Family History Better than Navigenics/DTCG Shill for Cancer Genes?

Yes,

You heard it here. A recent study abstract and pressed about from my friend Charis Eng MD PhD, Clinical Geneticist, Internist and all around really smart lady spoke today about her findings of a head to head, DTCG vs Family History at discovering cancer risk.

You can watch the webcast about it here!

I actually sent some data Ken Offit's way about a similar thing way back when, Ken is yet another, really smart guy. He wasn't surprised. Nor was I when I heard Dr. Eng's findings.

First, Caveat Emptor

This is an abstract! Repeat after me......

What does that mean?

1. It is not peer reviewed fully

2. It is not published yet

3. It is preliminary data

This test was Navigenics Compass vs Family History in 22 females with breast cancer, 22 males with prostate cancer and 44 people with colorectal cancer.

What was the result? Family History placed far more people in the proper high risk category. 8:1

Family History put 22 people in the appropriate High Risk Hereditary Category, DTCG only one.

Further, it looks to me that the Navi "Gene" Scan missed several high risk patients who actually had MMR mutations (I.E. Genetic Cancer).....D'Oh.

First off, this is like a case study. But it signals a HUGE shortcoming of DTCG. False reassurance.

I have been beating this over the head for 3 years now! These tests that have "medical" relevance need to be couched with proper medical guidance.

I told Mary Carmichael of Newsweek this!

This stuff is medical data and I Told Thomas Goetz of Wired this!

Even the WSJ has gotten it!

There are huge shortcomings in the current offering of DTCG tests and those offering medical information need to be regulated as medical. This is a classic case in point of potential and REAL missed cases.

Not Good.

That being said. It is November AKA Family History Month. You should absolutely take your family history and bring it to your doctor. If they don't know what to do with it, call us. We do.

The Sherpa Says: No surprises Charis, I saw this with some DTC cases I have had, passed it on to Ken who passed it on to NIH and The IOM. This is the huge problem with hype and over promise. It always fails to deliver, unfortunately in this case at a great risk to consumers.

NIH Draft Consensus Statement on Family History

The NIH conference on Family History came and went.

What were we left with?

A Consensus Statement.

What is the crux of it?

"The panel recognized that family history has an important role in the practice of medicine and may motivate positive lifestyle changes, enhance individual empowerment, and influence clinical interventions. The panel found that it is unclear how this information can be effectively gathered and used in the primary care setting for common diseases."


Well ladies and gentlemen. I can give you all sorts of anecdotal evidence. That being said, we are evidence driven creatures, so I suggest you give me a call and we set up studies in Primary Care practices with different family history tools.

Things such as the "SCREEN" screen versus a detailed 3 generation pedigree versus 1st generation.

It is pretty easy and inexpensive to set these studies up if you use current technologies.

What else did the panel say?

"For a systematically collected family history for common diseases to become an evidence-based tool in primary care clinical settings, substantial additional research will be needed."

I agree, it is time we develop these tools as multifactorial shotguns which hit lots of targets. This IS what DTC is arguing that there puny little scans do. Without evidence Family History champions like myself run the risk of sounding like the marketing hacks out in Silicon Valley and PR firms like NYC.

That being said there are some evidence tools where Family History helps clinical classification. I think specifically of the Reynolds Risk and how it beat the Framingham

We should attack this one precisely the same way. Start by each individual risk calculator ADD family history and see what it does.

Then do a cohort study of practices which routinely perform 3 generation pedigrees and see how the incidence of diseases like diabetes, HTN and MI shake out.

That could be done over 5-10 years. Not a long wait to get some great evidence, if you ask me.

The Sherpa Says: The evidence may be weak for Family History as a Poly-Tool. But as a clinical marker in certain diseases it is ESSENTIAL.

Where from here?

This is the question I am asked so often.

1. We have the steady progress towards cheap genomes.
2. We have the biggest supporter of personalized medicine running the NIH
3. We have "some" clinical awareness of personalized medicine
4. We have the government aware of the shenanigans of some unscrupulous DTC advertising, etc
5. We have several milemarkers under our belts with genome science..... We are moving in the "right" direction, but where do we go from here

There are several areas we need to investigate. I would like to sum a few of them, both basic science and clinical. Basic Science first.

1. We need to understand precisely how gene regulation occurs in the face of certain common environmental exposures. Trans Fat, Tobacco Smoke, Alcohol, Stress. Is it RNA? Is it Methylation? What precisely is it? Maybe it is all of them and more. But the quicker we understand that, the quicker we can look for signs of these ill effects.....and stop them molecularly

2. We need a good CNV/Indel etc database. Toronto sure, I have heard that. But seriously. We need this and we need it now. Give me Normals, Give me abnormals, Give me phenotypes......This is a very key missing piece of the puzzle which neds to be completed in the next 2 years

3. Junk DNA investigation. This will come once we have a database like the one in Iceland......I am certain this will come. I think that next to nuclear fission, the investigation into the "junk dna" will prove to be one of the most fruitful works of governmental science. Yes, you can quote me on that one.

4. Systems biology. This is one of those areas where we will eventually realize the Greeks were right with phlegmatic systems vs bilious systems.......

Now onto the top 3 Clinical Science targets

1. A complete revamping of the current risk stratification system. What do I mean? We need to develop a process for efficiently introducing genotypic risks into current clinical risk stratification. We need to evaluate the with and without and change in AUC......
1b. We need to evaluate the role of integrating family history in some risk stratification models. I know Dr. Khoury/Scheuner et.al are working on these things, but it sure would be nice to have odds ratios and RRs/HRs for adverse drug outcomes, common autoimmune disease risks, COPD, Alcoholism, Suicide, etc. types based on fam hx integrated with current models.

2. Pharmacogenomics......end of story, we need more science here for more drugs. There is not nearly enough clinical study weight on outcomes. I understand why from the Pharma end, but the US government cannot ignore its utility, especially with the pain they feel from Medicare part D
This area has tremendous promise, but has not seen the will from genetics departments, mine looked at my cross eyed when I wanted to do a PGx study. There has to be a will in basic medical science departments like pharmacology and cell biology to understand the processes and polymorphism which really screw up a drug's effect.....or really enhance it. And there has to be a will in clinical departments to study the outcomes with different therapies based on genes.....

3. I want to know what behavioral outcomes are likely with knowledge of one's family history risk versus genome scan risk vs both together vs with no knowledge.

These are some low hanging fruit that could get accomplished and probably already are........

The Sherpa Says: These are not stretch targets, these are do-able things in the next 5 years or so. If we can accomplish most of these, we will be well on our way to evidence based personalized medicine, which is where we need to be........

Family History, State of the Science

The NIH/CDC is hosting a conference next week. I conference I wish I could go to, but alas, I will be DOING family histories on my patients that week.

The conference will be held at the NIH in Bethesda. This is an NIH state of the science conference about Family History and its usefulness.

I for one, am very glad that the government is trying to address this super important issue. It is beyond due for an evaluation.

Why?

With the cost of a genome going to drop to 5000 USD by the late fall (trust me), we will soon see another level of DTC and Clinical lab set offering the genome as a predictive tool.

There are several reasons that Family History beats a Genome (For Now)
1. Phenotypic data of family history represents complex interplay of genes and environment

There is no way that a simple genome will be able to give us the story of how a human will develop. That is predicted by environment and genes, which are successfully covered by..... A family history.

2. 5000 USD is still more than what it costs to obtain a family history.

By the time the software tools are released, we will see that social networking and the internet will transform the costs of family history next to nothing. Which is still a long way to go for the genome scans.

3. We have no clue what most of the genome data means.

Indels or CNVs or SNPs, we have no freaking clue what most mean, we do know what a heart attack at 40 means.......

4. Even if we had everyone's genome scans, we would still need phenotypic data and pedigrees.

What's the one thing we do when we have an intellectually delayed child with an abnormal CMA/CGH? We test the parents. Looking for THEIR phenotypes to make sense of the genome mess.

Look, people always give me reasons why the genome is important and a family history is useless.
I've heard them.

-"We don't speak with that side of the family"
-"My father lived with his uncle, because his father died (secretly running the empire as Darth Vader)"
-"I was adopted by Bail Organa, only to find out I have a lost twin brother"

There is one thing that will always be certain over time, there will be some screwed up family dynamics making it difficult (BUT NOT IMPOSSIBLE) to obtain an accurate family history.

That being said, it is still often useful to capture those who you can. And still less expensive.

I look forward to the briefings from this conference, and Muin, if you are listening, I would love to have the link to the webcasts.... Oh wait, they have that too! Sweet.

If you can't be there, you can get the information you seek!

Once again, we need a state of the science on genome prediction, not a consensus statement a real eval of the state of the science. When placed side by side with the state of the science for a family history, we will soon see why family history is the preferred screening tool and will likely to continue that way, perhaps in conjunction with a genome scan, but genomes will NEVER replace family history.

The Sherpa Says: The press better be at this conference and report on Family History. And to the founders of Geni.com, you missed on this one when Tindall presented to you. Or maybe you just are going to steal the idea.........

No Gene is an Island

This is a saying I have been using for about 4 years now.
When someone asked about testing for HFE and why we don't do it as the first screening step anymore.....

They often looked at me confused.....I then bring up the case of sickle cell disease.

Most doctors have seen a sickle cell patient in the hospital.......They may have even seen a family in the hospital, brother and sister, Son and Mother......but what most don't know is that the majority of sicklers never go into the hospital.....

That's when I ask, what is the mutation that the son and mother have? The answer Sickle-cell anemia is caused by a point mutation in the β-globin chain of hemoglobin, causing the amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position.


Now what about the patients who never come into the hospital?

Sickle-cell anemia is caused by a point mutation in the β-globin chain of hemoglobin, causing the amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position.

Why is that? I answer my question as they have lots of guesses....

"No Gene is an Island"

You see, there are several things linked to the development of the adverse outcomes with sickle cell disease. Environment, Modifier Genes, Epigenetics (which ultimately is environment) I could go on from there........but suffice to say, genes can only provide us a small answer into the majority of diseases......

Drug metabolism, is a very different story at times.....

I then go on to say that there are very, very few diseases for which severity of disease or even disease itself is attributable to JUST one gene........ Or frankly to JUST ONE MUTATION..........

The body is a set of systems and by being super reductionist and looking at one gene or one mutation versus another, we ultimately end up missing the boat and making a big deal out of something which is not so big a deal......

Or we apply something which may be clinically valid but have little clinical utility.......

Even worse, we take something which has wonderful analytic validity and to use it clinically, with a huge waste of money and a huge waste of resources........ This is the case with DTC.

Some may argue that we should allow people to waste their money on anything they want. I tend to agree with this.

However, what should not be tolerated is false claims and manipulation of claims without scrutiny.

In addition, something which meets the definitions of medicine, should be held to that standard......plain and simple........ Taking human tissues/samples and using them for research requires an IRB, taking human tissues and using them to predict risk of disease IS MEDICINE..........and should be regulated as such......

There are a whole host of laws which regulate how a doctor can advertise, why are we not applying them to these companies who are performing such analysis?

But more importantly, why are these companies the only people educating the public. And doing a very slanted and manipulative job here......

No Gene is an Island......thus no SNP is the end all or be all of risk.....It is much more complex than that.

Which is why I say "Family History is the cheapest and most clinically useful Whole Genome analysis"

The Sherpa Says: Someone is watching these claims, I hope you come here to debunk their junk.

New Family History tool to Debut

It's as if everyone in the technology land had been hearing my cries!

"Family history is the cheapest and the best whole genome scan we have!!"

The Government fixed theirs others are working on it as well.......

With the potential in ancestry companies to turn their tools into family history gathering machines we are now seeing a big shift in focus from merely ancestry to ancestry AND medical history. One great tool that is coming comes from a website called ItRunsInMyFamily.com

And like every self respecting entrepreneur looking to boost SEO, they have started a blog.

But what's even better, they beat me to the punch when comparing genetic testing versus family history...

They pit them head to head.....

From the blog:

Breadth of Diseases
Over 6,000 known single-gene disorders. (This does not include multi-factorial diseases) “Every human disease has a genetic component.”

Family History: Can track an unlimited number of diseases. Any disease that has an inherited or genetic component can be listed on a family health history.

Genetic Tests: ~1,000 clinically relevant genetic tests available today. Most are for single-gene disorders, few adequate genetic tests are available for multi-factorial diseases. Direct-to-consumer (DTC) genetic testing services (# of diseases): 23andMe (26), deCODEme (35), Navigenics (23), Myriad BRCA (2).

ADVANTAGE: Family History

The result?

You'll just have to read their post!

The Sherpa Says: with all of these fly by night and limited clinical utility genotech companies out there, it is sure nice to see someone with good business AND Clinical sense!!!

Surgeon Generals Family History Redux!!!

Have you guys seen this yet? A reader let me know that the Surgeon General had officially launched the revamped site.

Family history is the key the tool that geneticists and counselors use to look for patterns of disease and heritability. Some people just pay attention to cancer, others focus on all diseases.....heck, I even look for history of adverse drug reactions in families. You never know what you will find, but if you look, you often find something.

The problem? It often takes a long time and information can be inaccurate. This is why counselors spend days on end trying to track down accurate records for cancer prediction risk.....This is time consuming and doesn't get paid for.....so now there is help.

Yes, after much adjustment and web-work, the Surgeon General's Family History tool is now much more than that. From the site:

What are the key features of the Surgeon Generals family health history tool?
The Surgeon Generals "My Family Health Portrait" is an internet-based tool that makes it easy for you to record your family health history. The tool is easy to access on the web and simple to fill out. It assembles your information and makes a "pedigree" family tree that you can download. It is private--it doesn't keep your information. It gives you a health history that you can share with family members or send to your health care practitioner

This tool is exactly one of several tools set to debut which allow patients to enter family history and email family members to collect further information. I am working on one as well, but ours is a little more than that......

CBS News covers the launch here.

"The goal: Just as people create ancestral family trees, create a family health tree. It may sound old-fashioned in this era of gene discovery. But genetics specialists use these "pedigrees" to look for patterns of inherited illnesses that can provide a powerful window on someone's brewing health risks. "

It turns out the tool has been piloted up in Boston.

But a small pilot study at Partners Healthcare in Boston suggests the digital potential. Embedding the e-family tree straight into software that adds in a patient's test and exam results produced a personalized report on cancer risk in minutes.

No surprises here. I have been saying this all along....Family history is the best genome scan available, the quickest, the cheapest and likely the most accurate.....

The Sherpa Says: Too bad V.C. can't make money off of this, maybe we would have NY Times articles about family history instead of SNP scans......Either way you slice it, the attention is good, provided you have a Sherpa to guide you up the mountain....

HT: JW

Heavy Heart

I vowed I would never post when family took precedence. I have to break that vow today. I wish I didn't but there is something so vitally important that I must share with you. Why is this important? Because it might save more lives than have been previously lost.

The scourge of Ovarian and Breast cancer has ravaged several populations. With very few cases of early detection in Ovarian cancer, many women present with spread of the cancer and very poor prognosis. Even more importantly, women who have ovarian cancer and BRCA mutations still are at risk for other cancers including breast cancer.

Despite this I have heard comments from Oncologists like "Why do we need testing?" This is why I have pulled myself away from my grief stricken family.


To fight this lack of knowledge I have dedicated and arm of Helix Health of Connecticut to educate and promote genomic medicine. This arm will host at minimum monthly podcasts on very important topics. The first of these is Hereditary Breast and Ovarian Cancers and the BRCA genes.


The panel will include a patient with BRCA1. She not only happens to be afflicted, she has written about her experiences. Jessica is gifted with the pen and is a very successful writer. Her book "Pretty is What Changes" raises significant issues and serves as a wake up call to clinicians and patients. It serves to empower us all.


Jessica will join David Ewing Duncan, bestselling author of Masterminds: Genius, DNA and the Quest to Rewrite Life, and a panel of distinguished medical and legal professionals to discuss how the doctor-patient relationship is changing and what the potential liability is for physicians in this new era of breast & ovarian cancer and genomic medicine.


The Sherpa Says:
The Helix Health of Connecticut webcast series is dedicated to my grandmother who died at 35 years of age from metastatic breast cancer. Too young for me to ever know. Please sign up for this conference. The information may just save a life......If Helix Health of Connecticut can save just one life then all the hard work is worth it. Please sign up now. Seats are limited, but you can also sign up for the podcast.

Family History Tidbits

In my search for useful news today, I have come across something near and dear to my heart. Karen Lu at M.D. Anderson has posted on the importance of taking a family history. Her spin is obviously tilted towards cancer, but the benefits of family history or just as important in diseases like heart disease.

From the site:

“Family gatherings are the perfect time to ask family members detailed questions about their health history,” says Karen Lu, M.D., co-medical director of the Clinical Cancer Genetics program at M. D. Anderson.
“It is important to gather information about the health history of your parents, siblings, grandparents, aunts and uncles, and even your cousins.”

She points out that there are some red flags to watch out for in your family.

1. Early onset of Cancer. (I say not only cancer, any disease is important here)
2. Family member with 2 or more "related cancers" (These include things like breast and ovaries. For more info see here)
3. Two or more family members who have related types of cancers. (Too bad some insurers require 3 members to be afflicted in order to pay for BRCA testing)

If you find some of these red flags you should at a minimum ask your physician about genetic evaluation. If you live in the CT, NY, NJ area give Helix Health of Connecticut a call. Genetic Testing may be appropriate for you and evaluation is needed.

Genetic testing involves looking for abnormal genetic changes in a person’s blood sample. People who inherit abnormal genes from a parent may be at increased risk of developing cancer.

“The benefit for the cancer patient who tests positive for an abnormal gene is that doctors can use this information to determine if they are at increased risk for a second cancer and to help family members,” says Molly Daniels, a genetic counselor at M. D. Anderson.

For family members, the benefit to learning that a close relative carries an abnormal gene is that they too can be tested to determine if they are at increased risk for developing cancer.

Those who test positive may begin routine cancer screening exams at a younger age than what is usually advised for the public. High-risk screening enables health professionals to detect cancers as early as possible when there is the best chance of successful treatment and cure. Those who test negative can be reassured that they are not at increased risk because of family history.

The Sherpa Says: The major risk factor in both heart disease and cancer is family history. Perhaps more so in heart disease. Evaluation for these risks need to be done on an ongoing basis. Remember, your family history changes with time. So if you have taken your family's history, up date it yearly or when something you know has changed. A great tool for this is found at the HHS website!

Multiple Sclerosis Risk Passed Equally By Parents

Recently a phenomenon known as the Carter effect has been put in to doubt. At least for the horrible disease Multiple Sclerosis (MS).

A study published in the journal Neurology last week indicated that the transmission of MS risk is not skewed based on sex.

"Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. The precise nature of these factors and mode of inheritance remains unknown. A female predominance is universally found. Recently, offspring of affected fathers were reported to be more likely to have MS than those of affected mothers. This was attributed to the Carter effect, which is seen in polygenic disorders. The Carter effect predicts that affected parents of the sex lesser affected by a disease/trait are more genetically loaded for risk alleles and thus transmit these more often to their offspring."

The study found that both men AND women afflicted with MS transmitted the disease about 10% of the time to their offspring.

The Sherpa Says: This is a study which calls into question old notions of thinking regarding genetic predisposition. Unless this is a sex linked disease, we should not see skewing. This old thinking was much along the lines of "Only women pass on breast cancer". I am glad to see it go. However the critics of this study will note that 3 times as many afflicted mothers were studied. Also no genome wide association studies have identified any genes in this likely multifactorial disease. Patience......they will come.

African Americans, Family History and Lung Cancer

A pre-publication release of the Journal Chest includes a study assessing family history of lung cancer and likelihood of acquiring a tobacco related malignancy.
From the study:

"In 2006.....estimated that 174,470 new lung cancer diagnoses and 162,460 deaths from lung cancer will occur. Lung cancer remains the leading cause of cancer related death, regardless of gender."

I just saw 2 new cases yesterday myself :(

"Among case relatives, African Americans were 2.44 fold more likely to have head and neck cancers and 1.86 fold more likely to have any tobacco-related cancer compared to white case relatives"

This is where we have to wonder what role detoxifying genes such as GST polymorphisms. It has been show that they do play a role in risk of disease. If only DNA was collected from the participants in this study..........

Most scary for African Americans with a first degree relative diagnosed with Lung Cancer in this study

1. They are 13 times more likely to have head and neck cancer


2. Almost 4 fold more likely to have any tobacco related cancer


3. 4 times more likely to have any tobacco related cancer other than lung

For the Caucasian analysis it appears that African Americans are at 2 fold increased risk compared to their White counterparts when it comes to Lung Cancer.

The Gene Sherpa Says:

We all know smoking causes cancer. But those who continue to play Russian roulette with Marlboros would like to know how hard they should try to quit. This study was limited by only studying early onset lung cancers (less than 60) Kick the Habit Now!

Family History and Stroke Risk

This week at the American Academy of Neurology's annual meeting results from a study were announced. Persons who had a brother or sister who suffered a stroke were almost 2 times as likely to have a stroke. All strokes in the study were due to an occlusion of a blood vessel which either resolved in less than 24 hours (TIA) or not. Of note the risk to Mexican Americans was even higher. Not surprising to me especially because they have a higher rate of metabolic syndrome in their population. Interestingly this risk was almost 3 fold in Mexican American men! My questions are many fold and will be found out over time. What role do hormones play? What about epigenetic changes in sperm? The list goes on forever.

So once again family history rules the day. I hate to tell all of these testing companies, but family history is the cheapest and best genetic test you have. Now if we can only convince physicians that family history is never noncontributory unless you believe in spontaneous generation!

True there are those like myself with only half a tree and that is where targeted testing guided by a physician will play a role.

More on colon cancer.

While preparing to give a lecture on colon cancer for my curriculum study I came across another piece of evidence that should give most patients pause. I hope my readers take this to heart and begin assembling their own family histories. This week in the Journal of General Internal Medicine there is an article surveying patients about their experiences and screening offered for colon cancer prevention. The first survey identified patients with a family history of colon cancer and the second survey evaluated the care they received by their internist. The care was given at a Harvard affiliate! Here's what they found:

1. Only 39% of patients under 50 were asked about family history
2. Only 45% of patients with a significant family history had been screened appropriately
3. Only 46% of patients knew that family history of colon cancer can indicate a need for earlier cancer screening!

These averages might be good in baseball, but we are talking about human life here!

I am sure that with the database options in these new electronic medical records we will see more of our shortcomings. Especially when it comes to genetic care. That is if tracking family history is an option for an EMR. Most programs have woefully inadequate genetic options.

Here's what I will tell these young doctors: You better ask for family history, because the patient will not tell you they are at risk!

Here's what I will tell you: Please take your family's history and give it to the doctor, because they likely won't ask! More importantly, educate yourself about screening at the United States Preventative Services Task Force(USPSTF)