Therapeutics and the F1 race.....

There are quite a few variables operating in the context of an F1 race. Where the driver is concerned there are questions about his mental alertness, situational awareness, speed of reflexes, knowledge, experience and even his risk for appetite. Clearly there are also variables related to machine performance and conditions affecting road and track. All this variability create exciting conditions and an unpredictable outcome. Yet, no matter who wins eventually, most car-machine partnerships perform outstanding well.

The operation of any high performance machine system requires complex and sophisticated servo-systems operating at multiple levels. At its most simplistic level, the race car driver need to sense the speed of the car and adjust the speed through an interplay of acceleration and deceleration.

Precision therapeutics is really not any different. The physician must be able to recognize the effect of his procedures (drug regiment) and modulate these through the adjustment of his procedures (drugs dosages, for example). What is surprising is how many physicians do not recognize that they need to do this. They function like race car drivers who don't know their car, have no speedometer and are blinded. What's worse....don't even know they have brake and accelerator pedals.

For them, the patient is represented by a virtual description of a population average. Their expectation of a therapeutic effect is a relatively crude measurement of eventual outcome - cured, didn't work...died(often they don't even recognize they are driving blind). And they don't seem to realize, they can actually adjust drug doses in scientifically rational ways.

We can actually do a whole lot better than that. And many physicians have.

It's good to blog - Nature Editorial

Reprinted here is an Editorial from Nature about researchers blogging.I am smugly pleased I started before they said it ......

Editorial
Nature 457, 1058 (26 February 2009) | Published online 25 February 2009

It's good to blog

More researchers should engage with the blogosphere, including authors of papers in press.

Is blogging a part of science, journalism or public discourse? In fact it may be all of these — an ambiguity that can sometimes leave scientists feeling uncertain about the rules of the game.

Imagine, for example, a case in which Nature's blog The Great Beyond highlights new scientific results presented at a conference on climate. That blog entry then stimulates an online debate, with climate sceptics interpreting the results their way, and others firing off rebuttals. Imagine also that the work is described in a paper that had been accepted, but not published, by Nature. The authors of the paper want to enter the fray, but feel inhibited from doing so because of the embargo imposed by Nature and many other journals on communication by authors to the media ahead of publication. And why was Nature blogging their work anyway, ahead of its publication?

This scenario highlights a need for clarification about Nature publications' procedures, and about how embargoes apply to blogs. It also highlights more generally the potential importance of scientists engaging in the blogosphere.

All Nature journals maintain confidentiality about submitted papers, so that only the editors directly responsible for those papers know about them. Other staff — including the various publications' journalists — are usually informed about a paper only once it has been accepted, and with the proviso that they do not disseminate any information about it to external contacts or readers. Likewise, we ask that authors refrain from actively promoting their work to the media and public ahead of its publication. This embargo policy rests on the principle that scientists' and the public's best interests are served by press coverage of work that has been peer reviewed, and is available for others to see for themselves.

At the same time, however, our cardinal rule has always been to promote scientific communication. We have therefore never sought to prevent scientists from presenting their work at conferences, or from depositing first drafts of submitted papers on preprint servers. So if Nature journalists or those from any other publication should hear results presented at a meeting, or find them on a preprint server, the findings are fair game for coverage — even if that coverage is ahead of the paper's publication. This is not considered a breaking of Nature's embargo. Nor is it a violation if scientists respond to journalists' queries in ensuring that the facts are correct — so long as they don't actively promote media coverage.

The blogosphere differs from mass media and specialized media in many respects, but the same considerations apply in disseminating new scientific results there. Authors of papers in press have the right to correct misrepresentations and to point to results that will appear in a paper. But a full discussion should await the paper's publication.

Indeed, researchers would do well to blog more than they do. The experience of journals such as Cell and PLoS ONE, which allow people to comment on papers online, suggests that researchers are very reluctant to engage in such forums. But the blogosphere tends to be less inhibited, and technical discussions there seem likely to increase.

Moreover, there are societal debates that have much to gain from the uncensored voices of researchers. A good blogging website consumes much of the spare time of the one or several fully committed scientists that write and moderate it. But it can make a difference to the quality and integrity of public discussion.

Durian lovers vs durian haters

Here's a slight frivolous post inspired by tonight's after dinner conversation.

The durian (Durio zibethinus), reckoned by many as the king of fruits in Asia. Others have less flattering descriptions. It's a fruit that you either love or hate.

Some descriptions of its taste (shamelessly plagiarized from Wikipedia):
Writing in 1856, the British naturalist Alfred Russel Wallace provides a much-quoted description of the flavour of the durian:
“The five cells are silky-white within, and are filled with a mass of firm, cream-coloured pulp, containing about three seeds each. This pulp is the edible part, and its consistence and flavour are indescribable. A rich custard highly flavoured with almonds gives the best general idea of it, but there are occasional wafts of flavour that call to mind cream-cheese, onion-sauce, sherry-wine, and other incongruous dishes. Then there is a rich glutinous smoothness in the pulp which nothing else possesses, but which adds to its delicacy. It is neither acid nor sweet nor juicy; yet it wants neither of these qualities, for it is in itself perfect. It produces no nausea or other bad effect, and the more you eat of it the less you feel inclined to stop. In fact, to eat Durians is a new sensation worth a voyage to the East to experience. ... as producing a food of the most exquisite flavour it is unsurpassed.”

While Wallace cautions that "the smell of the ripe fruit is certainly at first disagreeable", later descriptions by westerners are more graphic. British novelist Anthony Burgess writes that eating durian is "like eating sweet raspberry blancmange in the lavatory." Chef Andrew Zimmern compares the taste to "completely rotten, mushy onions." Anthony Bourdain, while a lover of durian, relates his encounter with the fruit as thus: "Its taste can only be described as...indescribable, something you will either love or despise. ...Your breath will smell as if you'd been French-kissing your dead grandmother." Travel and food writer Richard Sterling says:

“... its odor is best described as pig-shit, turpentine and onions, garnished with a gym sock. It can be smelled from yards away. Despite its great local popularity, the raw fruit is forbidden from some establishments such as hotels, subways and airports, including public transportation in Southeast Asia.

Other comparisons have been made with the civet, sewage, stale vomit, skunk spray and used surgical swabs.

There are clear indications that this is a pharmacogenetic differentiation of durian lovers from haters, though I do not know of any study to this effect.

Go ahead and take the Great Durian Poll!!

The not so normal distribution

The normal distribution is a convenient tool when you need to describe your data. Unfortunately it introduces a blind spot when it comes to interpreting the data.

When we look at the distribution, our eye intuitively focuses on the centre of the distribution. We see the central tendency of the distribution and the variance around it. This is fine when you are describing the data. But averages don't really help you if you are the storeman who's responsible for purchasing clothes for a bunch of factory workers.

This is the odd thing about studying variability in therapeutic response to drugs. We all know variability exists. We see this in every sphere of human activity, from buying clothes and cosmetics to the ability to complete a physical fitness test. Yet inexplicably, when it comes to dosing patients, people imagine that a dosage regiment based on the mean of a relatively small unrepresentative study sample will somehow represent the dosage requirement for everyone on this planet.

Here is a series of distributions of the clearances of CYP3A5 substrates midazolam and alfentanil (Kharasch et al, Clinical Pharmacology & Therapeutics (2007) 82, 410–426). The distributions are skewed to the right and so are clearly log-normally distributed.

Here is a frequency distribution of the log-metabolic ratio for midazolam in a Chinese population (Zhu et al, Br J Clin Pharmacol. 2003 March; 55(3): 264–269).

Notice from these plots just how variable the clearances and the metabolic ratios (more about this later) are. How do we, under these conditions determine the correct doses for each patient? Clearly applying population averages will not work. Are we able to do it?

The earlier posting on wafarin show how it can be done for warfarin.More on dosage optimization issues later.

Highlighted report: Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose

Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients.

Huang, Sheng-Wen, Chen, Hai-Sheng, Wang, Xian-Qun, Huang, Ling, Xu, Ding-Li, Hu, Xiao-Jia, Huang, Zhi-Hui, He, Yong, Chen, Kai-Ming, Xiang, Dao-Kang, Zou, Xiao-Ming, Li, Qiang, Ma, Li-Qin, Wang, Hao-Fei, Chen, Bao-Lin, Li, Liang, Jia, Yan-Kai, Xu, Xiang-Min

Objectives: To develop a warfarin-dosing algorithm that could be combined with pharmacogenomic and demographic factors, and to evaluate its effectiveness in a randomized prospective controlled clinical trial.

Methods: A pharmacogenetics-based dosing model was derived using retrospective data from 266 Chinese patients and multiple linear regression analysis. To prospectively validate this model, 156 patients with an operation of heart valve replacement were enrolled and randomly assigned to the group of pharmacogenetics-guided or traditional dosing for warfarin therapy. All patients were followed up for 50 days after initiation of warfarin therapy. The log-rank test was compared with the time-to-event (Kaplan-Meier) curves. Cox proportional hazards-regression model was used to assess the hazard ratio of the time to reach stable dose.

Results: The linear regression model derived from the pharmacogenomic model correlated with 54.1% of warfarin dosing variance. The final multiple linear regression model included age, body surface area, VKORC1, and CYP2C9 genotype. The study showed that the hazard ratio for the time to reach stable dose was 1.932 for the traditional dosing group versus the model-based group and a close and highly significant relationship was observed to exist between the predicted and the actual warfarin dose (R2=0.454).

Conclusion: A pharmacogenetics-based dosing algorithm has been developed for improvement in the time to reach the stable dosing of warfarin. This model may be useful in helping the clinicians to prescribe warfarin with greater safety and efficiency.

See also:

Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data.
The International Warfarin Pharmacogenetics Consortium.

BACKGROUND: Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base. METHODS: Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators. RESULTS: In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001,>/=49 mg per week). CONCLUSIONS: The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation.
Eckman MH, Rosand J, Greenberg SM, Gage BF.
University of Cincinnati Medical Center, Cincinnati, OH 45267-0535, USA. mark.eckman@uc.edu

BACKGROUND: Variants in genes involved in warfarin metabolism and sensitivity affect individual warfarin requirements and the risk for bleeding. Testing for these variant alleles might allow more personalized dosing of warfarin during the induction phase. In 2007, the U.S. Food and Drug Administration changed the labeling for warfarin (Coumadin, Bristol-Myers Squibb, Princeton, New Jersey), suggesting that clinicians consider genetic testing before initiating therapy. OBJECTIVE: To examine the cost-effectiveness of genotype-guided dosing versus standard induction of warfarin therapy for patients with nonvalvular atrial fibrillation. DESIGN: Markov state transition decision model. DATA SOURCES: MEDLINE searches and bibliographies from relevant articles of literature published in English. TARGET POPULATION: Outpatients or inpatients requiring initiation of warfarin therapy. The base case was a man age 69 years with newly diagnosed nonvalvular atrial fibrillation and no contraindications to warfarin therapy. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Genotype-guided dosing consisting of genotyping for CYP2C9*2, CYP2C9*3, and/or VKORC1 versus standard warfarin induction. OUTCOME MEASURES: Effectiveness was measured in quality-adjusted life-years (QALYs), and costs were in 2007 U.S. dollars. RESULTS: In the base case, genotype-guided dosing resulted in better outcomes, but at a relatively high cost. Overall, the marginal cost-effectiveness of testing exceeded $170 000 per QALY. On the basis of current data and cost of testing (about $400), there is only a 10% chance that genotype-guided dosing is likely to be cost-effective (that is, <$50 000 per QALY). Sensitivity analyses revealed that for genetic testing to cost less than $50 000 per QALY, it would have to be restricted to patients at high risk for hemorrhage or meet the following optimistic criteria: prevent greater than 32% of major bleeding events, be available within 24 hours, and cost less than $200. LIMITATION: Few published studies describe the effect of genotype-guided dosing on major bleeding events, and although these studies show a trend toward decreased bleeding, the results are not statistically significant. CONCLUSION: Warfarin-related genotyping is unlikely to be cost-effective for typical patients with nonvalvular atrial fibrillation, but may be cost-effective in patients at high risk for hemorrhage who are starting warfarin therapy.

The normal distribution

The normal distribution, often referred to as the Gaussian distribution, and at other times, the bell curve, takes its name from the prodigious German mathematician Carl Friedrich Gauss (1777-1855), who discovered it while studying the distribution of measurement errors in astronomy.

It is something we take very much for granted in clinical and biomedical research. It is certainly something inherently useful in being able to group our observable data, and to be able to describe a central tendency that can be used to represent groups of subjects or patients. Another way of looking at the normal distribution of data is to do a probit analysis. Here is an example of the apparent normality in the frequency distribution as applied to the CYP1A2 metabolic ratio in a Chinese population. Under these circumstances, the probit plot approximates linearity.

Frequency and probit distribution of CYP1A2 activity in a Chinese population as indicated by plasma log-transformed 1,7-dimethylxanthine/caffeine [lg(17X/137X)] ratios (n = 419).Chen et al, Clinical Pharmacology & Therapeutics 78, 249-259 (September 2005)

In this instance however, the normality of the distribution hides a plethora of heterogeneity as the CYP1A2 gene is highly polymorphic, and the authors in this study reports that the G–3113A polymorphism is associated with decreased CYP1A2 activity, haplotype pairs 10 and 13 are responsible for high CYP1A2 activity, and haplotype pairs 5, 8, 9, 12, and 15 are responsible for low CYP1A2 activity in Chinese subjects.

In understanding diversity of human drug response, understanding 'normality' is an important starting point, but we need to look beyond this. Normality can work against us.

Genetics of taste?

Bimodal distribution of PTC sensitivity

Here's a a bit of an update on Arthur Fox's PTC taste blindness story from. Not a whole lot of people interested in this other than the food industry and nutritional scientists.

There is a rather dated review of this here (2001) and here (1995). Apparently the frequency of non-tasters among Caucasians is about 26-30%, but only 6-10% among Asians (whatever that means for the Americans!). Apparently tasters have a lower acceptance for bitter foodstuff such as broccoli/cruciferous vegetables, naringin, green tea and tofu. But this does not seem to be borne out in real life given the high acceptance of green tea and tofu in Asia despite a much lower incidence of non-tasters.

One of these ethnic confounders.

Carbamazepine - Stevens-Johnson Syndrome

In 2004, a Taiwanese group (Chung et al, Nature 2004, 428:486) reported a very strong association between the HLA-B*1502 allele with the development of Stevens-Johnson Syndrome with the anti-epileptic drug carbamazepine.

This is actually a very interesting story about an drug SAE (serious adverse event) associated with a specific HLA genotype. Not only genetics, but also an intriguing tale about ethnicity and populations.

So far all the clinical data verify the association in Han Chinese (Taiwan, Hong Kong) and Thai. No associations have been found for Europeans....and here is what is also interesting...not for Japanese as well. Ferrel and McLeod (2008) have reviewed the data, and there have also been a number of more recent studies reporting on the HLA-B*1502 allele frequencies from different populations.

A Table of these frequencies from Ferrel and McLeod is reproduced here.
There are a couple of more recent data not only showing the same patterns but also showing how the Northern Chinese group pulls apart from the Southern Chinese. Han Chinese from Shaanxi, Koreans and Japanese have a Caucasian type frequency while Southern Chinese in Guangdong cluster with the rest of South East Asia (Philippines, Java). The Indian subcontinent occupies an intermediate position, and depending on the population sampled, with frequencies ranging between Caucasian frequencies to those similar to South East Asians and Southern Chinese. The association between HLA-B*1502 and carbamazepine SJS appears not in doubt, but apparently only for Southern Chinese (Taiwan, Hong Kong, most of Singapore) and people of South East Asian ancestry. It does not seem to apply for Caucasians, and remains doubtful for Northern Chinese, and people of a more northern ancestry such as the Japanese (and possibly the Koreans). There remains a big question mark for people from the Indian subcontinent.

The FDA did us a major injustice when in their haste they recommended that genotyping for HLA-B*1502 be done prior to dosing, for people of an "Asian ancestry". We have no idea what this means. For Singapore, it is probably reasonable for Chinese and Malays (although it may not apply to the more northern Chinese among us), but we are totally in the dark with regards to "Indians" and "Eurasians".

Pharmacogenetics in Singapore - beginnings

It is easy to want to think of Pharmacogenetics as a fairly recent science in Singapore, but actually its roots go back quite far. And it is a story worth telling.

This goes back to just before when Vogel first coined the term Pharmacogenetics in 1959. In 1957, a young paediatrician, Wong Hock Boon (he was barely 34 years old then), discovered that the cases of neonatal jaundice giving rise to the devastating condition of kernicterus in Singapore was very different from those reported in the West (Wong HB, Archives of Diseases in Childhood, 32:85, 1957). Collectively, the causes of kernicterus in the West (Rhesus incompatibility, ABO incompatibility and prematurity) only accounted to about a thrid of cases in Singapore. At the time of reporting, he was not able to figure out what lay behind the remaining two thirds, but about a year previously, Carson (Carson, P. E.; Flanagan, C. L.; Ickes, C. E.; Alving, A. S. : Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 124: 484-485, 1956) had described an inherited deficiency in glucose 6 phosphate dehydrogenase that predisposed to drug (primaquine) induced haemolytic anaemia. Subsequently these dots connected, and it became clear that kernicterus in Singapore was largely due to neonatal haemolytic anaemia in babies who had G6PD deficiency.

What followed was perhaps the most underrecognized, success stories in pharmacogenetics. In 1964, Singapore started its systematic neonatal screening programme for G6PD deficiency (unless I am mistaken, it may have been the first in the world to do it), and was able to bring down dramatically the incidence of kernicterus in our newborns. Taiwan and Hong Kong didn't get into it until the 80's.

And this was all due to clinical astuteness of Dr Wong Hock Boon, who in 1962 became Professor Paediatrics in the then University of Singapore. Sadly he passed away last year (December 2008) at the age of 85.

Variability in drug response - Pharmacogenetics

It has long been recognized that patients differ substantially in the way they respond to their medications. These differences may relate to compliance issues, or to the way their medications interacted with other concurrent medications and chemicals in their diet. Often differences may reflect the individual genetic makeup in terms of how the body deals with drugs and exogenous chemicals. The complex interactions between one's genetic makeup, environment and culture ultimately determine the balance of health and disease, as well as one's response to drugs.

It was Friedrich Vogel of Heidelberg, Germany in 1959 who first coined the term "Pharmacogenetics" (Vogel, F. Moderne problem der humangenetik. Ergeb Inn Med U Kinderheilk. 1959;12:52–125). But in reality, the hereditability of drug response was already being recognized as far back as 1931, when a DuPont chemist Arthur Fox discovered (Fox, A. L. : Tasteblindness. Science 73: 14, 1931) that some people were actually 'blind' to the taste of PTC (phenylthiocarbamide). As has often been the case, this was a very serendipitous discovery because it resulted from a lab accident when the PTC exploded into the air. While others around him experienced the bitter taste, Fox did not. It was subsequently discovered that he lacked the N-C=S group for his taste receptor. (see Yale Scientific Magazine)

The rest, as they say, ... is history.

Genesis

Always wanted to do this but never ever got around to do it. The idea really started from all the Pharmacogenetics Lab research activities and my involvement with the LSM4212 Module on "Pharmacogenetics and Drug Response Variability".

After lots of mistakes I think I finally mastered the basic tools of blogging...well, at least enough, I think, to get started. So here goes. Here's hoping we can get some sort of discussions going on all those thoughts and ideas floating around issues related to pharmacogenetics and variability in drug response.

Coincidentally, The Scientist just published a report on a blogging high school biology teacher, and how she transformed the teaching of biology. I reproduce an excerpt here, but you can go here for the real stuff (just need to register).

"High school biology teacher Stacy Baker was sick of waiting by the photocopier to make handouts for her students. So in 2006, she launched a website, missbakersbiologyclass.com, to serve as central repository for class notes, pictures, and extra credit assignments.

At first, the site was simply an online extension of her classroom, and information flowed strictly one-way: teacher to pupils. But Baker wanted the site to be more than that; she wanted to engage her students in the full interactive potential of the Internet. So she transformed the site into a participatory blog, and let her students take it over."

Cool.