A new an improved RCT - the Registered Report

The Registered Report concept is just an extension of clinicaltrials.gov which has not been functioning as well as intended. It would be great if this idea works as intended. If the registered report catches on it could help address issues of publication bias and shed some light on the replication crisis.

Freakonomics - Three Episode Podcast on Evidence-Based Medicine

I always enjoy the Freakonomics podcast. Their most recently relevant podcast is a three-parter on evidenced-based medicine. Perhaps not super informative for those familiar with the topic but it is entertaining as always.
Part I
Part II
Part III

How is your favourite research area doing?

Just out of curiosity I wanted to check out some of the publication trends on some of my favourite research topics. I used an online tool that outputs data the number of query publications for each year (available here). Below I plotted the results of a few. The queries with multiple words were put in quotations. Importantly the results for cancer in the plot were divided by 100 as to fit on the scale of the graph. So not only is cancer a much larger topic, with about 14 000 / 100 000 papers on pubmed, but it is also growing at over 100 / 100 000 papers every year. This is much faster than the other topics presented. Data up to to and including 2013 is included because the tool itself suggests that more recent data may not be very accurate.

I was fairly surprised to see the growth in papers on cancer stem cells especially when compared to oncolytic viruses. There are obviously lots of problems with evaluating a research area with this data. First is that the growth of a smaller topic may not be apparent when using data that is / 100 000 papers. Second is the issue of the query. It may not encompass the field well and a more popular term may be gradually replacing an older query. Third is that while there may be fewer papers, the papers that are published may be of higher impact factor. It is possible for example that oncolytic viruses are moving more into the clinic and that kind of research takes longer and the rate of publication may be reduced but the importance of the research may be greater than ever. A tool to evaluate the trends in impact factor of a query would be very interesting also.

CRISPR/Cas9

Never have I missed being in a lab as much as I have since I started hearing about CRISPR/Cas9 a couple years ago. This is a genome editing technology that was developed by adapting an antiviral mechanism found in bacteria. If anyone has some first hand experience I would love to hear about it.
Here is a good introduction to CRISPR/Cas9, where it came from, and how it works.

I was also interested in what kind of commercial products are available to make this even easier, and here is a video of the CRISPR/Cas9 offerings from ThermoFisher (long 41:49). I don't think I've really grasped the implications of this technology however it seems it is facilitating the beginning of the genetic engineering of our species.

Response to the current Zika virus epidemic

Scientific American has an article that briefly summarizes the link between Zika virus infection during pregnancy and fetal microcephaly. While the circumstantial evidence is strong for a causal link, the article discusses the fact that conclusive evidence will likely only come from retrospective analysis of the current epidemic. Wired magazine has a more speculative article that has some additional interesting facts about the outbreak and the response to it."Most of Brazil's microcephaly cases are in the northeast, and it's unclear why Zika would cause more birth defects there than in other places." Multiple Zika strains or perhaps lagging microcephaly diagnosis may account for this observation. Unfortunately, these types of issues complicate efficient analysis of the current situation. Recent responses to the epidemic reflect serious concern. El Salvador has recommended that pregnancy should entirely be avoided until 2018, and the WHO has declared Zika a public health emergency of international concern allowing it to make decisions that are international law. Do these responses and the responses to the 2014 Ebola outbreak inspire any confidence in our ability to contain these and future frightening viral epidemics? The fact that the vaccine development is already underway, without many confirmed numbers and a lack of conclusive causal evidence, is amazing to me.

Physician's choice of intervention - DNR

This doctor has a tattoo that reads, "No CPR" as a living will.

Unfortunately many of us will, one day, have to make choices about aggressive interventions aimed at prolonging our lives. The default is, of course, do everything possible since life is precious and our family and friends want to keep us around. It has been known for quite sometime however that doctors themselves are less likely to opt for aggressive interventions near the end of their natural lifespan. I first heard of this on an old radiolab podcast I listened to recently, The Bitter End.


Somewhat related is a freakonomics podcast I also recently listened to about the costs associated with end-of-life care and whether we should be given the option to take the money instead of the intervention.
I don't know what I find more disturbing: that some doctors give interventions to their patients that they would not have done to themselves, that some doctors are so traumatized by what happens frequently during end-of-life interventions, or that some of those with the most experience think that modern medicine has the wrong emphasis for end-of-life care. Maybe I'll ask for the money.

BIKES!

If I didn't break my finger mountain biking a couple of weeks ago, I'd like to be on my bike right now. So I've been watching lots of videos about bikes. Most are of the !Xtreme MTB! variety, however there are also some great Bayblab worthy videos that I would like to share.
Bikes are a pretty cool intersection of physics and muscle memory. This first video is about the physics of how bikes are so stable.


This second video is about the backwards bicycle and some insights into neuroplasticity
And then, of course, bicycles and robots.

Dr. Siri is hiding on your wrist

The Apple Watch harbours undisclosed hardware capable of measuring blood oxygen content as revealed by iFixit's teardown. The hardware is not activated yet, but I don't understand how securely it has been made inaccessible by third party software. There is speculation that Apple is waiting upon FDA approval to enable the device for medical indications.
The currently inactive hardware is a pulse oximeter which, as previously mentioned, enables the noninvasive measurement of blood oxygen content. You may recognize a pulse oximeter as the red light that is clamped onto a patients finger in a hospital.
If the FDA approves the device for any medical application the implications would be interesting. The amount of health related data that could be collected would be enormous, and would likely reveal some interesting and unexpected correlations.
I'm somewhat unclear as to the range of potential applications for the individual user. The pulse oximeter seems to have applications in an acute medical setting, but I'm not clear on the usefulness in an everyday setting. It may have applications for analysis of sleeping disorders, chronic disease, or for serious athletes doing high altitude training, but otherwise I'm not sure of its utility. Could it be useful for alerting care givers to out-patient emergencies? Perhaps the use of the device will become apparent once deployed on a large scale and everyday activity data is collected.

Time your next heart attack to conincide with national cardiology meetings

Surprisingly, high-risk patients with heart failure and cardiac arrest admitted to US teaching hospitals during dates of national cardiology meetings had lower 30-day mortality rates. The surprise is that outcomes improved despite the absence of the cardiologists who attended the meetings. While the cause of this correlation and the generalizability of the methodology are unclear, the finding is very significant. A Freakonomics podcast covering this study expressed the magnitude of this effect in a powerful comparison. While the combination of common interventions (beta-blockers, statins, aspirin, and blood thinners) reduce mortality risk by 2-3% in these patients, this effect reduced mortality risk by up to 10%. The Freakonomics podcast also entertainingly asks some cardiologists attending a cardiology meeting about the findings. The most compelling reason presented in the podcast to explain this effect is that the health professionals not attending national cardiology meetings use more conservative interventions during this time.

The rising cost of cancer drugs

A recent research letter in JAMA oncology presented a quick analysis of the costs of cancer drugs. The article cites evidence that cancer drug prices are rising faster than prices of drugs in other therapeutic areas. The authors found no significant price difference between next-in-class drugs and novel drugs. Drugs that were granted US FDA approval based upon disease response rate were priced significantly higher than drugs approved based upon overall survival or progression- or disease free survival, however no significant relationship between cost and the percentage improvement in end point was found. The authors concluded that current pricing is "not rational but simply reflect what the market will bear." The price which the market will bear is indeed rational from the perspective of a business though I would think. There was also no consideration given to the costs of drug development but perhaps it is insignificant, I don't know. Nonetheless, an interesting analysis that makes me wonder about drugs in other therapeutic areas.

Dendroclimatology: The divergence problem

I was reminded about dendroclimatology when reading a book about the geological evidence of climate change by E. Kirsten Peters. Dendroclimatology is the study of inferring past climactic conditions based upon tree ring width and/or density. The resulting data is high resolution since a tree ring is formed every year. Tree ring width and/or density correlates well with various climate parameters like sun, water, and temperature. Using techniques from dendrochronology (tree-ring dating), long climate records of thousands of years can be reconstructed using this technique. For example, summer temperature anomalies for the past 7000 years in Siberia were constructed using tree ring proxies in the figure below.

R.M.Hantemirov - Institute of Plant and Animal Ecology. Summer temperature anomalies of the Yamal Pennisula.

Dendroclimatologists have developed methods to ensure that the samples examined contain tree ring properties that best reflect only the climactic parameter of interest. Despite this there are confounding factors, as outlined in the dendroclimatology wikipedia entry, including nonlinear responses and environmental conditions and events that can otherwise affect tree ring width and density. The most interesting confounding effect has only been evident since the 1950s and is known as the divergence problem.

The divergence problem was first identified in Alaska by Taubes (1995)[1] and Jacoby & d'Arrigo (1995)[2]. The recognition that this problem was widespread in high northern latitudes was published in 1998 by Keith Briffa[3]. A study by Cook in 2004[4] demonstrated that the problem is unique in the past 1000 years, suggesting the possibility of an anthropogenic cause. The problem is that, in northern latitudes, tree ring proxy measurements have diverged from instrument-based temperature data since the 1950s (see figure below). Growth of trees at these latitudes is declining despite instrument-based temperature data that would normally correlate with increased tree-ring width. The cause is unknown but it is likely to be a combination of local and global factors such as global warming-induced drought and global dimming.[5]

Twenty-year smoothed plots of tree-ring width (dashed line) and tree-ring density (thick solid line), averaged across a network of mid-northern latitude boreal forest sites and compared with equivalent-area averages of mean April to September temperature anomalies (thin solid line). (Briffa 1998)[3] taken from wikipedia

Dendroclimatology seems like a fascinating field that, given some reasonably inexpensive equipment, could be done as an amateur. It would be a great excuse for a hike or backcountry ski while collecting data and learning about botany, local climate, local geography, statistical analysis, and sampling methods.


[1] Taubes, G. (17 March 1995), "Is a Warmer Climate Wilting the Forests of the North?", Science 267 (5204): 1595–1526.
[2] Jacoby, G. C.; d'Arrigo, R. D. (June 1995), "Tree ring width and density evidence of climatic and potential forest change in Alaska", Global Biogeochemical Cycles 9 (2): 227.
[3] Briffa, Keith R.; Schweingruber, F. H.; Jones, Phil D.; Osborn, Tim J.; Shiyatov, S. G.; Vaganov, E. A. (12 February 1998), "Reduced sensitivity of recent tree-growth to temperature at high northern latitudes", Nature 391 (6668): 678.
[4] Cook 2004
[5] d'Arrigo, R.; Wilson, R.; Liepert, B.; Cherubini, P. (February 2008), "On the 'Divergence Problem' in Northern Forests: A review of the tree-ring evidence and possible causes", Global and Planetary Change 60 (3–4): 289. 

Skiing Robots!

While I welcome our new robot overlords, I'm unsure that I want them to be better at skiing than me. Hats off to a team from Slovenia and another team from the University of Manitoba for making robots that are cool enough to ski.

Richard Dawkins debates homeopathy with Dr. Peter Fisher (2007)

Richard Dawkins made a television documentary called "The enemies of reason" in 2007. A large portion of the first part of the documentary is on homeopathy. You can watch it here. While I think it was a pretty good documentary that consisted of legitimate criticism, it was edited for television and was focused on "gotcha" moments. I think it also missed out on an educational opportunity to explain the rigorous methods of a well conducted randomized controlled trial. I recently ran across Dr. Peter Fisher's defence of NHS funding for homeopathy in the 'uncut' interview with Dawkins from the documentary.

This was probably the best defence of homeopathy I have ever seen. Despite this, with his usual style, Dawkins had Dr. Fisher on the ropes the entire time without even citing the evidence for a lack of homeopathic efficacy. Admittedly Dr. Fisher is an easy target, however I would hate to have to debate Dawkins on any subject. He finds common ground, concedes valid points, asks great questions, and lets his opponent talk him/herself into tight corners. From my biased perspective, in this interview Dawkins essentially had Dr. Fisher admit that homeopathy is a form of placebo. However, is there any context in which homeopathy could provide a safe, cost-effective treatment that is completely placebo? Probably not, however water is pretty cheap and safe.

Nature enables sharing of articles

The journal Nature now enables subscribers to share articles for free though hyperlinks to a proprietary document format. The hyperlink to the article can then be subsequently shared by anyone. A year subscription to Nature costs $200 and an article costs around $30. While this is a somewhat awkward model in my opinion, I appreciate that such a prestigious journal can demonstrate some flexibility and adapt to the changing publishing business.
Here is a link to a paper on the identification of the remains of Richard III in the proprietary ReadCube format.

Accidental discoveries

Below is a video on accidental chemical discoveries. The last two were particularly interesting to me, the discovery of Teflon, and Gore-Tex. The real challenge it would seem to me would be seeing the potential and figuring out uses for newly synthesized chemicals.

Mogul Migration

Anticipation for the upcoming ski season is building and it is currently snowing outside. In order to keep my excitement under control I thought I would write a post on the worst aspect of resort skiing, moguls. Moguls are spontaneously forming speed killers and are ubiquitous on certain slopes that don't get machine groomed. They are admittedly impressive as self-organizing structures and their checkerboard regularity can be attractive from a distance. However, how is it possible that the seemingly random actions of skiers going down the slope create and maintain this "mountain acne"? Not only does their formation defy intuition but moguls also migrate uphill! Watch the video.

 

Three scientists, presumably also skiers, published a paper in 2009 on the subject of mogul formation and migration. These guys estimated that it takes as little as 100 ski passes to create moguls. If the snow is hard pack a bump as small as 10cm can start a mogul. Importantly the authors also calculate that a skier requires the equivalent of 'half a light beer' of calories to move a mogul one meter uphill. Unfortunately the authors offer no solutions to moguls, although I don't know if they tried enough beer. The reality is that the only solution is a huge dump of fresh powder!

Human Altitude Evolution

An interesting comment on quirks and quarks this week inspired me to do a little research on the adaptations to high altitude in different human populations. The evolution of human traits in response to high altitude environments differs between different populations. There are the legendary Tibetan highlanders of the Himalayas but there are also physiological adaptations of human populations in the Andes and in the Amhara of Ethiopia. Interestingly we also know the genetic basis for these adaptations through comparative genomics.
High altitude environments present many challenges for human physiology. These challenges are due to the thin air at higher elevations. The partial pressure of oxygen decreases with air pressure and air pressure decreases exponentially with altitude. Air pressure is half of sea-level air pressure at 5000m. This decreased availability of oxygen at higher altitudes, or hypoxia, causes altitude sickness and potentially fatal high altitude pulmonary edema and high altitude cerebral edema. The frequency of these conditions and others increase with increasing altitude.
Mere mortal lowlanders are able to partially adapt to these physiological challenges. Initially, low oxygen partial pressure is detected by the carotid body triggering increased breathing rate. Additionally at high altitudes the heart beats faster with a lower stroke volume. Longer term exposure, over days or weeks, results in further acclimatization to altitude. The most well known acclimatization feature is an increase in hemoglobin and red blood cell (RBC) mass in order to increase the amount of oxygen that can be carried by the blood. Increased RBC mass leads to increased demand on the heart, and other complications such as hypertension, chronic mountain sickness, and high fetal mortality.
The Tibetan highlanders often live at elevations of over 3500m above sea level. One of the hallmark evolutionary adaptation of these populations is a lack of increased hemoglobin at high elevations correlating with a variant of the HIF2A gene encoding HIF2alpha. The HIF2alpha transcription factor protein is active under low oxygen conditions and helps control RBC production. The HIF2A gene variant found in Tibetan highlanders traces its ancestry to a recently discovered extinct human relative - the Densisovans. So this particular adaptation is due to interbreeding between the Denisovans and the ancestors of modern Tibetans. EGLN1 and PPARA are also positively correlated with Tibetans low hemoglobin adaptation to hypoxia. Other unique traits of Tibetans contribute to their altitude aptitude including an increased basal breathing rate that does not go away when exposed to lower elevation, a larger lung capacity, and a higher blood nitric oxide (NO) concentration which can help blood vessel dilation and circulation. Tibetans also have experienced selection for genes involved in metabolism, DNA damage response, DNA repair, and genes for high infant birth weight.
Genetic adaptation to high altitude among Andean populations are distinct from the Tibetan adaptations. While HIF2A and EGLN1 both exhibit evidence of selection pressure in these populations the particular variants are not associated with decreased hemoglobin. In fact these populations demonstrate the same temporary increase in hemoglobin with increasing altitude that lowlanders experience. They do have an increased oxygen level in their hemoglobin and thus a more efficient oxygen blood carrying capacity. The Andeans do not have an increased breathing rate, however one Andean subpopulation also has increased NO blood concentrations. The Andeas are the least well adapted to high altitude as evidenced by the frequency of chronic mountain sickness. An examination of Andeans with chronic mountain sickness found that many individuals have maladapted gene variants of SENP1 and ANP32D.
The Amhara of Ethiopia are also unique in their adaptations to a low oxygen, high altitude environment. This population are immune to the dangers of high elevations over 2500m, and have been inhabiting these environments for much longer, yet they do not have either the decreased hemoglobin or high oxygen saturation of the Tibetans or Andeans respectively. However one study had identified several candidate genes for involvement in high-altitude adaptation in Ethiopia. Two of these play a role in the HIF1alpha pathway, suggesting some degree of convergent evolution.

An O2 mask is a pretty good altitude adaptation

Can't replicate your previous experimental work? Publish it.

A morale booster for those cynical about the state of scientific publishing was published this week in PLoS ONE. Psychology researchers from Northwestern University were unable to replicate previous experimental results, and instead of hiding from scrutiny and switching gears, published their inability to replicate in PLoS ONE. While obviously the best thing to do for the field, it may have also been a good idea based upon the positive response. Would such a paper be accepted in a closed-access scientific journal? I wonder if it was submitted to the original journal. In any case this is a breath of fresh air at a time when scientific misconduct seems to be given more attention than the successes of peer-review and scientific integrity.

Cotton Candy Grapes

Fruit hybrids are nothing new as pluots and tangelos become increasingly visible in grocery store produce aisles. Recently I had the opportunity to sample a fruit that looked no different from your run-of-the-mill seedless grape, but with a unique flavour of cotton candy. The taste is more than reminiscent of the pink spun sugar - it's uncanny. The fruit, a product of The Grapery in California are the result of selective breeding of different grape varieties, increasing sugar content and heightening vanilla flavour to result in the familiar taste. Personally, while I found the taste remarkable, I don't think I could eat a whole bowl of them, but maybe this is a way to get picky eaters to munch on fruit. The company is already working on other varieties that taste like strawberry or pineapple.

The UV index and cancer incidence

Originally developed by Canadian scientists, the UV index is now a standard measurement of UV radiation that reaches the earth's surface. It is an open-ended linear scale, meaning that there is no upper limit and that, for example, a 4 on the UV index is twice as much radiation compared to when the UV index is 2. The purpose of the UV index is to enable informed choices about sun protection/avoidance as per the recommendations in the chart. In fact the UV index is weighted more heavily for wavelengths in the UV spectrum that cause more skin damage. It is therefore not a pure measurement of the quantity of radiation but a direct measure of the skin damaging potential of the UV radiation. The UV index is typically forecast for solar noon, the time in the day where the UV radiation is at its peak potential. Impressively, the UV index forecast is based on computer models that account for the effects of sun elevation and distance, stratospheric ozone, cloud conditions, air pollutants, surface albedo, and ground altitude.

Slip on a shirt, slop on sunscreen, slap on a hat and wrap on shades.

Getting lots of UV radiation causes skin damage and ages skin. A higher mean UV index has also been associated with increased incidence of melanoma in non-Hispanic whites. A prospective study of UV exposure and cancer incidence also confirms a higher incidence of melanoma in those receiving higher UV exposure. This same study however found a decreased risk of non-Hodgkin's Lymphoma and colon cancer with increasing UV exposure. The study also found significant protection from thyroid, pancreatic and squamous cell lung cancer at intermediate UV exposure levels. Over nine years this study found that UV exposure was inversely correlated to total cancer incidence. The authors hypothesize that the protective effect is due to vitamin D production that occurs in human skin under exposure to sunlight. Is it surprising that the benefits of sun exposure aren't nearly as well known as the risks? I clearly have not done a thorough literature search however there doesn't seem to be much information on UV exposure and total cancer risk. The benefits of UV exposure are possibly less established and have an unconfirmed mechanism which may contribute to the lack of publicity. Also various authorities on skin cancer encourage acquisition of vitamin D through dietary sources.