"Personalized medicine." You've probably heard the term. It's a bit of a buzzword these days and refers to a vision of future medicine in which therapies are much more tightly tailored to individual patients than they currently are. That's not to say that as physicians we haven't practiced personalized medicine before; certainly we have. However it has only been in the last decade or so that our understanding of genomics, systems biology, and cell signaling have evolved to the point where the vision of personalized medicine based on each patient's genome and biology might be achievable within my lifetime.
I was thinking about personalized medicine recently because of the confluence of several events. First, I remembered a post I wrote late last year about integrating patient values and experience into the decision process regarding treatment plans. Second, a couple of months ago, Skeptical Inquirer published an execrably nihilistic article by Dr. Reynold Spector in Skeptical Inquirer in which he declared personalized medicine to be one of his "seven deadly medical hypotheses," even though he never actually demonstrated why it is deadly or that it's even really a hypothesis. Come to think of it, with maybe--and I'm being very generous here--one exception, that pretty much describes all of Dr. Spector's "seven deadly medical hypotheses": Each is either not a hypothesis, not deadly, or is neither of the two. Third, nearly a month ago I was attending the American Association for Cancer Research (AACR) meeting in Orlando. I don't really like Orlando much (if you're not into Disney and tourist traps, it's not the greatest town to hang out in for four days), but I do love me some good cancer science. One thing that was immediately apparent to me from the first sessions on Sunday and perusing the educational sessions on Saturday was that currently the primary wave in cancer research is all about harnessing the advances in genomics, proteomics, metabolomics, and systems and computational biology, as well as the technologies such as next generation sequencing (NGS) techniques to understand the biology of each cancer and thereby target therapies more closely to what biological abnormalities drive each cancer. You can get an idea of this from the promotional video the AACR played between its plenary sessions:
Which is actually a fairly good short, optimistic version of my post Why haven't we cured cancer yet? As I mentioned before, with this year being the 40th anniversary of the National Cancer Act, as December approaches expect a lot of articles and press stories asking that very question, and I'm sure this won't be the last time I write about someone declaring the "war on cancer" a failure this year.
"Personalized medicine" in CAM
In the meantime, before I discuss a couple of examples of how science-based medicine is moving ever more closely to personalized medicine, I can't help but note that part of what inspired this bit of my typical blather on this topic was sitting in the audience at AACR hearing about all these tour de force genomic analyses that begin to reveal the individuality and complexity of tumors, and, more importantly, to suggest strategies to target the specific abnormalities that drive the growth and metastasis of each cancer and contrasting in my mind the claims of "personalized" or "individualized" medicine that practitioners of "complementary and alternative medicine" (CAM) and "integrative medicine" (IM) like to make. As I pointed out about a year ago, "individualized" treatment in CAM-world basically means "making it up as you go along." Consider, for example, homeopathy, which postulates prescientific ideas for the cause of disease, claiming that "like cures like," and then using unscientific "provings" to determine which remedies can be used to "treat" each condition. Never mind that homeopathy is water (how often does it need to be said?), consisting of remedies serially diluted and succussed so many times that in many of them it is highly unlikely that there is a single molecule of remedy left in the concoction. Not only that, but one of the most popular homeopathic remedies for flu consists of basically the ground-up liver and heart of a Muscovy duck.
In CAM-world, "personalization" or "individualization" means "making it up as you go along." A good example of this is a post on that wretched hive of scum and quackery, The Huffington Post, by Dr. Mark Hyman, he of "functional medicine" fame, where, under a section entitled "Treating individuals, not diseases" he writes:
There is no effective known treatment for dementia. But we do know a lot about what affects brain function and brain aging: our nutrition, inflammation, environmental toxins, stress, exercise, and deficiencies of hormones, vitamins, and omega-3 fats.
It is not just one gene, but the interaction between many genes and the environment that puts someone at risk for a chronic disease such as dementia. And we know that many things affect how our genes function -- our diet, vitamins and minerals, toxins, allergens, stress, lack of sleep and exercise, and more.
Hyman then goes on to describe an anecdote of a man with developing dementia. Typical of many CAM doctors, Dr. Hyman chased down all sorts of "abnormalities," prescribed all sorts of supplements to "fix" those abnormalities, and subjected the man to various "detox" regimens, including unspecified "medications that helped him overcome his genetic difficulties by getting rid of toxins." As Steve Novella (and yours truly) pointed out at the time, in reality what Dr. Hyman was doing was a "bait and switch," in which he extrapolates from preliminary results in real science and uses them to come up with proposed treatments that have not been validated for the purposes that he uses them for. His evidence for success? Not science, not clinical trials, not even preclinical data, that's for sure. Instead Dr. Hyman presents a couple of anecdotes.
Indeed, much of this sort of "making it up as you go along" is on full display in the anti-vaccine movement. Indeed, the anti-vaccine crank blog Age of Autism has numerous examples of just this sort of "personalization," including the hijacking of mitochondrial disorders as a predisposing factor for "vaccine injury" causing autism, the serial use of all manner of "biomedical quackery" to "recover" their children, up to and including stem cells, and de facto unethical experimentation on autistic children. Be it chelation therapy, supplements, hyperbaric oxygen, dubious stem cell therapies, and other quackery, the anti-vaccine movement, "biomedical" quacks "individualize" their treatments to each autistic children, using dubious labs like Doctor's Data to come up with lab abnormalities to "treat." Of course, there is a fundamental disconnect between the claims of DAN! doctors to "individualize" therapy to each patient with their unwavering belief that vaccines cause autism. No matter how much they try to hide it, vaccines remain The One True Cause of the conditions known as autism and autism spectrum disorders.
There are many, many more examples of this kind of "personalization" of medicine in CAM based on either no science or unjustified extrapolation from existing science, dubious lab tests, practitioner biases, and a veritable panoply of One True Causes of disease. So let's contrast with evolving personalized medicine in science-based medicine.
Personalized medicine in SBM
Because I'm a cancer researcher and surgeon, I find that currently the most promising examples of how genomics can contribute to personalized medicine come from cancer. This should not be surprising, because cancer is not one disease. It's hundreds, perhaps thousands, of diseases, and even cancers arising from the same cells in the same organ can have very different biology. Basically, as I put it before, stealing liberally from The Hitchhiker's Guide to the Galaxy, Cancer is complicated. You just won't believe how vastly, hugely, mind-bogglingly complicated it is. I mean, you may think it's complicated to understand basic cell biology, but that's just peanuts to cancer. This point was driven home in the AACR video above, and I see it driven home with each new study of cancer genomics or heterogeneity that comes out in high impact journals every month.
For example, couple of months ago, I described a tour de force study of changes that occur in the genome of prostate cancer cells compared to normal prostate. The study demonstrated a number of alterations in the genome affecting molecular pathways that drive growth and metastasis and that could potentially be targeted for therapy. Then, not long before going to the AACR meeting, I came across this article in my news feed, Lung Cancer Evolves With Treatment, Study Finds, which refers to this study from Harvard by Sequist et al, Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. The study itself demonstrates something we've known for quite some time, which is that tumor cells evolve under selection by various modalities used to treat them. In this case, the authors studied how non-small cell lung cancer (NSCLC) evolves resistance under treatment with drug therapy targeted to the specific mutation driving their growth. In this case, the gene in which mutations result in its being turned on is the epidermal growth factor receptor (EGFR), and the targeted therapy consists of inhibitors of EGFR such as gefitinib (brand name: Iressa) or erlotinib (brand name: Tarceva). Basically, the investigators subjected tumor tissue from patients who had developed resistance to EGFR tyrosine kinase inhibitors to systematic genetic and histological analysis. What they found represented a confirmation of some known genetic changes that occur to result in resistance but also some unexpected changes, including:
All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.
Or, as Dr. Lecia Sequist, lead author of the study, put it:
"It is really remarkable how much we oncologists assume about a tumor based on a single biopsy taken at one time, usually the time of diagnosis," lead author Dr. Lecia Sequist said in an MGH news release. "Many cancers can evolve in response to exposure to different therapies over time, and we may be blind to the implications of these changes simply because we haven't been looking for them."
"Our findings suggest that, when feasible, oncogene-driven cancers should be interrogated with repeat biopsies throughout the course of the disease," Sequist said. "Doing so could both contribute to greater understanding of acquired resistance and give caregivers better information about whether resumption of targeted therapy or initiation of a standard therapy would be most appropriate for an individual patient."
Now, that would be personalized medicine, based on science, in marked contrast to what passes for "personalized" medicine in CAM.
Another cancer for which new findings in genomics and systems biology hold great promise is the cancer I spend most of my time treating and researching, breast cancer. Current methods to predict prognosis and guide treatment are crude and include stage as measured by volume of the primary tumor; presence and number of lymph node metastases; presence or absence of distant metastases; tumor grade as measured histologically; expression or lack of expression of important hormone receptors such as estrogen receptor (ER) and progesterone receptor (PR); and amplification of ErbB2 (HER2). Used together, these factors allow, albeit roughly, a degree of prediction of prognosis, as well as of personalization of therapies such as hormonal treatments (tamoxifen or aromatase inhibitors) or agents targeted at HER2 (trastuzumab). Aromatase inhibitors had not yetbecome widely available, and Herceptin (trastuzumab) had been FDA-approved for women with HER2-positive metastatic cancer but not yet for the adjuvant therapy of women with earlier-stage HER2-positive breast cancer. (That did not come until 2006, and then only with chemotherapy.) Then, in 2000, Perou et al published a classic paper in Nature that used then state-of-the-art cDNA microarrays to divide breast cancers into subtypes based on gene expression patterns, which, based on this work and work done since then, currently include normal-like, basal-like, luminal (A and B), and HER2(+)/ER(-), and there is a growing body of literature (for example, this study) that suggests that these different subtypes respond differently to different chemotherapy and targeted agents.
We learned many things from this work, which has accelerated over the last decade. For example, we now know that there are several intrinsic groups of breast cancer based on the patterns of gene expression they exhibit, and these groups subdivide many of the "classic" divisions we have been using for at least two decades, such as ER(+) or ER(-). More importantly, there is one form of breast cancer that expresses none of these markers. Dubbed "triple negative breast cancer" (TNBC), this form of breast cancer is defined as expressing neither ER, PR, nor HER2. TNBC is a close relative of a type of breast cancer categorized a decade ago through gene expression profiling and dubbed "basal-like" (synonymous terms include "basal-type," "basal-epithelial phenotype," "basal breast cancer," and "basaloid breast cancer"). For the most part, currently the same treatments are used for TNBC and basal-like breast cancer because the sine qua non of TNBC is that there are no known molecular targets in this breast cancer subtype, while non-TNBC basal-like breast cancer tends to express HER2 and thus be susceptible to Herceptin. Because TNBCs do not respond to drugs targeting ER or HER2, cytotoxic chemotherapy is currently the only option for adjuvant or neoadjuvant therapy in women with operable TNBC or for systemic treatment for metastatic disease. Paradoxically, TNBCs are more sensitive than ER(+) luminal tumors to standard chemotherapy regimens, but unfortunately this increased chemosensitivity does not translate into prolonged overall or disease-free survival. Consequently, the identification of new molecular targets or oncogene signatures that can be targeted for therapy, either with new agents and/or of new synergistic combinations of old agents, is a critical problem to be overcome for TNBC. Tantalizing hints of how this might be done arose at AACR, for example, this study in which the genomes of 50 breast cancers were sequenced.
Another area in which genomics might assist us as clinicians in breast cancer is through answering a rather vexing question regarding racial disparities in cancer outcome. For example, although the incidence of breast cancer among premenopausal African-American women is lower than among Caucasian women, African-American women are more likely to die from their disease, with a breast cancer-specific mortality of 33 per 100,000 and five year survival of 78% compared to 23.9 per 100,000 and 90%, respectively, for Caucasians. Breast cancer among African-American women tends to be characterized by higher grade, later stage at diagnosis, and worse survival, even after controlling for age and stage. Although it is true that the causes of these observed differences are likely to be multifactorial and include socioeconomic factors, such as differences in access to screening and treatment, there also appear to be biological differences in breast cancer in AA women. Indeed, evidence supporting biological differences as a major part of the explanation for these observed racial disparities was reported from the Carolina Breast Cancer Study. This study reported that that the TNBC/basal-like breast cancer subtype is nearly three times more common among premenopausal African-American women than among Caucasian women In marked contrast, the HER2(+)/ER(-) subtype did not vary appreciably with race or menopausal status, and the less aggressive ER(+) luminal A subtype was less prevalent in premenopausal African-American women. These results suggest that two questions remain open: (1) whether there is a difference in breast cancer biology that drives the tendency of young AA women to develop TNBC at a much higher rate than Caucasian women and (2) whether these biological differences, if they exist, can be exploited therapeutically to develop personalized regimens targeted at patients' individual tumors. These are the sorts of questions that genomics can potentially answer and personalized medicine be based upon.
Don't get me wrong. We are not yet near true personalized medicine for breast cancer. Indeed, if you want to get an idea of the challenges that remain, several of the talks I attended are available for free at the AACR website. Talks that are worth watching include:
- Harold Varmus, New Directions in Cancer Research
- Lynda Chin, Translating cancer genomics: From discovery to medicine (unfortunately, nearly none of the slides from this talk have been made available)
- Waun Ki Hong, The landscape of cancer prevention: Personalized approach in lung cancer
- Andrea Califano, A systems biology approach to integrative cancer genomics (Another one without slides.)
There are many others, but unfortunately most of the relevant talks are either not posted yet, require payment, or both. It's annoying to me, but on the other hand I understand that it costs money to produce these and put them up on the web. Still, the sheer number of talks on The Cancer Genome Atlas, which goes by the annoyingly cutesy acronym TCGA, is telling. Every day, or so it seemed, there were multiple talks on TCGA, reporting findings, telling investigators how to access the data on its website, and discussing the progress. Basically, TCGA is becoming a repository of genome sequences of many cancers, a resource that can be mined. It's not too hard to envision that one day, when it has many thousands of cancer genomes stored away from before and after treatment, its database might serve as the basis for computer algorithms that compares a patient's tumor genome to the database and comes up with a list of recommended treatments.
Unfortunately, the move towards personalized medicine not without its share of opportunists and companies selling kits based on genetic tests that either haven't been validated in clinical trials sufficiently to support their clinical use, for example Anne Wojcicki of 23andMe, whose pitch is has a lot more in common with "health freedom" arguments than it does with actual scientifically validated uses of genomic data, complete with heavy promotion in various social media. It's a trait shared with enthusiasts of direct-to-consumer genetic testing, whose language really does harken to that of the "health freedom" movement. For example, compare this post with this post by Mike Adams, and the main difference you'll find in the arguments will be in degree, not kind. It's "health freedom" all around.
Even while promoters, in a fit of cognitive dissonance, simultaneously accuse physicians of paternalism on this issue and admit that the burgeoning personal genomics industry needs to be "purged of scammers and bottom feeders," it's an effort designed to create an army of people who "will go nuts" at any attempt by legislators to legislate direct access to personal genomic data or regulatory agencies to control more tightly access to direct-to-consumer genetic testing. As Harriet Hall put it correctly, when it comes to routine genomic testing, we're not there yet, not the least of which because there are lots of problems with the testing. As I put it, much of the promotion of personal genomic testing is disturbingly similar to the promotion of various autism "biomedical" therapies by DAN! doctors or Dr. Hyman's panoply of woo to which he subjects his patients in that it is an extrapolation from data that are too preliminary to justify widespread use. That may well change one day, but today is not yet that day, and saying so, to me at least, is akin to pointing out that the "do it yourself" use of unproven cancer therapies like dichloroacetate is usually not a good idea.
We are, however, making progress, and we're making that progress not based on speculative extrapolation of preliminary science or accepting dubious science as true. I'll close with an example that is now routinely used in the treatment of ER(+) breast cancer. As I mentioned above, ER(+) breast cancer tends not to be as sensitive to chemotherapy as ER(-) (and in particular, triple negative) breast cancer, even though it has a better prognosis. Over the last decade, a 21-gene assay has been developed for women with ER(+)/HER2(-) cancer that has not yet spread to the axillary lymph nodes called the OncotypeDXÂ® assay. Based on the results of this assay, a recurrence score can be calculated. If it's high, the tumor is likely to be sensitive to chemotherapy, which will improve the woman's chances of survival. If it's low, the tumor is likely to be insensitive to standard chemotherapy, and the recommendation is for the woman not to undergo anything other than anti-estrogen therapy. In this way, thousands of women will be spared chemotherapy that will not help them. Current trials are investigating the utility of this and other genetic prognostic tests in node-positive tumor or, in the case of Oncotype, in determining whether patients with intermediate scores can be spared chemotherapy, and, if so, which ones.
The revolution in genomics has been likened to a flow of water. In the late 1990s, it was a trickle. Five years later, it was a firehose. Today, it's Niagara Falls, with terrabytes of data being produced every month. The cost of sequencing an entire genome has fallen from $100,000,000 ten years ago to under $30,000 per genome by late 2010, with the era of sub-$1,000 genome sequences in sight. There is definite promise in genomics to result in truly personalized medicine. The key will be to combine it with proteomics, metabolomics, and an understanding of environmental influences. Doing that will not be easy, and, despite the Niagara Falls of data currently deluging us, it will not be fast. Unlike the claims of personalized medicine that arise from CAM and IM, it will take science and clinical trials to tease out the true associations from the noise, to differentiate correlation from causation, to separate and quantify effects of environment from effects of genome, and to figure out the interactions between them all. Oddly enough, that's why I find last year's AACR promotional video to be a bit more realistic than this year's, annoying techno background music aside:
There are successes, challenges and even failures, but always hope. It's our time, but when it comes to actually delivering the hope, I'll stick to science-based medicine.
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Good discussion of science based medicine (SBM) that tracks some of the cause and effect research and findings now emerging. This kind of thinking is quite different from evidence-based medicine (EBM), thinking that only a set of statistical metrics from a randomized controlled trial tell us anything about the effect of a new treatment or concept. It is imperative that our entire system shift to SBM with EBM relegated to scrap heap. Unfortunately, that shift is happening very, very slowly due to an almost cult-like belief in EBM among most physicians. Someone should talk to the FDA about SBM and the pressing need for a shift in its regulatory approaches and standards away from EBM toward SBM. They talk about it a lot, but so far haven't moved much at all. I would take only one major exception to the opinions in this article. The pace of advance and understanding is happening faster than anyone can predict. So far, most estimates of how fast we would get to where we are now, with actual application of genomic medicine already emerging, were too pessimistic. The flood of new information is indeed seemingly overwhelming, but the ability to understand it and turn it into usable therapies is also turning vertical in response. The knowledge and ability to deliver personalized medicine is here. We know cancer is a morphing, genetic disease, and that beating it will absolutely require SBM applied in a personalized manner. The scientific base for transforming that knowledge into therapies is already operating and expanding, even if need of much improvement. The only remaining major lag and barrier to even faster progress is the FDA. They have barely started adjusting, and probably don't have the right people in house to make the transition. There needs to be more discussion, and action, on what to do about that. It may well be that it is going to take decades more to greatly improve our ability to treat genetic diseases, but it shouldnât. If it does, that will be a massive failure.
Personalized medicine is a terrible buzzword. I really doubt that if you asked a lay person what personalized medicine for cancer treatment is about that they would say genomics and proteomics. I think the phrase conjures up more of an idea that your doctor will also be playing amateur psychologist.
"Evidence-based medicine" comes in for a lot of slagging, but there is some usefulness to ensuring people get known effective treatments unless there is some damn good reason not to give them in a particular case. If one wants to retain the good bits from EBM, enhance it and call the result SBM, hey, fine.
Re OncotypeDX, Medicare currently pays for it only in certain states - those in the immediate vicinity of the producer of the test. Private insurers are "ahead" of Medicare in this regard - all the major private insurers pay for it. This almost certainly reflects the fact that these private insurers are subject to state laws mandating coverage for various aspects of breast cancer testing and treatment.
Both the Medicare and the private insurer situation in turn reflect politics. The regional Medicare contractor's decision to cover OncotypeDX was no doubt encouraged by California Congresspersons and/or Senators. The state mandates are directly attributable to the focus on breast cancer as a women's issue. (Note that publicity surrounding autism has resulted in a recent wave of state mandates for autism screening and treatment.)
Thus do medical advances, slowly and in piecemeal fashion, get their costs covered in our current system.
While we are not yet at the point where we have personalized medicine, the differences I've seen over the past 20 years are encouraging.
20 years ago, a screening mammogram found a small cluster of abnormal cells in my mother's breast. The two months that it took to determine that the biopsy was sufficient treatment where excruciatingly painful for my mother and my family. The process included endless waiting for results, the recommendation for a mastectomy from one surgeon, and even the indignity of my mother being forced to wait for 4 hours for an appointment with the oncologist who then added to the insult by having her change in a room without appropriate window coverings. A nightmare over a cluster of precancerous cells the size of a pinhead.
20 years later, my mom discovered a lump in the opposite breast and it's been an entirely different situation. Her team of doctors understands the urgency of getting results to her, and they go out of their way to make sure they keep her up to date. She's been treated with dignity and respect at every step of the process. The surgeon's priority was to do as little damage as possible while removing the 2cm tumor, and the breast conserving surgery had minimal impact on her appearance. Her schedule, income, and personal preferences have been considered at all stages of treatment. And of course, the biggest aspect of her personalized treatment is the use of Herceptin as an adjuvant therapy for her HER2+ tumor.
Granted, there is room for improvement in personalized medicine, but it's clear that at least in breast cancer treatment, we are getting closer everyday.
How often I have heard the woo-meister berate SBM advocates for their cold, impersonal approach to patients- "You're only a number to them!"- they tell the marks- whereas in the all-embracing light of woo, you are revealed to be a soul, a spirit ( indeed, a *kindred* spirit), a solitary flame that is encased in a highly individualistic temple- what is the body- blossoming forth like a flower. They respect you to the depths of your innermost being! As the Ayurvedists have pointed out, there are 3 doshas and many variants to be considered and Astrologists *know* that the 12 signs are merely a jumping off point to myriad other factors that determine who you actually *are*. You are told how unique and special you really are- a "wonder of creation"- how flattering! and in the words of my late father- "Flattery will get you *everywhere*!".
And it does. The anti-vax crew talks dismissively about "one-size fits all" vaccination policy, as Adams talks about the conveyor belt style of medical care, Mercola talks up his own spin, ad nauseum. But then, let's look into what they actually preach and prescribe ( even though many are not legally able to prescribe anything).
Prevalent memes about disease causation *chez woo* down-play genetics and highlight environmental and personally controlled factors: which gets us to nutrition, toxins, and exercise. If we look at _all_ illness; from colds to cancer- the truly unique aspects our esteemed host describes above ( re cancer) are overlooked for a ( dare I say it) "one-size fits all" approach.
Here's my take on the model: the precious temple gets polluted by toxins -which are everywhere and need be dealt with posthaste -and thus, the spirit gets all bogged down. Toxins can be removed by various means ( ahem...) then the bogged-down spirit needs get revitalised through super-nutrition to make up for its formerly sorry-state of lack: so pile on the nutritents via supplements, juicing, and organic vegan "gourmet foods". The body- connected to the spirit- gets enlivened through nutrition which is supplemented by exercise- "healing itself"- which in turn enriches the spirit. Easy.
Problem is that *all* illnesses- from this perspective- boil down to the same causes. *And* all get the same rx: clear out toxins, add nutrients and exercise - *et voila!*. Right now, one of our celebrated woo-meisters has innaugerated a lifestyle transformation project for students, parents, and staff at a Newark, NJ charter school that tackles the problems of obesity, blood glucose levels, high bp, learning disabilities, and asthma simultaneously via nutrition and exercise. Many problems, many individuals, *one cure*. Easy.
I agree that there's progress mixed with hype. I have had a genome scan done, and I am finding interesting things in my genes. Some is actionable, some is not. But as an academic sort of exercise it's been fun.
However, I'm finding that the personal genomics social media is pulling in 2 types of people: science/evidence based, and the "worried well" who are promoting the same crappy nutritional mythology, vaccine toxins, conspiracy theories, etc. I would say right now that the sciency folks outnumber teh toxin/ct crowd. But I don't know that it will stay that way.
Orac, has this study been retracted, debunked, censored, banned, villified, etc. just like Wakefields? If not, when?
Acute encephalopathy followed by permanent brain injury or death associated with further attenuated measles vaccines.
Pediatrics. 1998 Mar;101(3 Pt 1):383-7.
Acute encephalopathy followed by permanent brain injury or death associated with further attenuated measles vaccines: a review of claims submitted to the National Vaccine Injury Compensation Program.
OBJECTIVE: To determine if there is evidence for a causal relationship between acute encephalopathy followed by permanent brain injury or death associated with the administration of further attenuated measles vaccines (Attenuvax or Lirugen, Hoechst Marion Roussel, Kansas City, MO), mumps vaccine (Mumpsvax, Merck and Co, Inc, West Point, PA), or rubella vaccines (Meruvax or Meruvax II, Merck and Co, Inc, West Point, PA), combined measles and rubella vaccine (M-R-Vax or M-R-Vax II, Merck and Co, Inc, West Point, PA), or combined measles, mumps, and rubella vaccine (M-M-R or M-M-R II, Merck and Co, Inc, West Point, PA), the lead author reviewed claims submitted to the National Vaccine Injury Compensation Program.
METHODS: The medical records of children who met the inclusion criteria of receiving the first dose of these vaccines who developed such an encephalopathy with no determined cause within 15 days were identified and analyzed.
RESULTS: A total of 48 children, ages 10 to 49 months, met the inclusion criteria after receiving measles vaccine, alone or in combination. Eight children died, and the remainder had mental regression and retardation, chronic seizures, motor and sensory deficits, and movement disorders. The onset of neurologic signs or symptoms occurred with a nonrandom, statistically significant distribution of cases on days 8 and 9. No cases were identified after the administration of monovalent mumps or rubella vaccine.
CONCLUSIONS: This clustering suggests that a causal relationship between measles vaccine and encephalopathy exists as a complication of measles immunization.
Wow. You sure have a closed-off brain to anything other than your own personal view of medicine, don't you?!? Wow..... And I'm starting to think that you're pretty good at holding grudges, too, as that's what it sounds like in many of your postings on this website.
Polly, quoting the results:
Forty eight out how many total vaccinations? I can't see the entire article, so how does it compare to the over 150 deaths from measles between 1987 and 1992 in the USA?
Really, what other evidence do you have that the MMR is more dangerous than measles? Because combined with other papers, your cite seems to show that vaccination is safer than the disease.
Walker @1: It would help if those with "SMB" attitudes published more papers instead of just blogging to claim some problems have been solved. The typical Kimball Atwood blog on SBM references no studies done using SBM, just other blogged pieces.
On direct testing, besides the accuracy, the problem is with the interpretation. I've known I have e3/e3 genotype for the ApoE gene since 1984. That's just a fact, and I have almost no problem with "just the facts". What to do about it is another matter since our knowledge is imperfect and changing with time. Example: At that time, I knew I could have had a better genotype wrt heat disease (we were studying lipids), but a few years later others showed that it also means my risk of Alzheimer's is lower, and not just by a little - and that does comfort me. The rare variant at the dopamine receptor is another matter - the food tastes great (and other benefits), but is it part of my being an asshole?
Encephalopathy or encephalitis following MMR vaccination is known to happen in some small fraction of cases, yes. It's even on the Vaccine Injury Table. What's your point?
My point is "mental regression and retardation, chronic seizures, motor and sensory deficits, and movement disorders" sounds a heck of a lot like what we now call autism to me!
And BJD, yes this is more personal than you could ever understand. Holding grudges? How is this. "I hold the entire cruel, incompetant, condesending, arrogant, non-caring pediatric profession responsible for the pain and suffering they have inflicted on an entire generation of children." They know the truth. They just don't care!
On topic, this was a great little summary of the progress and hype in personalized treatment of cancer.
The articles by Daniel McArthur, linked above, about deceitfully advertised (or just plain deceitful) direct-to-consumer genetic tests support old suspicions of mine. Yes, you could do as he suggests and require them to disclose how their work is conducted and what evidence supports their claims, but a lot of people won't be able to judge that information anyway and I don't see that stopping direct-to-consumer scammers.
Some people marks want the genetic test that claims to tell you what sport your kid should play and what their job should be. Disclosing their dubious methods hasn't burried Astrology. What hope is there it would work for direct-to-consumer genetic tests? I'd think false advertising is best handled as false advertising.
Hmm. Looks like I went off the rails too.
@Polly: Autism patients have been tested for evidence of encephalopathy and encephalitis and there is no proof of your claim in the data. Perhaps you have a citation to something useful rather than implication of a study that found a slight positive correlation between MMR and encephalopathy?
And it happens more often when kids actually get measles (about one in a thousand to three thousand cases of measles). Plus congenital rubella syndrome is a known cause of autism. You still have to weigh the risks: less than one in a million chance with MMR or one in a thousand chance with measles.
Tell how good you are at fractions, which is the bigger number, a or b?
I've yet to find a pediatrician that didn't care deeply and personally for their patients - and were extremely upfront and understanding of any questions that we may have had.
I find your insinuations both insulting and without basis.
Polly, I once spent months thinking I was covered in biting insects and my doctors were all incompetent not to figure it out. Nope. It now appears it was stress and lack of sleep from the extreme violence down the hall. I was calling police about twice a night, (often at 1:00 and 4:00,) four nights a week, over a neighbour's extremely violent husband. Apparently five months of fear without sleep will make me go crazy. It's also possible that, unbeknownst to me, someone may have been cooking drugs in the building, too. I can''t rule it out - I'm a student renting appartments.
My point is, apparent relationships aren't always real. Callous, ignorant enemies that deny your observations aren't always that either. My doctors were certainly innocent of my accusations.
Got any actual, you know, EVIDENCE that such is the truth?
@ Polly: which sites have you been visiting that provided you with that "edited" article from Pediatrics Journal...or did you do your own paste up job? The real abstract is available at:
The article which Polly (deliberately?) misquoted omitted the dates of the study of the 48 children in the "Methods" section. The dates were 1970 - 1993 inclusive...a total of 23 years.
Polly also misquoted the "Conclusions" section by (deliberately?) omitting two key words: Per the Pubmed abstract, "Conclusions" are:
"The clustering suggests that a causal relationship between measles vaccine and encephalopathy MAY exist as a RARE complication of measles immunization".
Polly asks, "Orac, has this study been retracted, debunked, censored, banned, villified, etc. just like Wakefield's? If not, when"
Polly both the actual study and the deliberately edited study that you provided have been totally disproved in a study published in Pediatrics 2002 Nov (5): 957-63...also available in abstract form at:
Let me provide you with a few details. Hospital registry discharges of 535,544 children ages 1-7 who had received MMR vaccine within the three months prior to hospital admission, were reviewed by Finnish researchers. The period of study is November 1982 - June 1986.
Conclusions: "We did not find any association between MMR Vaccine, encephalitis, aseptic meningitis or autism."
If you truly are an interested parent, you should be upset that you were provided with a deliberately edited abstract. And, no need to thank me for providing you with the two correct abstracts.
Are those... crickets?
@lilady: Were it in my power to bestow a comment response award youâd get top honors!
Wow, lilady. Good work. It also included the era when more than three times that many people died from measles between 1987 and 1992. Which is in the paper I referenced.
Jacob V, I also vote for that award!
My point is "mental regression and retardation, chronic seizures, motor and sensory deficits, and movement disorders" sounds a heck of a lot like what we now call autism to me!
I begin to suspect that Polly is not a clinician, or indeed acquainted with autism as anything more than a word.
News flash: Former South Korean president admitted to hospital for surgery to remove an acupuncture needle from his lung:
"Doctors are puzzled how the needle ended up in his lung, and acupuncturists say that none of their procedures involved penetrating the lung."
You can't make this stuff up!
@ Yojimbo: Crickets?
@ Jacob V & Chris: In my dotage and with a vodka/tonic on board I can still smell bullshit reports of vaccines/vaccine injuries.
Adverse effects from the CDC
Ms. Young, that is exactly where I got the one in a million for severe reactions to the MMR. If you read it closely you will see the problems that Polly specifically writing about were even more rare. Thanks.
@ Sheila Young: Adverse effects have been reported following MMR Vaccine, but the number (48) of severe adverse events reported by Polly above and cited in a (deliberately?) misquoted abstract raised red flags for me.
As you know the misquoted abstract "conveniently" left out the time period when these 48 cases were reported to the NVIC program...the 48 cases were reported during a 23 year time period. Even if we were to assume that the severe adverse events/deaths were caused by single antigen or combined MMR vaccines, 48 cases over 23 years works out to 2 cases per year. Furthermore, the 48 cases were reviewed and "qualified" due to the fact that each of the children had a severe neurological event (seizures, encephalitis, etc.) within 15 days of receiving measles vaccine. We simply don't know if the full reporting of the study that appeared in Pediatrics (journal) found any children who had a pre-existing neurological condition or a previously undiagnosed genetic disorder...or an infectious disease that caused fever induced seizures or encephalitis.
The (edited) "Conclusions" of the study that Polly provided also left out two key words...that completely changed what the study researchers' actual "Conclusions" were.
No Pubmed citation was provided and I really had to work to find the original abstract.
That's how these anti-vax web sites work and that's how individuals who are fixated on the vaccine injury/vaccine-autism bogus science post. They cherry pick, don't provide citations and deliberately "edit" abstracts.
What evidence do you have that if 300 million americans naturally acquired measles that there would be 300,000 deaths and 300,000 cases of encephalopathy? I would love to examine that rocket science data.
What are the odds of evey American acquiring measles at the same time? More importantly, there were numerous cases of both before the vaccine was developed, just check the CDC's records.
How about the actual observed rate since the 1950s has been greater than 0.1% for every data set with a high enough n to give a meaningful stat? And those data sets aren't limited to the US, they cover all well-developed countries that collected that data.
Sorry I was obscure - I was just noting a significant lack of a Polly response, and the near certainty that there would not be one after your excellent reply.
"Mental regression and retardation, chronic seizures, motor and sensory deficits, and movement disorders".
This is autism in today's children. I'm not talking about adults who surf the internet and claim to be autistic. If the 1.5 to 2 million children who are currently labeled as autistic were properly diagnosed and treated for encepholapathy (inflammation), the number injured by vaccines would be closer to 1:100.
There are over 100 published papers which identify the underlying medical condition of autism as neuroinflammation (encephalitis). Go to pubmed and type in the terms autism and inflammation for yourselves.
Ed, did you take the time to go through those 100 articles? I went through the first 20. I don't think you know how to read these articles. Why don't you go find a few and post the DOI or the PMID?
Perhaps you think the number of returned searches is all that is required? In the first 10 returned articles, only one comes close and it talks about lead-poisoning in autistic non-communicative children and happened from in-home lead sources that the children ingested.
Next time do your homework.
How about the actual observed data instead of the rate and your inference?
If the 1.5 to 2 million children who are currently labeled as autistic were properly diagnosed and treated for encepholapathy (inflammation), the number injured by vaccines would be closer to 1:100.
Indeed, if we abandon the usual definition of "autism" in favour of Ed's prefered diagnosis and throw out all the cases that don't fit, no doubt we could find a higher proportion of post-vaccination side effects among the group that were left.
Or we could impose some other definition designed so that the people who met it contain a high proportion of alien abductees. But that would be silly.
Or they give a citation which they confidently claim found X, but when you look it up and read it, it says the exact opposite of X, or something entirely unconnected. Presumably the author either is an idiot, or is dishonestly hoping no one follows up the citation. When I first came across this phenomenon I was quite discombobulated. I think most people don't immediately consider the possibility that what they are reading is a blatant lie.
@ Jay K: And I went through the next 20 articles on Pubmed as suggested by "Ed" and found nothing to suggest autism as neuro-inflammation. I did however, find one article that piqued my interest:
The Gut Brain Axis in Childhood Developmental Disorders (Andrew J. Wakefield, 2002)
Who's going to review the next 20 articles for Ed?
Here's the raw data from one data set:
US reported cases with known patient age (1983-2000)
Total cases: 67,032
Need me to do the math?