Normal Limits

"Chance is the very guide of life"

"In practical medicine the facts are far too few for them to enter into the calculus of probabilities... in applied medicine we are always concerned with the individual" -- S. D. Poisson

October 31, 2005

Flickr's alterednate - Absorbed


This is on Belle-Ile, at a famous spot called "Port Coton." The sky is certianly real, however sometimes when I look through my shots I wonder myself.

October 30, 2005

New journal: Public Library of Science Clinical Trials

Public Library of Science has a new journal for clinical trials:
Each published paper in PLoS Clinical Trials will be linked to its corresponding entry in the relevant registry. PLoS is collaborating with Global Trial Bank (GTB), a non�profit subsidiary of the American Medical Informatics Association, to ensure that trial results are captured and stored in a computer�readable, standardized format.

According to the editors,
Publication decisions will not be affected by the direction of results, size or perceived importance of the trial.

This should help mitigate publication bias.
What does this mean for researchers? Manuscripts will have to follow the CONSORT structure:
We intend to go beyond CONSORT (a tool developed to improve the quality of reporting of randomized trials; http://www.consort-statement.org/), asking authors to not only submit a CONSORT checklist and flow diagram, but also to organize their papers according to the CONSORT structure. Readers will be able to quickly identify where in the paper they need to look to find out about a particular aspect of the design.

Interestingly, peer review will also be a bit atypical:
Rather than making recommendations about acceptance or rejection, peer reviewers of papers submitted to PLoS Clinical Trials will be asked to focus on improving the quality and transparency of trial reporting. Each trial report will be accompanied by an editorial summary of its strengths and weaknesses, including what it adds to current scientific knowledge. Readers will have the opportunity to post comments.

I really like this idea. Perhaps PoLS Clinical Trials will one day set the standard for publishable RCTs?
(via Microarray and Bioinformatics Blog)

PubMed Assistant (PuMA), the PubMed front-end of your dreams!

What I like the most about this program:

  1. Small and fast to load
  2. Ability to save complex searches and their results
  3. Breaks down complex query strings hierarchically and visually
  4. Displays Outlook-style the list of results, the abstracts, and the MeSH terms

My only gripe, in my limited experience with it, is the sometimes-awkward arrangement of the UI. Also a few keyboard shortcuts would be nice. Oh yes and in this Web 2.0 era, perhaps a central site of storage of my search results. (hint hint, Google)

October 29, 2005

Science - Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer (Tomlins et al 2005)

In this week's journal Science, by Dr. Tomlins et al:
We used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression.

We identified recurrent gene fusions of the 5' untranslated region of TMPRSS2 to ERG or ETV1 in prostate cancer tissues with outlier expression.

By using fluorescence in situ hybridization, we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1. Cell line experiments suggest that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer.

This is a beautiful piece of computational biology with significant clinical implications. More review of the methods and of the ETS transcription factor family (which I encountered in grad school) to follow...

October 27, 2005

Arch Int Med - Efficacy of Bupropion and Nortriptyline for Smoking Cessation Among People at Risk for or With COPD (Wagena et al 2005)

Bupropion SR is known to be effective in helping smokers quit. Smoking cessation is particular important for patients suffering from COPD, since this is the only things that is known to slow the progression of the disease. This RCT studied the effectiveness of bupropion SR for smoking cessation in patiens with COPD or at risk for it. This is a well-crafted study that enrolled 255 patients, with an impressive less than 5% lost to follow-up at 26 weeks.

Some interesting findings:
- Amongst patients with stages I, II, and III COPD, 27% (12 of 44) of those on bupripion SR vs 8% (4 of 48) of those on placebo remained abstinent from week 4 to week 26 (chi-square p-value 0.02). NNT = 5.3 patients with COPD. (Note that COPD stratification was initially done using the European Respiratory Society definition, but presented with according to the GOLD guideline)
- Amongst depressed patients, 35% (8 of 23) of those on bupropion SR vs 11% (2 of 19) of those on placebo remained abstinent from week 4 to week 26 (Fisher's exact test p-value 0.08... this can be seen as statistically significant because of the exactness and discreteness of Fisher's test). NNT = 4.1 patients at risk for COPD or with COPD who have depression. (Depression was defined as Beck Depression Inventory score <= 15, which is associated with having clinical depression)

Arch Intern Med -- Effect of a Clinical Trial Alert System on Physician Participation in Trial Recruitment (Embi et al 2005)

Patient referral and recruitment are important rate-limiting steps of clinical trials. It is not surprising that electronic health records (EHRs) can automate some of the mechanical steps involved and remind busy practicing physicians that the patient they are seeing may qualify for a particular trial.

In this study, a clinical trial alert (CTA) system was built on top of an existing EHR, and the rates of patient referral and recruitment before and after implementation was compared. They found:
- 10x increase in the number of referrals made by physicians who referred This effect was seen not only at sites that previously did not refer, but also at sites that previously generated the bulk of the referrals.
- 2x the patient enrollment rate With an EHR in place, researchers can determine the eligibility of referred patients directly on their computers. This simplifies the process and allows them to use lowered thresholds for screening. While this raises false-positive rate, it also tends to increase recruitment rate as well (Bell-Syer et al 2000).

accompanyin editorial

Molecular Medicine - Molecular Identification of Simian Virus 40 Infection in Healthy Italian Subjects by Birth Cohort (Paracchini et al 2005)

It is not disputed that polio vaccines manufactured from 1954 to 1963 were contaminated with the polyomavirus SV40. However there has been accusations that the vaccine made from monkey kidney cells continue to be in part contaminated, and that the virus is responsible for certain types of cancer (eg malignant mesothelioma) based on animal studies. Epidemiological studies of humans have been inconclusive as a whole. (for a more-than-likley biased review see The Virus and the Vaccine).

Even if current batches of vaccines continue to be potential sources of SV40 contamination, and even if SV40 virus indeed causes cancer in a subset of people infected, an important question had thus far been unanswered--is the vaccine the only potential source of SV40?

This study studies the prevalence of SV40 in donors in Italy who had no known cancer. Using the peripheral blood lymphocytes of 134 solid organ donors (all anonymous) they screened for SV40 using PCR and then confirmed it with DNA sequencing. They found 15 of these (11%) to contain de facto SV40 genome sequences. If indeed the contaminated polio vaccine was capable of infecting its receipients, then we would expect those donors who were born between that period of time would be more likely to be infected with SV40. This was not found to be the case.

One major drawback is the small sample size. But I see this as the beginning of a very important new line of research. At the very least it should settle the SV40-vaccine debate, if not rendering it moot.

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BMJ - Mortality associated with passive smoking in Hong Kong (McGhee et al 2005)

There's plenty of evidence for the association between cigarette smoke on one hand and lung cancer, coronary heart disease, and stroke on the other. This study, based on retrospective study of Hong Kongese patients, confirmed again the association of passive smoking with stroke, COPD, and lung cancer. The does-response curve is that much more dramatic in this particular study perhaps due to the crowded living conditions not atypical for urban cities in Asia.

We note that China, with 20% of the world's population, smokes 30% of the world's cigarettes! (sorry can't locate original source)

This is a follow-up to their 2001 case-control study:
In the general population of Hong Kong in 1998 tobacco caused about 33% of all male deaths at ages 35�69 plus 5% of all female deaths, and hence 25% of all deaths at these ages.

In the male smokers tobacco caused about half of all deaths at ages 35 to 69

Thomas Friedman - Living Hand to Mouth

Thomas Friedman on the increasing awareness in China of the environment and pollution.

Recent article in New England Journal of Medicine on major causes of death in China. Both vascular diseases and cancer have become leading causes of death.

A study by the Chinese Academy on Environmental Planning, found that in the year 2003, 300,000 people died from outdoor pollution, while 111,000 people died from indoor pollution each year.

Combination Therapy: The Future of Medical Management for PAH

Will review...

NEJM -- Trajectories of Growth among Children Who Have Coronary Events as Adults

Growth trajectories of 8760 people born in Helsinki from 1934 through 1944 are associated with outcome as adults.

Accompanying editorial has a nice review to other studies of similar spirit.

But how generalizable is this particular result? The Finland population is rather genetically homogeneous due to small founder population.

October 24, 2005

NYT - Scare Yourself Silly, but the Real Terrors Are at Your Feet

From Dr. Zuger's essay
"I'm really scared about Lyme disease," she said. "I really need to get treated."
"If you want to be scared, how about that untreated AIDS of yours?"

The Observer - Sue the Lancet!?

Nick Cohen suggests:
The editor of the Lancet is a more tempting target. Wakefield's original research was based on a sample of just 12 children, which was too small to be meaningful, as the Lancet ought to have known. Medical journals are not the richest of institutions, however, and it would probably take only a couple of thousand single jab bills to close the Lancet down.
via blacktriangle

Wakefield's "research" is largely responsible for an entire cohort of British children not receiving the MMR vaccine.

I prefer holding the editors responsible.

October 23, 2005

In the Pipeline - The Tar Pit Beckons.

"The short version: (1) Pfizer's ever-increasing size means that most everything scales up except what they need the most: research productivity. (2) Billion-dollar drugs must roll off their conveyer belt, one after the other, and that's something that no one has ever figured out how to do. (3) Lipitor, mighty monster that it is, is the main thing keeping the music playing. But it will go away, and there is nothing to replace it. Perhaps nothing ever could. (4) While a massive sales force is quite a thing to have, they do need things to sell, don't they?"

Roche AmpliChip Video

Through Personal Genome blog:
"Roche has posted a video describing their Amplichip CYP450 test, a DNA
microarray that can identify 2D6 and 2C19 gene variants...."

Annals of IM - Prevention of Exacerbations of COPD with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator

This multi-center, double-blinded RCT of 26 VAs compared the effects of inhaled tiotropium QD versus placebo in patients with COPD, in terms of frequency of exacerbations and hospitalizations.

Patients are:
  • > 40yo
  • Cigarette smoking hx >= 10 pack-years
  • Clinical Dx of COPD
  • FEV1 <>
  • Free of significant co-morbidities or other pulmonary diseases such as asthma.


JAMA - Effect of Muraglitazar on Death and Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus

In the Pipeline's Dr. Derek Lowe has a interesting post on this. He noted that in the FDA briefing document submitted by GlaxoSmithKline, a noticable association of CV adverse effects could be seen.

His suspicion was confirmed when JAMA rushed out the current article which points out the true magnitude of the CV adverse effect. The accompanying editorial explained that CV risk estimate was diluted by the inclusion of low-dose (hense low-risk) groups. It also points out some other potential sources of bias:

- Selecting a study population unlikely to have adverse outcomes but nonrepresentative of potential future users (eg, exclusion of elderly patients, even though more than one third of type 2 diabetes occurs in this group)

- Conducting underpowered studies increasing the failure rate to detect meaningful safety differences (ie, maximizing rather than minimizing type II errors)

- In contrast to efficacy determinations, reporting individual rather than composite safety outcomes to decrease the likelihood of establishing statistical significance (eg, separate cardiovascular events from CHF)

- Limiting preapproval peer-review publication of results so as to minimize scrutiny and debate of both methods and results (eg, of all submitted data only 1 study of 340 patients has been published8)

- Evoking biological implausibility of safety concerns by the use of surrogate measures (eg, treatment reduces C-reactive protein [CRP]) implying safety, despite no proof that CRP reduction is clinically correlated with improved safety)

- Recording outcomes only in patients who are fully compliant with prescribed treatment because this self-selected group will likely have fewer adverse events (eg, unknown impact of the nonanalysis of the 15% discontinued cases)

- Ignoring the totality of the evidence by excluding consideration of confirmatory safety signals seen in studies of similar molecules (eg, CHF and bladder cancer outcomes with pioglitazone)

- Diverting attention to unproven but potential benefits by concentrating on reductions in surrogate laboratory values (eg, hemoglobin A1C) rather than in meaningful patient health outcomes.

Very intersting....

The Cutter Incident

Dr. Paul A. Offit from U Penn writes about the Cutter Incident. Soon after the Salk vaccine was shown to effectively immunize children against the polio virus in the 50s, pharmaceutical companies around the country started to produce the vaccine. Sadly, the vaccines produced by Cutter Laboratories contained live viruses, making thousands of vaccinated children ill, and 200 children paralyzed. As Dr. Offit explains, many of the problems with today's vaccines, such as frequent shortages and lack of new development, can be traced to the legal and political aftermath of this unfortunate incident.

Note that Dr.Offit is a patent-holder on the rotavirus vaccine. It was withdrawn after post-market surveillance showed statistically significantly increased occurrence of intussuception.

He also has an article in the May/June issue of Health Affiars on vaccines.

Review pending.

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NEJM - KCLIP: Incidence and Outcomes of Acute Lung Injury (ALI)

A prospective population-based study of King County in Seattle, the 13th largest county in the US with > 1.8 million residents. During the period from 4/1999 to 7/2000, a total of 1,113 King County residents >15yo who underwent mechanical ventilation met the American-European Consensus Conference on ARDS definition of ALI.

Only arterial blood gas measurements obtained while the patient was intubated
were assessed. The arterial blood gas values with the worst PaO2:FiO2 ratio,
regardless of the positive end-expiratory pressure, were used to assess
oxygenation for each 24-hour period.

Because the PaO2: FiO2 ratio becomes an increasingly unreliable assessment of shunt when the FiO2 is below 0.40, the ratio was used to assess oxygenation only when the FiO2 was 0.40 or more.

Risk factors present during the four days before the onset of ALI: severe sepsis (sepsis with a suspected pulmonary source, sepsis with a suspected nonpulmonary source or an unidentified source), severe trauma (with an Injury Severity Score > 15), witnessed aspiration, transfusion of > 15 units of blood within a 24-hour period, drug overdose, pancreatitis, near-drowning, and inhalation injury.

In-hospital mortality, ICU LOS, etc.

Pearson chi-square, Mann-Whitney, t-test.

1. The incidence of ALI is 2.5~5.0x as high as previously believed, with age-adjusted incidence of 86 /100,000 person-years. Mortality is about 39%.
2. The incidence of ARDS is 2~40x as high as previously believed, with age-adjusted incidence of 64 /100,000 person-years. Mortality is about 41%.
3. The most common risk factor for developing ALI is severe sepsis with pneumonia (46%), f/b severe sepsis with suspected nonpulmonary source (33%).

Accompanying editorial raises 2 points worth considering:
  • Why is the incidence in this study seemingly higher than in others? Is this possibly a reflection of US Hospitals overusing ICU beds?
  • While the main outcome measured was in-hospital mortality, post D/C morbidity is high and the logistics of care need to be carefully arranged.

Tagging with BlogThis! - Freshblog

Tagging with BlogThis! - Freshblog

Filed in:

October 22, 2005

HCPro: Hospitals Vary in Spending, Costs for Overseas-Based Radiology Services: Financial News - Yahoo! Finance

Press release from HCPro,

Twenty-five percent of the 133 hospitals HCPro surveyed use overseas-based radiologists, while 14% said they are strongly considering outsourcing MRI and CT preliminary reads by 2007.

From April 2005 in Washington Post

A 2003 NYT article "Who's Reading Your X-Ray?".

How Not To Give a Presentation

From Clinical Cases and Images blog: How Not To Give a Presentation: " Some advice how NOT to do a good job when presenting:- How not to give a presentation by the former BMJ editor Richard Smith. This article lists truly invaluable pearls of wisdom like:'Bad slides are the traditional standby of a bad presentation. There must be far too many. They must contain too much information and be too small for even those in the front row to read. Flash them up as fast as you can, ensuring that they are in the wrong order...' BMJ 2000;321:1570-1571 (23 Dec)- Maxims for Malfeasant Speakers - by Norman Ramsey at the Harvard Electrical Engineering and Computer Science And finally some real advice how TO give a presentation:- Tips on... Grand round presentations - BMJ Career Focus 2005"

CNN.com - FDA approves first brain stem cell transplant - Oct 21, 2005

Stem Cells Inc. from Palo Alto is proposing to transplant neural crest cells into children with Batten disease.

Science - [LETTERS] An Open Letter to Cancer Researchers

Stephen J. Elledge, Gregory J. Hannon

As cancer researchers, we have a special responsibility with respect to guiding resource allocation to fight cancer. We need to be able to look cancer patients and their families in the eye and say, "We are spending your money in the best way we know to find a cure for you." We must apply this standard in judging any large-scale proposal for dedicated research funding allocations. As currently configured, the [Human Cancer Genome Prokect (HCGP)] needs to be reconsidered and reprioritized to produce a program that gives us the best chance for fighting this disease. Therefore, because the most productive direction of research is still a debatable question, we propose that (i) sequencing be delayed until advances in sequencing technology are achieved; (ii) objective criteria be established to allow a go/no go decision for continued DNA sequencing based on pilot studies; and (iii) large-scale genetic screening to identify targets whose inhibition kills cancer cells should be incorporated into the HCGP.

$1.5 billion over 10 years!

Science - [REPORTS] Interlinked Fast and Slow Positive Feedback Loops Drive Reliable Cell Decisions

"Many cell signaling networks consist of dual feedback loops, enabling them to combine rapid response with reliable performance.Authors: Onn Brandman, James E. Ferrell Jr., Rong Li, Tobias Meyer"

Positive feedback is a ubiquitous signal transduction motif that allows systems to convert graded inputs into decisive, all-or-none outputs. Here we investigate why the positive feedback switches that regulate polarization of budding yeast, calcium signaling, Xenopus oocyte maturation, and various other processes use multiple interlinked loops rather than single positive feedback loops. Mathematical simulations revealed that linking fast and slow positive feedback loops creates a "dual-time" switch that is both rapidly inducible and resistant to noise in the upstream signaling system.

Of interest are platelet activation and coagulation cascade activation (E Beltrami and J Jesty 1995).

Science - [PERSPECTIVES] CHEMISTRY: The Renaissance of Natural Products as Drug Candidates

"In recent years, the use of natural products for drug discovery has declined in favor of combinatorial methods and the rapid generation of large libraries of potential lead compounds. In their Perspective, Paterson and Anderson suggest that it may be time to revisit the prevailing dogma and consider ways in which natural products could continue to inspire the development of new drugs. Natural products offer high potency and selectivity as a result of long evolutionary selection. Taking bioactive natural substances as a starting point, researchers can then use the methods of organic synthesis to design targeted modifications of specific structures to create new therapeutic agents.Authors: Ian Paterson, Edward A. Anderson"

Instapundit talks about portable defibrillators an...

Instapundit talks about portable defibrillators an...: "Instapundit talks about portable defibrillators and a recent Popular Mechanics story: There's an article in the latest Popular Mechanics -- not on their website yet -- saying that the home defibrillators really do save lives. As they get cheaper and more ubiquitous, it's likely to make a real difference. A lot more people die from sudden cardiac death, where a defibrillator will save them but nothing else much will, than is generally realized. Likewise, inexpensive blood pressure monitors mean that -- since you don't have to go to a doctor -- more people will track their blood pressure. Just another way technology is empowering ordinary people.I wrote about this awhile back, looking at the data showing a minimal survival benefit. For some, that may be worth the $1,295: To put that in perspective, in a low-incidence practice (which would still have a higher incidence of sudden death than an average home), over 1900 AEDs (automatic defibrillators) would have to be purchased to treat 16 cardiac arrests over a 7 year period.Despite any form of advertising, the prognosis of sudden cardiac death is quite poor, whether a defibrillator is available publicly or not. A retrospective study suggested that targeted public placement of AEDs increased overall survival rate from a cardiac arrest from 5.0 to 6.3 percent.Certainly some may"

A Lifetime in Recovery From the Cultural Revolution

A Lifetime in Recovery From the Cultural Revolution: "Xu Tian, a scientist being mentioned by his peers as a potential Nobel laureate, is among those Chinese whose transition to adulthood was hijacked by the Cultural Revolution."

Cornell President Condemns Teaching Intelligent Design as Science

Cornell President Condemns Teaching Intelligent Design as Science: "Interim president Hunter R. Rawlings III denounced the theory as 'a religious belief masquerading as a secular idea.'"

Rain over Manhattan skyline

Rain over Manhattan skyline: "mihay has added a photo to the pool: "

When Even Health Insurance Is No Safeguard

When Even Health Insurance Is No Safeguard: "Many families, even ones with insurance, do not realize how vulnerable they are to high medical costs until the bills arrive."

Japanese giant hornet video

Bootstrap analysis of multivariate failure time data.

Bootstrap analysis of multivariate failure time data.: " Bootstrap analysis of multivariate failure time data. Stat Med. 2005 Oct 19;24(22):3387-3400 Authors: Monaco J, Cai J, Grizzle J Multivariate failure time data often arise in research. Cox proportional hazards modelling is a widely used method of analysing failure time data for independent observations. However, when failure times are correlated the Cox proportional hazards model does not yield valid estimates of standard errors or significance tests. Many methods for the analysis of multivariate failure time data have been proposed. These methods commonly test hypotheses about the regression parameters, a practice which averages the treatment effect across time. The purpose of this paper is to examine the bootstrap method for obtaining standard errors in the multivariate failure time case, particularly when the focus is the survival probability or the treatment effect at a single time point such as in a surgical trial. Our motivating example comes from the Asymptomatic Carotid and Atherosclerosis Study (ACAS) in which the outcome of stroke or perioperative complications could be observed for either or both carotid arteries within each patient. Extensive simulation studies were conducted to examine the bootstrap procedure for analysing correlated failure time data under a variety of conditions incl"