 60 million

members.

With more than 20,000 employees dedicated to improving patient health and reducing costs for a wide

range of public and private sector clients, and 2008 revenue exceeding $51 billion, Medco ranks 45th on

the Fortune 500 list and is named among the world’s most innovative, most admired and most trustworthy

companies.

For more information, go to http://www.medcohealth.com.

About DNA Direct

DNA Direct was founded in 2005 to deliver guidance and decision support for genomic medicine to

patients, providers and payers -- reducing health risks, preventing disease, and better targeting therapies.

The first genomics-focused company to receive full URAC accreditation for utilization management in

the U.S, DNA Direct’s comprehensive clinical programs combine proprietary technology with genetic

expertise including a national call center of genetic experts, web-based applications, and educational

resources and training. The company is based in San Francisco and was backed by Firefly Investments

and Lemhi Ventures. For more information, visit www.dnadirect.com.

Toward reading your own personal 'Book of Life'

What secrets about your risk for diseases are written in your own personal "Book of Life" - the 30,000 or so genes that make you you?

Advances in DNA-sequencing technology are bringing closer the day when it will be more economical for consumers to get an answer to that question, and others, by ordering up the deciphering of their entire genetic endowment - their "personal genome." With their Book of Life in hand, consumers and their physicians could map out strategies for the prevention, early diagnosis, and more effective treatment of diseases ranging from cancer to rare-genetic disorders.

C&EN Senior Editor Celia Henry Arnaud notes that the first human genome sequence cost more than $2 billion and took about a decade to complete. Technological advances now have cut the time to as little as one week, and some companies are charging individuals $48,000 for the service, a cost that experts expect to drop sharply in the coming years, the article notes.

But the technology also raises important ethical and legal issues, including the possibility of discrimination on the basis of genetic information in the areas of employment and insurance coverage. Many believe that personal genomes are inevitable. "In the future, sequencing will be so cheap and so easy to access that everybody could get sequenced if they want. It'll be iPod pricing," says the CEO of a company that specializes in direct-to-consumer genome sequencing.

Structural variation in the human genome.

Nat Rev Genet. 2006 Feb;7(2):85-97.

Feuk L, Carson AR, Scherer SW.

The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Department of Molecular and Medical Genetics, University of Toronto, Ontario, Canada.

The first wave of information from the analysis of the human genome revealed SNPs to be the main source of genetic and phenotypic human variation. However, the advent of genome-scanning technologies has now uncovered an unexpectedly large extent of what we term ’structural variation’ in the human genome. This comprises microscopic and, more commonly, submicroscopic variants, which include deletions, duplications and large-scale copy-number variants – collectively termed copy-number variants or copy-number polymorphisms – as well as insertions, inversions and translocations. Rapidly accumulating evidence indicates that structural variants can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility

IBM promette la genetica personalizzata

Per ora è solo una simulazione al supercomputer. Ma i nanotubi, altro campo di eccellenza di BigBlue, potrebbero garantire cure più efficaci: non appena passeranno dalla teoria alla pratica

Roma - Da quando, all'inizio del nuovo millennio, il tanto chiacchierato Human Genome Project ha portato all'identificazione dei circa 25mila geni di cui è composto il codice ereditario di ogni singolo essere umano, la scienza biomolecolare ancora manca di un approccio pratico adeguato alle mirabolanti promesse della "medicina personalizzata" su base genetica. Stando a quanto sostiene IBM, però, uno dei problemi fondamentali di questa particolare branca della ricerca starebbe per essere risolto grazie all'impiego di apposite nanostrutture in grado di veicolare (con opportuni meccanismi di "stop-and-go" bio-elettronico) i filamenti di DNA da analizzare.

La fase di sequenziamento del DNA, utile a identificare i singoli geni del paziente per valutare eventuali predisposizioni a patologie o a condizioni metaboliche particolari, è col tempo diventata una pratica abbastanza comune ma ancora ferma ai laboratori che hanno i fondi sufficienti a permettersi la strumentazione adeguata. Anche in questo caso, a ogni modo, la procedura di sequenziamento dei geni non va esattamente alla velocità della luce, e anche per i kit attualmente disponibili come prodotti commerciali occorre aspettare qualche settimana per conoscere i risultati.

"Sono stati fatti alcuni tentativi per sequenziare il DNA molto più velocemente di quanto fatto con il primo genoma umano", dice il ricercatore di computational biology Gustavo Stolovitzky in forze a IBM, e il meglio chi si è ottenuto finora è stato "usare complicati preparati di sample" in cui il DNA viene tagliuzzato, amplificato, analizzato attraverso la trascrittasi inversa e ottiche sofisticate il cui impiego richiede parecchio lavoro: per giungere a risultati comunque insufficienti in prospettiva di una medicina personalizzata.

L'approccio seguito dal dottor Stolovitzky e colleghi prevede invece l'utilizzo di strutture nanotubiche bucherellate, con fori delle dimensioni di tre miliardesimi di metro attraverso cui far passare il filamento di DNA da analizzare. Un'idea che gli scienziati carezzano da tempo, quella di usare la nanotecnologia per mimare il funzionamento delle proteine "sequenziatrici" presenti nelle cellule vive, che però risolta la questione del "passaggio" del DNA all'interno di un nano-cunicolo obbligato continua a presentare il problema della velocità eccessiva di tale passaggio.

L'applicazione di un voltaggio alle due estremità di un chip contenente i nanotubi di cui sopra farebbe insomma scorrere il DNA da un'estremità all'altra senza problemi, ma troppo velocemente per poter misurare i nucleotidi e sequenziare il corredo genetico del paziente. Nelle simulazioni al supercomputer Blue Gene di IBM tale problema è stato risolto con il design di un chip composto da uno stack di strati di silicio, ognuno dei quali capace di condurre un particolare tipo di voltaggio all'interno dei nanopori.

I singoli voltaggi sarebbero poi in grado di intrappolare i gruppi fosfato presenti nei quattro tipi di nucleotidi esistenti, bloccando il velocissimo scorrere del filamento di materiale genetico e facendo letteralmente avanzare la procedure di sequencing un nucleotide alla volta per non lasciarsene scappare nessuno. Stabilito che il sistema funziona a livello di principio, sostiene IBM, per trasformare in realtà di tutti i giorni la medicina personalizzata a base genetica e le diagnosi veloci delle infezioni ora non resterebbe che trovare il modo di "leggere" i voltaggi corrispondenti ai singoli nucleotidi e convertirli in informazioni digitali manipolabili al computer.

Alfonso Maruccia

Out of the hat of medical research

Of many interesting stories for us to blog about this week -- so many that they'll be spilling over into next week -- here's one that seems to represent a more sensible approach to disease than the relentless focus on genetics that we so commonly see. It's about a new effort by pharmaceutical companies to invest in vaccine development. The AP story says

Malaria. Tuberculosis. Alzheimer's disease. AIDS. Pandemic flu. Genital herpes. Urinary tract infections. Grass allergies. Traveler's diarrhea. You name it, the pharmaceutical industry is working on a vaccine to prevent it.

Another story of what seems to be money well-spent appears on the BBC website. Researchers have developed a new-fangled lab-on-a-chip that will allow easier, faster and cheaper diagnosis of dozens of diseases.

The device relies on an array of antibody molecules that are designed to latch on to the protein-based molecular markers of disease in blood.

The antibodies are chemically connected to molecules that emit light of a specific colour when illuminated - but only when they have bound to the disease markers.

Some of the vaccines in the pipeline won't pan out, but some surely will, and we can imagine the lab-on-a-chip device being useful in many settings, including medically underserved areas, so we find these stories rather heartening. The money being invested is private, not taxpayer money, but not long ago a lot of pharmaceutical money was being bet on personalized genomics, and so on, which our regular readers will recognize as efforts we wouldn't have put our money on. So, it's good to see that following the money takes us in a different direction these days -- industry sees a lot more promise in preventing and treating infectious disease than in fixing genes. Indeed, a lot more disease seems to be infectious than the age of genetics led us to believe.

The Fall of deCode Genetics
It's interesting to juxtapose these two stories with this story from the Wednesday New York Times that reports on the demise of a company established to "exploit the promise of the human genome", that is, to profit from what it could learn about genetic disease from the genealogies of Iceland. Predicated on the idea that common genetic variants would be found to explain most complex disease, deCode Genetics set out to find those variants in Iceland and then develop drugs to target them. But, it turns out that complex disease is too complex for that. Again, regular readers won't be surprised if we find it hard to suppress a little "told you so".

Now, here we want to be careful about the concepts -- and it's related to central issues in The Mermaid's Tale. Life is lived, day to day, on the molecular level. Infection is essentially attack from without, and the immune system tries to recognize molecular signatures of the invading soldiers, to latch onto them and destroy them. Vaccines traditionally help the immune system do that, by exposing it to harmless mimics of the real thing (dead viruses, so to speak).

There are countless infectious diseases, affecting of most body systems, and more and more complex 'chronic' diseases that were thought to be 'environmental' or 'genetic' in the traditional senses, seem to be turning out to have infectious or inflammatory components. Thus, enhanced abilities to make vaccines could have farther-reaching implications than has been thought.

The immune system is 'genetic' of course, and its functions are fairly close to genes in many ways. But there may be other and perhaps even surprising ways this subject can bring us back to genetics. We'll deal with them in a post in the near future....

Health care and personalized genetics

How does a simple petri dish of DNA constitute the identity of a complex human being—from the way she laughs to her love of Cocoa Krispies? It turns out that the question of how biology determines identity interests not only the philosophically-inclined, but those in the drug and healthcare industry as well.

In a recent study published in Molecular Systems Biology, a computational biology team at Columbia explored the very questions that drive the current research on personalized care: How does a cell take a genotype and translate it into a phenotype? More specifically, how do genes determine our responses to medicine?

“The idea behind personalized care is that each of us is very different - we look different, we behave different, we have clearly different disease susceptibilities. All these things are genetically determined. Genetics also determines our responses to drugs,” Dr. Dana Pe’er, head of that computational biology research team, explained. Like many gadget lovers today, patients are clamoring for one-pill-fits-all cures. Tylenol, for instance, claims to relieve four different types of aches, fever, cold, cramps and arthritis. But with standardization comes the possibility of unpleasant side effects, such as, in the case of Tylenol, liver damage.

Medicines tailored to individuals would reduce the possibility of such side effects. But wouldn’t personalized care be much more expensive than the generic options we have now? “It would be cheaper!” Pe’er exclaims. “It would do away with the trial and error. A cancer patient has to pay $100,000 for chemotherapy. Won’t it be nice to tell them, ‘This won’t work for you because of your genes?’ Instead of getting it right on the third try, you can get it right on the first try.

”She also points out that avoiding all the adverse effects saves “tons of money and pain,” and that the “right meds put you back in the workforce in one day instead of three.”

A genotype scan currently costs a hefty $399, but patients only need it once in a lifetime. So what’s stopping personalized care from becoming an everyday reality? Part of the reason is that the science hasn’t yet come that far. According to Pe’er, the technology developed to investigate the connection between genotype and phenotype in terms of drug-responses is only a few years old, and the task it faces is gargantuan.

Pe’er analogizes: “Imagine there’s this huge cave, maze-like, with lots of passageways and everything’s pitch dark. Trying to do research on humans is like searching in this cave without even knowing what you’re looking for.”

To improve the search for the human genes that are related to drug resistance, Pe’er and her team focused on an easier subject: yeast, the common “workhorse” that scientists use to develop technology to apply to humans. By manipulating and testing 104 strains of yeast, they improved old search methods that traditionally relied on genetics by creating a new method that also harnesses gene expression (RNA), which indicates which genes are actively used. Their RNA-utilizing algorithm accurately predicted strain resistance for 87 of the 94 drugs tested, effectively narrowing down the number of genes related to drug resistance.

The main opponents of personalized care are not health insurers. For them, Pe’er believes, profits will rise with the reduction of the trial-and-error process which forces insurers to pay up with every treatment. Instead, pharmaceutical companies are the real antagonists: in order to maximize profit, they want standardized drugs to serve the whole population and not just a section of it. Recent pressure from the FDA—which has threatened to take drugs with adverse side effects off the shelves—has lead to heavy investment in a new field that combines pharmaceutical research and genetics: pharmocogenics. Pharmeceutical companies like Eli Lilly, who’ve been involved in legal disputes for marketing unapproved drugs, are now increasingly involved in studies on patient responses due to genetic variation.

But even if all pharmaceuticals participate to produce personalized medicine on a large scale, the truth is that we are not yet ready for personalized care. Patients and doctors are not adequately trained to interpret genotypes and translate them into appropriate treatments.

Specialized knowledge needs to be transferred from genetic-researchers to everyday medical practitioners. As Joel Burrill points out in an interview with Wired Science, unless medical schools adapt their training programs, there will be a shortage of DNA interpreters. Web sites like 23andme.com do a good job of explaining what the data means, but a large-scale implementation of personalized care would require more than Web sites.

Perhaps just as importantly, the legal infrastructure to protect the privacy of genetic information isn’t sufficiently established. It would be a veritable disaster if health insurers or workplaces got a hold of their clients’ or employees’ genetic predispositions to illnesses.Despite these obstacles, Pe’er believes that personalized care will be a reality within our lifetimes. Things are moving, even if slowly, in the right direction.

By Sarah Ngu

Whole-Genome Sequencing: Any Useful Data?

ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data.

In the initial phase of ClinSeq, we are enrolling roughly 1,000 participants; the evaluation of each includes obtaining a detailed family and medical history as well as a clinical evaluation. The participants are being consented broadly for research on many traits and for whole-genome sequencing. Initially, Sanger-based sequencing of 300-400 genes thought to be relevant to atherosclerosis is being performed, with the resulting data analyzed for rare, high-penetrance variants associated with specific clinical traits.

He also mentioned the 1000$ genome project and the unofficial estimation is that now it’s possible to sequence a person’s genome for under 5000$ and the 1000$ aim can become a reality at the end of this year.

Personalized medicine: The Doctors are OK with this?

Yesterday in "The Times" a nice article was posted about the revolutionary way in which doctors will receive education about CLINICAL genetics, this time it is from NonClinical Scientists......

At the tune of 4.5 Million British Pounds!

This may work with CGCs, oh wait, they don't do much of anything in the UK system.

What about clinical geneticists?
Who?

Ok, scientists it is......

So I can just see it now.

A busy NHS practice, patients out the door, flu shot here, flu shot there and in rolls the "Scientist"

Clinician-"Oh hi, you must be the genetics guy sent from the government. Have a seat, I'll be right with you"

4 hours later

Scientist-Sitting nicely, waiting

Clinician-"Ok, lets chat over lunch"

Scientist-"Glad to be here, Let's talk about what a chromosome is"

Clinician-Scarfing down a sandwich "Ok, that was great, gotta go. I am double booked. See you in a few"

4 hours later

Scientist-Sitting Nicely, waiting

Clinician-"Sorry about that, I had a sickie and then the crazy lady....G-d where did the time go?"

Scientist-"See you tomorrow?"

Clinician-"You bet, I feel better prepared already"

As nice as this one is, I have already tried it with a clinical geneticist who actually can create billable events and see patients........ I am not so certain that going to the doctors will help as much as being on their iPhone or on a hotline.......

Personalized Genomic Medicine: Are We and Our Doctors Ready?

Entangled with the national debate about the future of healthcare, there’s a personal debate about the future of medicine. Futuristic medicine will rely on personal genomics, because as consumer-patients, we will demand more integrated – more holistic -- less segmented medical care from our doctors. Personalized genomic medicine is not only our pipe dream for future, it is here, now. But, are we ready? Are our doctors ready? Are healthcare policy makers ready?

In June 2009, I gave a speech at the first Consumer Genetics Conference in Boston, where Dr. Francis S. Collins gave a riveting keynote speech. I was on the panel of speakers because I am a long-term consumer of genomics, having started in 1999, after reading that Dr. Collins and other geneticists were able to use DNA to trace human ancestors. I used DNA to trace ancestors to dozens of ethnic groups in Africa, and confirm my specific ancestral families in Ghana, West Africa. I have always been grateful to Dr. Collins and the other geneticists. This week, President Barack Obama nominated Dr. Francis S. Collins, a physician and genetic researcher, as Director of the National Institutes of Health (NIH), the government’s research laboratory in Maryland. Previously, Dr. Francis Collins directed the publicly-funded team at the National Human Genome Research Institute (NHGRI).

The public team he led brought us the Human Genome Project, which sequenced the human genome in 2000, completing the sequencing in 2003. He was locked in a fierce race to the finish line against J. Craig Venter, CEO of the private venture, Celera Genomics. Venter also sequenced the genome. Medical research, then and now, happens in waves, and is a race to the finish line by leaders and teams in the public, academic and private sectors.

At the Consumer Genetics Conference, the private, academic and public sectors were fully represented. As an author who has written about using DNA, genealogy and American family history to trace my ancestors to Ghana and Scotland, I was one of the few speakers on the panel who was not a MD/Ph.D. or CEO of my own biotechnology company. Other speakers were Kari Stefánnson, CEO of DeCode genetics, Linda Avery, Co-CEO of 23andMe, and CEOs of the country’s leading genetics companies. So today, while consumer-patients and politicians debate the future of healthcare and healthcare funding, biotechnology and pharmaceutical companies race ahead at the speed of light to develop personalized medicine. They race to tailor diagnoses, prescriptions and treatments to the each patient’s DNA.

Dr. Francis Collins’ speech at June’s Consumer Genetics Conference was very forward-looking and inspirational. He focused on how we can make the present and future delivery of medicine more efficient and more effective; how we can respond to what has to be researched and developed in genomic and molecular medicine; how we remain aware of current research and what is neglected or overlooked; and what we must all remember about scientific research and scientific progress. Scientific progress is unique and it explores the unknown.

Personalized medicine, he said, is at the frontier of medical research, it is the future of medicine. Cooperation and collaboration among the government, academic and private sectors must be fostered. Knowledge of the genome will revolutionize medicine, but for preventive medicine to be effective, there has to be usable data from a study that gives a genetic profile of the population. He called such a study, massive.

Now, as the Director of the National Institutes of Health, Dr. Collins will manage a $37 billion research fund, which will distribute grants for medical research and development. But how much will be used to train and retrain doctors in personalized medicine and genomics?

I spoke at the conference about how my use of ancestral DNA, what some at the conference called, “recreational genetics” led to medical genetics. I also highlighted the challenge of educating doctors and patients and finding doctors who are knowledgeable enough about genetics to diagnose and treat rare, unusual genetic-based symptoms or common ailments that have a genetic connection. I echoed and illustrated what Dr. Francis Collins said about integrating family history in genomic research, and how vital it is for doctors to be able to decipher genetic tests and in report genetic results to patients. He said family history must be an integral part of genomic research. I said not only personal and family history but ancestral history must be weighed when developing a patient’s medical profile.

Is it possible that some of us are genetically predisposed to be interested in genetics? From my search in 1999 and 2000, I was able to confirm the specific Ghanaian individuals and families who are my ancestral cousins, and discover others. I was impressed with the diversity in my ancestry. Among the groups in my ancestry, there are dozens of ethnic groups and ancestral cousins in Africa, especially in Ghana, one group in the Middle East, ancestors who were Maroons, escaped slaves in the Caribbean, and nobles in the British Isles. I interviewed elders in New York and in the Caribbean in Jamaica, and corresponded with ancestral cousins in Ghana in West Africa and in Scotland in the British Isles, specifically nobles who are related to the royal families of Scotland and England, including current and retired members of the British Parliament’s House of Lords. (I was granted my Scottish ancestors’ coat of arms in 2005.)

So this week’s report on genomic medicine was fascinating, not only because of its thoroughness, (it covered the American progress better than many American reports), but because of its source. It shows which thinkers and policymakers are preparing for the future of medicine.

A riveting 126-page study and report, “Genomic Medicine,” from Britain’s House of Lords, the upper house of Parliament, echoed Dr. Francis Collins’ statements that genomic medicine must be at the frontier of medical research, because it is the future of preventive medicine and effective treatment, and personalized medicine. The House of Lords’ Science and Technology Committee reported that personalized genomic medicine is not only in our future, it is already here. The committee emphasized that genomic medicine must become an integral part of medical training. Medical schools must instruct doctors, not only about rare single-gene inherited diseases such as cystic fibrosis, Huntington’s disease, hemophilia and sickle cell disease, but they must educate them about the internal and external environments and genetic predispositions that trigger common diseases such as cancers, coronary heart disease, rheumatoid arthritis, diabetes and obesity.

This future wave is called epigenetics – the study of how diseases are influenced not only by changes in one gene but by changes and the interaction of many genes. It’s an examination of the internal and external environments in which our genes are triggered, get turned on, or turned off, unleashing or squashing a predisposition to disease. Doctors must be educated about environmental factors, internal molecular changes, personal family history and ancestry, which are factors in the diagnosis and treatment of diseases.

Doctors must be trained how to tailor individual genetic profiles in prescribing drugs – what is called pharmacogenomics. Given the results of patient’s genomics and molecular tests, they should know which drugs produce a positive response and which produce an adverse reaction.

The House of Lords’ report discusses how genomics will play a vital part in improving the drug development pipeline, how it will result in more effective and safer drugs, and how we will be more prepared to face social, legal, ethical and private genetic challenges. The lords’ report highlights how traditional government-funded and private medical training must recapture the genomic field and get ahead of the commercial front runners. But it also says, the commercial direct-to-consumer companies such as deCODEme and 23andMe should be carefully regulated, not restricted.

The most dramatic statements in the report says, “The new knowledge of these genomic studies is still very fresh.” Genomics-based prevention of disease is in the future. “But the use of many types of genomic tests is increasing rapidly,” and will “have a dramatic impact on disease diagnosis and management.”

The effect of these developments are, “This is already placing strain on the expertise of doctors, nurses and healthcare scientists who at present are poorly equipped to use genomic tests effectively and to interpret them accurately. . . .” (Britain’s House of Lords’ Genomic Medicine Report).

The responses in the press were alarming. The London Times Online reported that the members of the House of Lords’ Science and Technology Committee who did this study is composed of scientists, doctors and philosophers. (Members in the House of Lords inherit their seats as peers or are appointed as leaders in a given field.) And, “It is hard to imagine even a body like the US Senate producing a report of quite this quality and authority.” So all I can say to Dr. Francis Collins is, as the medical research branch of the U.S. Department of Health and Human Services, he has to build the best medical research team possible. His team has made major discoveries about genes and rare and common diseases, from cystic fibrosis to cancers, neurofibromatosis, Huntington's disease and type 2 diabetes. But as he said at the Consumer Genetics Conference, scientific progress means facing the unknown.

The British have laid down the gauntlet. So let the medical research race and the debate begin.

Pearl Duncan

The author is completing a book about she used DNA, genealogy, rare historical records and folk narratives to trace her ancestors.

Breakthroughs in DNA medicine to revolutionise doctors’ training

Doctors are to be given more specialised training in genetics to prepare the NHS for a revolution in DNA-based medicine, The Times has learnt. A review of medical education in genetics is to examine what doctors need to know about the influence of DNA on common diseases and patients’ response to drugs, so they can exploit science’s growing understanding of the human genome in clinical practice.

In an interview with The Times, Professor Peter Farndon, director of the National Genetics Education and Development Centre, said recent advances in genetic science made it essential for doctors to have more access to information. Though the last genetics syllabus for medical students and junior doctors was introduced in 2006, so much has changed since then that the centre was already working to update it, he said. It was also developing guidelines for professional education in the field.

Over the past three years, costs of reading DNA have fallen so sharply that many scientists predict that it will be possible to sequence any individual’s entire genetic code for less than £1,000 within a year or two. Research has also revealed hundreds of genetic variations that affect an individual’s risk of disease or response to medicines. Companies such as 23andMe and deCODEme have started to sell genome scans directly to consumers, assessing their genetic risks of developing a range of diseases for between £300 and £600. Last week a report from the House of Lords Science and Technology Committee said that these developments required urgent reforms to medical training and NHS infrastructure so they could be translated into benefits for patients. The importance of genetic tests was “placing strain on the expertise of doctors, nurses and healthcare scientists, who at present are poorly equipped to use genomic tests effectively and to interpret them accurately, indicating the urgent need for much wider education of healthcare professionals and the public in genomic medicine”, the report said. While doctors learn about genetics in undergraduate and postgraduate training, the focus is on rare disorders caused by mutations in single genes, such as Huntington’s disease and cystic fibrosis.

More recent genetic research has identified hundreds of DNA variants with more complex and subtle effects on a wide range of much more common conditions, such as heart disease, cancer and rheumatoid arthritis. Each raises or lowers a patient’s predisposition to disease only slightly, but can combine to create a significantly raised risk, and their influence can be difficult to interpret.Family doctors, in particular, need an understanding of this area so that they can give appropriate advice to patients, Professor Farndon said. Scientists have also started to discover genetic variants that affect whether drugs are likely to be effective, or the safe dose that a patient can take. This practice, known as pharmacogenomics, is forecast to become increasingly important to more personalised medicine, but currently it is not highlighted as an important teaching subject. “It definitely needs to go into the main syllabus now, absolutely,” Professor Farndon said. “Suppose there’s a set of eight DNA variants that predispose a woman to a high risk of breast cancer. Even though she has no family history, you might target her for screening much sooner than the current recommended age.”

coriell personalized medicine centre (PMC)

Coriell is a non-profit medical research institution providing the same SNP testing technology, but as a responsible, accountable medical research collaboration to determine its clinical application. Coriell provides its SNP tests at no cost to participants, and they only offer testing in a medical setting, not directly to consumers through the mail. Further, Coriell fully claims that their genomic tests are to be used by physicians to produce actionable medical advice (NOT as “information only”). Finally, unlike other SNP test competitors, Coriell has always operated with CLIA certification, has always operated under the supervision of an Informed Cohort Oversight Board (ICOB), and has obtained a Certificate of Confidentially which authorizes Coriell “to withhold the names and other identifying characteristics of individuals who participate protecting them against the compelled disclosure of any personally identifiable information in any Federal, State, or local civil, criminal, administrative, legislative or other proceedings.” No other similar service offers this protection.

deCODEme

deCODEme has blundered into the same “medicine that’s not medicine” fraudulent territory as Navigenics, but they do not make as good of a negative example as Navigenics does because deCODEme is not the DTC genomics leader. If deCODEme survives, it will follow the examples of others, so I propose no special effort to make them a negative example. It’s more important to focus the already diluted messages of the personalized medicine community than it is to be “fair.” However, I propose to hold deCODEme to the same standards as Navigenics if the challenge arises.

navigenics

Navigenics clearly states that it accepts no responsibility in all contexts —including medical advice. Thus, no responsible physician can promote Navigenics. Yet, Navigenics continues to promote themselves as “partnering with physicians” to provide their “Health Compass” service to “ensure state-of-the-art medical advice” and to “help you make informed, personal health decisions.” Left unchallenged, these statements will continue until they are assumed true. Thus, no responsible physician may practice non-participation. I have yet to see one single actionable medical claim about Navigenics—a fact explicitly expresses in their Terms and Conditions  and never contradicted by Navigenics‘ medical director, Michael Nierenberg. Thus, in a “partnership” between Navigenics and a physician, Navigenics gets all the money and the credit, the patient gets to pay more for less care, and the physician gets all the liability and the work of producing the medical advice. This is your roll in the “medical revolution” pledged to you by your bleached-out BIZDEV! “friends.” Participate, and you’re either a sucker or a sellout —not a responsible physician.Worst of all, Navigenics thinks that they can sell “medicine that’s not medicine” through clever marketing and physician partnerships, enriching Navigenics now while they dodge the liability of medical responsibility later. For the same reasons that credit-swapping “insurance that’s not insurance” should have never been tolerated, this kind of “is isn’t” sophistry sets an industry precedent by which one may sell  a promise now without accepting any of the expected future value of liability already built into the system to prevent abuse. Like insurance, since preventive medical advice is an abstract promise, once the precedent of accepting no liability has been set and successfully tested, non-liable preventive medical advice can be infinitely created and sold with no physical limits… until the system breaks. Understandably, some people will be less likely to trust non-liable advice. The solution is to package non-liable advice with liable, trusted medical institutions until the public is so confused that it is unable to sort reality from fiction. Finally, once the business model of selling free and infinite non-liable medical assets by packaging them with and laundering them through trusted medical advice has been sufficiently demonstrated to the investment community, responsible ventures will not be competitive for investment capital.Thus begins the great genomic industry sellout race to zero trust. At the end, disposable start-up companies like Navigenics cash out and collapse (or just collapse), and surviving trusted institutions of medicine get stuck with the loss.Navigenics is an unprofitable venture-funded web start up created by Silicon Valley investors to test the limits of the personalized medicine market. I propose that the physician community compose the results of that test.

23andMe

The pragmatic, political reality is that 23andMe is the public pet project of a billionaire’s wife. It’s not going to die, it’s not going to be thwarted by institutional disapproval, and it has to go somewhere.Thus, I propose to let 23andMe have their novelty consumer web service “data democracy,” but firmly block any implied medical application until the accountability and clinical application demands of the medical community are met. It’s wholly appropriate to have no medical opinion about an inactionable novelty consumer product so long as that product is not marketed otherwise.Maintain state control: you want to know what 23andMe is going to do and why. Do this by blocking where you don’t want them and making it easy for them to be somewhere that’s not valuable to you (novelty consumer web services). Don’t unilaterally block them with weak ideas like “your feelings as a doctor” because that offers 23andMe no acceptable response. Again, 23andMe has to go somewhere, so offering no acceptable response forces 23andMe to behave unpredictably (and in your offered context, unacceptably) without achieving any useful objective. Worse, sloppy, disorganized attacks brand you as uncooperative partisan to be mitigated —not a as leader. That will be a problem for you in Silicon Valley as the medical application of informatics and the internet continues to advance. Maybe impulsive attacks once helped galvanize the medical community when 23andMe was first announced —and maybe that was necessary at the time— but these impulsive attacks are now counter-productive and should be discouraged. Further, unlike Navigenics, 23andMe is far more transparent regarding the scientific data justifying its reports and openly engages the scientific community. This transparency should be rewarded, not punished, and using this transparency to justify impulsive attacks will set a president that transparency is an untenable liability in preventative medicine. This helps nobody. Again, while scientific transparency may not be appropriate to include in medical advice, it is absolutely appropriate to include in novelty consumer web services. Thus, for the case I make above, while both Navigenics and 23andMe are guilty of irresponsible medicine by marketing, I propose that the medical community permits 23andMe to exist as a novelty consumer product only with no medical insinuations until 23andMe chooses to practice medicine responsibly.