Wednesday, September 3, 2008

The DNA Network

The DNA Network

The Gene Sherpa Path and T. Boone [The Gene Sherpa: Personalized Medicine and You]

Posted: 03 Sep 2008 08:26 PM CDT

Whether you agree with the plan or not this is an impressive argument made by T.Boone Pickens It's also a very impressive community he's building... When you think...

[[ This is a content summary only. Visit my website for full links, other content, and more! ]]

Evolutionary ecology of "hot" in chilies [Yann Klimentidis' Weblog]

Posted: 03 Sep 2008 06:50 PM CDT

Green chile season is underway here in New Mexico, so this paper is fitting.
They find that variation in production of Capsaicinoids (hot stuff) is explained by variation in the damage caused by a fungal pathogen of chili the hot stuff protects the plants from pathogens. I assume they discuss other ecological factors (climate, maybe) that explain why other species of plants don't do this also. I bet green chile farmers in New Mexico would know a lot about this since they maintain lines of varying hotness (hot, medium, mild) and have to deal with "pests".

Evolutionary ecology of pungency in wild chilies
Joshua J. Tewksbury, Karen M. Reagan, Noelle J. Machnicki, Tomás A. Carlo, David C. Haak, Alejandra Lorena Calderón Peñaloza, and Douglas J. Levey
PNAS 2008 105:11808-11811
Abstract: The primary function of fruit is to attract animals that disperse viable seeds, but the nutritional rewards that attract beneficial consumers also attract consumers that kill seeds instead of dispersing them. Many of these unwanted consumers are microbes, and microbial defense is commonly invoked to explain the bitter, distasteful, occasionally toxic chemicals found in many ripe fruits. This explanation has been criticized, however, due to a lack of evidence that microbial consumers influence fruit chemistry in wild populations. In the present study, we use wild chilies to show that chemical defense of ripe fruit reflects variation in the risk of microbial attack. Capsaicinoids are the chemicals responsible for the well known pungency of chili fruits. Capsicum chacoense is naturally polymorphic for the production of capsaicinoids and displays geographic variation in the proportion of individual plants in a population that produce capsaicinoids. We show that this variation is directly linked to variation in the damage caused by a fungal pathogen of chili seeds. We find that Fusarium fungus is the primary cause of predispersal chili seed mortality, and we experimentally demonstrate that capsaicinoids protect chili seeds from Fusarium. Further, foraging by hemipteran insects facilitates the entry of Fusarium into fruits, and we show that variation in hemipteran foraging pressure among chili populations predicts the proportion of plants in a population producing capsaicinoids. These results suggest that the pungency in chilies may be an adaptive response to selection by a microbial pathogen, supporting the influence of microbial consumers on fruit chemistry.

Familial Cancer Database Online | FaCD []

Posted: 03 Sep 2008 04:17 PM CDT

Familial Cancer Database Online is a very useful online tool for experts in cancer genetics to assist in making a genetic differential diagnosis in cancer patients as well as remind tumor spectrum associated with certain hereditary disorders.

And its dynamic cyberinfrastructure already brings the most updated content in the field of clinical cancer genetics with intention to develop further.

The content was created and is edited by dr. Rolf Sijmons (on the left - during poster presentation at ESHG meeting in Barcelona this year), clinical geneticist and associate professor clinical oncogenetics at the Dept. of Genetics of the University Medical Center Groningen (UMCG), the Netherlands. However, other experts who want to contribute to particular syndrome files are invited to contact the editor; these authors will be listed in the syndrome files they contributed to.

And I’m pleased of being included in the list of contributors for the contribution to rare hereditary disorder called Mosaic Variegated Aneuploidy syndrome, where in addition to other symtomes the risk for several cancers (leukemia, rhabdomyosarcomas and embrional kidney cancers) is increased.

FaCD is intended for free of charge use by health professionals with at least basic knowledge of clinical cancer genetics.

Does a blogger influences impact factor? [Reportergene]

Posted: 03 Sep 2008 03:42 PM CDT

It is quite common to infer that a paper from a journal with high Impact Factor (IF) would have a stronger scientific value that a paper appeared in a minor journal. Basically, citation numbers are used to gauge scientific influence in the same way as google research results depend on numbers of linking pages. Nevertheless a huge number of scientists criticized with those viewpoint, and other citation metrics, like H-index, have been suggested.

The June editorial of Nature Neuroscience, contributes to the overall discussion, taking note that probably most references are transcribed from other reference lists rather than from the original source article. If this is true, one can infer that most authors do not read the papers they cite, and (foremost) this makes citation counting far less significant. With the (discutible) assumption that everyone downloading the paper is reading it, can one predict how well any particular paper is cited years after publication, based solely on the number of downloads it receives immediately following its appearance online? Actually the correlation appeared to be linear (at least for Nature Neuroscience papers).

In perspective, the authors precognizes that new metrics (such as paper downloads and other "web 2.0 technologies) can find a place in a compilation of aggregated stats, painting a more accurate and informative picture of manuscript influence. Is Researchblogging community ready for such huge responsibility?

Balls electroporation? [Reportergene]

Posted: 03 Sep 2008 03:26 PM CDT

In my humble opinion, to study functional genomics in vivo, the best would be to place your reporter gene into humanized animals (i.e. making transgenic reporter-humanized mice). Pronuclear DNA micro-injection in the oocyte is the most frequently used technique for generating transgenic mice; unfortunately, pronuclear transfer is expensive, labor-intensive, time-consuming and require coordination of many experimental steps, so personally I feel an urgent need to alternate, cost-effective and more rapid approach to obtain desired transgenic founders.
Recently, I have been occasion to wonder about a male-driven transgenesis approach, and I found interesting literature. Here a few references (feel free to comment missing items).

Suveera Dhup, Subeer S Majumdar (2008). Transgenesis via permanent integration of genes in repopulating spermatogonial cells in vivo Nature Methods, 5 (7), 601-603 DOI: 10.1038/NMETH.1225

Chang KT, Takahashi M (1999). Production of Transgenic Rats and Mice by the Testis-Mediated Gene Transfer Journal of Reproduction and Development, 45 (1), 29-36

Maione B, Lavitrano M, Spafafora C, Kiessling AA (1998). Sperm-Mediated Gene Transfer in Mice Molecular Reproduction and Development, 50, 406-409

Genelex’s CEO Medicare Comments on Warfarin DNA Testing [A Forum for Improving Drug Safety]

Posted: 03 Sep 2008 02:58 PM CDT

Today is the last day to express your opinion on whether warfarin (Coumadin) DNA testing should be covered by insurance. Please post your comments on this important decision which will have far reaching effects on the field of personalized medicine and pharmacogenetics. Please go to to learn more about this study. To post your comments scroll to the bottom of the page and click on view public comments, then click on the orange comments button on the upper right of the page. 

Here is what Genelex’s CEO, Howard Coleman posted:

Thank you for the opportunity to comment on the importance to patients of insurance reimbursement for warfarin DNA testing.

Warfarin (Coumadin) therapy is expanding rapidly in the elderly population because of the increasing prevalence of atrial fibrillation and longer life spans. Numerous studies have documented that warfarin is underutilized in eligible patients. Physicians, while knowing that warfarin is effective, have fear about bleeding that may prevent its use. Physicians also have been shown to reduce their prescribing of warfarin after one of their patients experiences a bleeding event. Approximately 5 million patients currently take warfarin and 500,000 start this medicine every year. It is the seventh most frequently prescribed medicine in the US. Many anticoagulation experts believe that up to 50% more patients could benefit from taking warfarin, but don't because of the fear of the adverse outcomes of minor and major bleeds, or the inconvenience of frequent blood testing and the costs of travel and lost productivity.

Warfarin is a difficult and hazardous drug to prescribe because of its extremely narrow therapeutic index and twenty-fold variation in individual patient dose requirement. Non genetic factors, such as age, gender and body weight account for approximately 12% of this unusually wide variation in individual stable dose requirement. Most patients are started on 5mg per day and asked to return to the clinic weekly, or more frequently for INR blood testing (international normalization ratio based on prothrombin time) and dose adjustment, if needed. At the time of patient visits, prescribers don't know if the blood levels of warfarin are stable, going up or going down. The result is an inefficient, trial and error process if multiple INRs and dosing adjustments are required to achieve a stable maintenance dose. It puts patients at risk, especially when initiating warfarin and can take weeks or months to get the maintenance dose reliably and consistently right.

The elderly are especially at risk which is not appreciably mitigated by prescribers taking age into account. The severity of the risks of taking warfarin leads to 58,000 emergency room visits by patients over age 65 every year. It is second only to insulin in precipitating medication related ER visits and is listed by the FDA's Adverse Event Reporting System in the top ten of drugs with the greatest number of serious adverse events. The risks of warfarin therapy are so great that in 2006 the FDA added a "black box" warning to the label (see below). More information is needed in the elderly when starting warfarin in order to reduce costs and the reduction in quality of life resulting from adverse events.

Many studies in the last five years have demonstrated that patients prescribed warfarin and carrying variations in genes that reduce the clearance of warfarin via CYP2C9, or affect the sensitivity of its treatment target VKORC1 are at double or triple the risk for an adverse bleeding event or treatment failure (odds ratios up to 5X) in the time period after starting warfarin. Variation in these genes is the most important causal mechanism of warfarin intersubject variability. Therefore, the relationship between genotype and clinical outcomes of, INR control, number of INR blood tests required to reach a stable dose, number of dosing adjustments and time in therapeutic INR range is not empirical or due to chance.

These risk elevating genetic variations are present in the majority of patients seen by clinicians and as many as 60% of patients would benefit from genetic testing. Compared to patients without these variations they take as much as three months longer to reach a stable dose after starting warfarin, and spend more time at risky high doses or sub therapeutic low doses as dosing adjustments in response to unacceptable INRs are made by the prescriber. The quality of anticoagulant control, in turn, is related to the risk of having an adverse event. Mounting clinical studies from around the world, and between various ethnic groups, including large prospective trials, confirm the basic facts outlined here. These studies also point to the usefulness of genetic testing in helping patients avoid the personal hardship of a bleeding related hospitalization or recurrence of a stroke, myocardial infarction or thromboembolism. Compared to age, body weight and gender, genetic factors contribute three times more information about variability in stable dosage requirements, 35% for CYP2C9 and VKORC1 versus 12% for age, gender and body weight.

Some suggest that we wait for the conclusions to be reached by additional studies that are underway before taking action. These studies may further refine our knowledge of how best to prescribe warfarin, and are unlikely to overturn the conclusions of the many studies completed so far and cited below. In addition these studies, conducted under controlled conditions, may not be applicable to the primary or secondary medical care that is received by most warfarin patients in the US. Allowing these or other future studies to be the gatekeeper to the implementation of warfarin DNA testing is not in the best interest of patients.

DNA testing of CYP2C9 and VKORC1 to help determine the maintenance dose of warfarin has been available from licensed medical laboratories since before 2000. There are now several FDA approved DNA diagnostic tests of high quality for warfarin dosing on the market. These tests are readily available and with the short turnaround time needed during the initiation of warfarin therapy. Prescribers can act on the test results because algorithms that incorporate DNA testing results and a variety of currently recognized clinical factors and drug interactions are available that can account for up to 79% of the individual dose variation. They can also predict the maintenance dose to within a milligram per day. These tests do not replace INR testing but have been shown to reduce the frequency needed for INR tests by improving the prediction of stable maintenance dose. In August 2007 the FDA changed the Coumadin drug label to point out the impact individual genetic variation has on warfarin dose requirement and risk.

One of the last remaining barriers to the routine adoption and availability of warfarin dosing DNA testing to the elderly patient is reliable and consistent insurance reimbursement. Estimates of cost effectiveness suggest that almost $1000 per patient could be saved by routine use of warfarin DNA testing at a cost of $550 per test, consistent with the costs of other routinely prescribed genetic tests. As testing volumes increase the costs of warfarin genetic testing will drop, further increasing its cost-effectiveness. These estimates did not take into account the added costs of more frequent monitoring and dosing adjustments by health care providers or the personal costs to patients. In addition, the psychological impact on patients to improve warfarin compliance will be enhanced by knowing that their prescriber has done all they can to start warfarin safely.

If the Center for Medicare and Medicaid Services adopts a policy of reimbursement for warfarin DNA testing, the virtually unanimous body of evidence collected for more than a decade points to a net result of a reduction in adverse events, treatment failures and costs. If CMS declines to reimburse for warfarin DNA testing it will be a major set-back for pharmacogenetic based personalized medicine and more importantly the millions of patients who will be denied the utility of this test and suffer accordingly as we have seen by published reports of the risks and bleeding complications in elderly patients treated with warfarin.

In summary, the weight and quality of evidence supports genetic testing for 2C9 and VKORC1 gene variants in elderly patients before or shortly after starting warfarin to improve the quality of anticoagulation and define starting doses that are closer to the eventual stable maintenance doses of warfarin. I recommend that CMS seriously consider reimbursement for these tests.

Abstracts of key papers.

A recent summary of previous trials, the benefit of genetic testing to various measures of quality anticoagulation and their conclusions about risks of bleeding can be found in "The critical path of warfarin dosing: finding an optimal dosing strategy using pharmacogenetics." Clin Pharmacol Ther, 2008 Sep;84(3):301-3 by LJ Lesko, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, FDA is available at 

These papers were published following recent FDA labeling changes (see below for excerpts).  They have also not been included in previous assessments of genetic testing to guide warfarin therapy such as the California Technology Assessment Forum which covers published literature to December 2007.

The largest prospective warfarin-treated cohort supports genetic forecasting.

Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, Holm L, McGinnis R, Rane A, Deloukas P.: Blood. 2008 Jun 23

Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (p=6.63×10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (p=9.82×10(-100)). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygozity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95%CI 9.46;50.42) and 4.56 (95%CI 2.85;7.30), respectively. One of eight patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (p=0.066). A multiple regression model using the predictors CYP2C9, VKORC1, age, gender and drug-interactions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.

Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.

Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE, Aquilante CL, Grosso L, Marsh S, Langaee T, Farnett LE, Voora D, Veenstra DL, Glynn RJ, Barrett A, McLeod HL. Clin Pharmacol Ther. 2008 Sep;84(3):326-31. Epub 2008 Feb 27

Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website,

An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients.

Meckley LM, Wittkowsky AK, Rieder MJ, Rettie AE, Veenstra DL. Thromb Haemost. 2008 Aug;100(2):229-39

The objective of this study was to assess the relative influence of VKORC1 and CYP2C9 genetic variants on several clinical outcomes related to warfarin treatment. We conducted a retrospective cohort analysis of 172 anticoagulation clinic patients followed from warfarin initiation. We assessed the following clinical outcomes: time to stable dose; time in, above, and below therapeutic range; the probability of overanticoagulation (international normalized ratio [INR] >5); frequency of anticoagulation clinic visits; and the contribution of genetics to maintenance dose. Patients with CYP2C9 variants, compared to those without, achieved stable dose 48% later (p < 0.01), spent a higher proportion of time above range in the first month of therapy (14% vs. 25%, p = 0.07), and had a higher odds ratio (OR) of an INR >5 (OR: 4.15, p = 0.03). In contrast, the only statistically significant effect with VKORC1 was a higher odds of an INR >5 (OR: 4.47, p = 0.03) for patients homozygous for the VKORC1 low-dose haplotype (AA) compared to heterozygotes. We did not detect an influence of CYP2C9 nor VKORC1 on the frequency of clinic visits. CYP2C9 alone, VKORC1 alone, and a combination of genetic and clinical factors explained 12%, 27%, and 50%, respectively, of the variation in warfarin maintenance dose. In conclusion, genetic variation in VKORC1 appears to have a different influence than CYP2C9 on anticoagulation-related outcomes such as bleeding events and time in therapeutic range. This difference may be due, in part, to pharmacokinetics factors (e.g. drug half-life), which are influenced primarily by CYP2C9; these findings should be confirmed in additional studies.


Health Care Savings from Personalizing Medicine Using GeneticTesting: The Case of Warfarin

Andrew McWilliam, Randall Lutter and Clark Nardinelli Working Paper 06-23, November 2006 AEI-BROOKINGS JOINT CENTER FOR REGULATORY STUDIES.

Updated in Personalized Medicine (2008) 5(3): 279-284 confirming with sensitivity analysis that cost savings per patient who is tested genetically can be nearly $1000 per patient and improve health outcomes.

Executive Summary

Progress towards realizing a vision of personalized medicine—drugs and drug doses that are safer and more effective because they are chosen based on an individual's genetic makeup has been slower than once forecast. The Food and Drug Administration has a key role to play in facilitating the use of genetic information in drug therapies because it approves labels, and labelsi nfluence how doctors use drugs. Here we evaluate one example of how using genetic information in drug therapy may improve public health and lower health care costs.

Warfarin, an anticoagulant commonly used to prevent and control blood clots, is complicated to use because the optimal dose varies greatly among patients. If the dose is too strong the risk of serious bleeding increases and if the dose is too weak, the risk of stroke increases. We estimate the health benefits and the resulting savings in health care costs by using personalized warfarin dosing decisions based on appropriate genetic testing. We estimate that formally integrating genetic testing into routine warfarin therapy could allow American warfarin users to avoid 85,000 serious bleeding events and 17,000 strokes annually. We estimate the reduced health care spending from integrating genetic testing into warfarin therapy to be $1.1 billion annually, with a range of about $100 million to $2 billion.

Excerpts from the most recent changes to the Coumadin (warfarin) labeling. The complete label is available at:


The elimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4′-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin. NDA 9-218/S-105 Page 4

The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles CYP2C9*2 and CYP2C9*3 result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these allelles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively1. Patients with one or more of these variant CYP2C9 alleles have decreased S-warfarin clearance (Table 1).2

Table 1. Relationship Between S-Warfarin Clearance and CYP2C9 Genotype in Caucasian Patients

CYP2C9 Genotype


S-Warfarin Clearance/Lean Body Weight


Mean (SD)a



0.065 (0.025)b

*1/*2 or *1/*3


0.041 (0.021)b

*2/*2, *2/*3 or *3/*3


0.020 (0.011)b









A meta-analysis of 9 qualified studies including 2775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients.3 In this meta-analysis, 3 studies assessed bleeding risks and 8 studies assessed daily dose requirements. The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele.

In an observational study, the risk of achieving INR >3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of over anticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele.4 NDA 9-218/S-105 Page 5 Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined.5 About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication for warfarin therapy in Caucasian patients.5 Similar observations have been reported in Asian patients.6,7

Selected References:

Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002;287:1690-8

Takahashi H, Wilkinson GR, Padrini R, Echizen H. CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences. Clin Pharmacol Ther 2004;75:376-80.

Gage, B.F., Eby, C., Milligan, P.E., Banet, G.A., Duncan, J.R. & McLeod, H.L. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb. Haemost. 91, 87–94 (2004).

Aithal, G.P., Day, C.P., Kesteven, P.J.L. & Daly, A.K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353, 717–719 (1999).

Margaglione, M. et al. Genetic modulation of oral anticoagulation with warfarin. Thromb. Haemost. 84, 775–778 (2000).

Voora, D. et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb. Haemost. 93, 700–705 (2005).

Rieder, M.J. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med. 352, 2285–2293 (2005).

Wadelius, M. et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 5, 262–270 (2005).

D'Andrea, G. et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105, 645–649 (2005).

Yuan, H.Y. et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum. Mol. Genet. 14, 1745–1751 (2005).

Aquilante, C.L. et al. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin. Pharmacol. Ther. 79, 291–302 (2006).

Linder, M.W. et al. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms. J. Thromb. Thrombolysis 14, 227–232 (2002).

Shine, D. et al. A randomized trial of initial warfarin dosing based on simple clinical criteria. Thromb. Haemost. 89, 297–304 (2003).

Caraco, Y., Blotnick, S. & Muszkat, M. CYP2C9 Genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin. Pharmacol. Ther. 83, 457–467 (2008).

Anderson, J.L. et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 116, 2563–2570 (2007).

Millican, E. et al. Genetic-based dosing in orthopaedic patients beginning warfarin therapy. Blood 110, 1511–1515 (2007).

Marsh, S., King, C.R., Porche-Sorbet, R.M., Scott-Horton, T.J. & Eby, C.S. Population variation in VKORC1 haplotype structure. J. Thromb. Haemost. 4, 473–474 (2006).

Aquilante, C.L., Lobmeyer, M.T., Langaee, T.Y. & Johnson, J.A. Comparison of cytochrome P450 2C9 genotyping methods and implications for the clinical laboratory. Pharmacotherapy 24, 720–726 (2004).

Ridker, P.M. et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N. Engl. J. Med. 348, 1425–1434 (2003).

Sconce, E.A. et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106, 2329–2333 (2005).

Herman, D., Peternel, P., Stegnar, M., Breskvar, K. & Dolzan, V. The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb. Haemost. 95, 782–787 (2006).

Wu, A. Use of genetic and non-genetic factors in warfarin dosing algorithms. Pharmacogenomics 8, 865–872 (2007).

King, B.P., Khan, T.I., Aithal, G.P., Kamali, F. & Daly, A.K. Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism. Pharmacogenetics 14, 813–822 (2004).

King, C.R. et al. Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose. Am J. Clin. Pathol. in press.

Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest 2004;126:3 Suppl:204S-233S. [Erratum, Chest 2005;127:415-6.]

Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631-9.

Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001;119: 1 Suppl:108S-121S.

White, R.H., Beyth, R.J., Zhou, H. & Romano, P.S. Major bleeding after hospitalization for deep-venous thrombosis. Am. J. Med. 107, 414–424 (1999).

Beyth, R.J., Quinn, L. & Landefeld, C.S. A multicomponent intervention toprevent major bleeding complications in older patients receiving warfarin. A randomized, controlled trial. Ann. Intern. Med. 133, 687–695 (2000).

Hirsh, J., Fuster, V., Ansell, J. & Halperin, J.L. American heart Aassociation/American college of cardiology foundation guide to warfarin therapy. Circulation 107, 1692–1711 (2003).

Ezekowitz, M.D., James, K.E., Radford, M.J., Rickles, F.R. & Redmond, N. Initiating and maintaining patients on warfarin anticoagulation: the importance of monitoring. J. Cardiovasc. Pharmacol. Ther. 4, 3–8 (1999).

Ansell, J. et al. Managing oral anticoagulant therapy. Chest 119 (suppl. 1), 22S–38S (2001).

Ageno, W., Squizzato, A., Dentali, F. & Crowther, M. Tailoring warfarin induction doses to reflect individual and disease-specific factors. Am. J. Med.118, 143–144 (2005).

Lenzini, P.A. et al. Optimal initial dose adjustment of warfarin in orthopedic patients. Ann. Pharmacother. 41, 1798–1804 (2007).







It is time to get mad [Mary Meets Dolly]

Posted: 03 Sep 2008 02:35 PM CDT

I was on Sacred Heart Radio again this morning and I was asked a great question, "What do you think it will take to convince embryonic stem cell research supporters that adult stem cell research is not only morally more commendable, but also more successful?"

I gave a mediocre answer about being vocal and holding the media accountable for their lopsided coverage of the advances in both arenas. As I sat there after, I realized that I wished I would have given the following answer instead.

Nothing is more powerful than a person with paralysis, or diabetes, or Parkinson's or heart disease speaking out and demanding that public money and attention be paid to research and therapies that are already treating patients or are in human clinical trials. If I was suffering from a disease, I would be hopping mad that any taxpayer money was going to fund things like human cloning because it is a field that is decades behind adult stem cell research. Imagine how much faster cures would come if that 3 billion dollars that California has earmarked for stem cell research was put into ethical research instead of paying scientists to tinker around with human cloning for the next 20 years.

If society is to know that adult stem cells are the way to go, those with diabetes, Parkinson's, cystic fibrosis, blindness, Alzheimer's, lupus, sickle cell anemia, autism (and the list goes on and on) have to get mad and DEMAND it.

Interview With Forensic Genealogist Colleen Fitzpatrick, Ph.D. [The Genetic Genealogist]

Posted: 03 Sep 2008 12:42 PM CDT


Colleen Fitzpatrick, Ph.D. is one of the most recognizable names in the field of forensic genealogy.  She has authored two books entitled Forensic Genealogy and DNA & Genealogy, and continues to make headlines in this fascinating field.  Here is just an excerpt from her biography, located at her website:

“Colleen Fitzpatrick, Ph.D., is the author of two of the best-selling books in genealogy.  Forensic Genealogy has been widely recognized for its innovative forensic science approach to genealogical research.  She has been featured on NPR’s Talk of the Nation radio program (July 2005), and has written cover articles for Internet Genealogy (June 2006), Family Tree Magazine (April 2006) and Family Chronicle (October 2005).  Colleen writes a regular column for Ancestry magazine.”

Colleen’s work has been very much in the news during the past few weeks as a result of the a project to identify human remains found at the site of a DC-4 airliner that crashed on March 12, 1948.  As a result of this project, the remains were identified as belonging to Francis Joseph Van Zandt, a 36-year-old merchant marine from Roanoke, Virginia.  The story was picked up by hundreds of newspapers - see the Washington Post and Anchorage Daily News stories here, for example.  An MSNBC video is available here.

I recently had the opportunity to interview Colleen about the “Hand in the Snow” project, and about some of the other projects she has or is currently working on, including identifying Titanic remains, and potentially identifying the fate of Amelia Earhart.

The Genetic Genealogist:  You are the Principal Genealogist for the Armed Forces DNA Identification Laboratory in Rockville, Maryland, and you were recently part of a press conference to discuss efforts to identify remains of a serviceman who died in the crash of Northwest Flight 4422 in 1948. What can you tell us about this work?

clip_image006Colleen Fitzpatrick:  By far, the most meaningful moment of my life was last March when I stood in front of the Conway tombstone in the Mount Pleasant Cemetery, Askeaton, Co. Limerick, Ireland.  It read “Dedicated by John Conway, Mount Pleasant, in honor of his dear father and mother who died in 1853, aged 53 years.  Also his wife Ellen and her children Michael and Lizzie.” Our search for the identity of the remains found in the crash of Northwest Flight 4422 was at an end. It had been a long journey to this moment- almost nine years to discover the link between the Conway family of Askeaton and the frozen hand and arm found in the snow of the plane that crashed in 1948 in a remote area of Alaska.

Our investigation team was composed of the top experts in the field of DNA analysis, fingerprint identification, and forensic genealogy.  The key to our success was that not just that our team members were accomplished scientists and genealogists, but also that we were all dedicated to working together to making an identification. We worked side by side with no rivalry.  Each of us competed only with himself to do his best.  There were many times each of us faced discouragement, but everyone was determined to do everything possible to identify the remains of the serviceman who died in the accident.

As we eliminated one passenger on the plane after the other, through fingerprints, through DNA analysis, or through both, the possibility occurred to me, as it did to each of us, that we might never find a match.  It was possible that there was someone onboard who was not listed on the passenger manifest - perhaps a CIA agent.  Another possibility was that the victim’s female line had died out - that there were no living family members to use for a mitochondrial comparison. If so, a DNA match would be impossible, and if the victim did not have a fingerprint card archived by the military, there would be no fingerprint comparison to fall back on. Still another possibility was that one of the passenger's family members had not been honest and had submitted a DNA sample from a friend or another relative, producing a non-match where the results should have been otherwise.  In all of these cases, the hand and the arm would probably remain unidentified forever. We all held our breath.

clip_image008Finally on Thanksgiving Day 2008, our search was over. My forty years' experience with Irish genealogy, combined with a lot of creative thinking and persistence, paid off. We obtained a mitochondrial DNA match between the remains and Maurice Conway, a retired maintenance supervisor I had located in Askeaton, Co. Limerick. Maurice was a distant cousin of Francis Joseph Van Zandt along the exclusively female line of his family. Frank was the second to last passenger we had left to investigate. Even better, Maurice proved to be a double match to the remains – not only did his mtDNA match Frank’s exclusively female line, but his Y-DNA matched that of the descendants of Frank's maternal uncle from upstate New York. In the meantime, a fingerprint match was made between the hand and Frank's military records, for a triple confirmation that the remains were those of Van Zandt. This was the best we could have ever hoped for!

The publicity we have received announcing our success has been overwhelming to me. The news of our press conference was published by the Associated Press and was picked up by 300 newspapers worldwide. A video clip of the conference was shown on both MSNBC and CNN. Feature articles are now coming out– two appeared just this week in the Irish Daily Mail and the Irish Independent. There is even a documentary planned for the coming year.

Yet amid all of the excitement, our team has not lost sight of the purpose of our investigation. It had been judged impossible to identify the arm and hand through DNA or fingerprint analysis because they had been embalmed and were severely degraded and contaminated by bacteria. Yet AFDIL devoted much time and effort to developing new techniques for teasing out DNA from the remains, hoping that these techniques could be used to identify nearly 900 embalmed remains of unidentified Korean War veterans buried in the Punchbowl Cemetery in Honolulu. Our fingerprint experts developed new techniques to rehydrate the hand that led to the oldest fingerprint identification ever. In the end, the hard work of our world-class team of DNA analysts, fingerprint experts, and forensic genealogists was rewarded with success. It was thrilling to be part of a team that had accomplished the impossible.

TGG:  Stay Tuned for Part II tomorrow!

I see PLoS in everything III: PLoS Hats [The Tree of Life]

Posted: 03 Sep 2008 12:26 PM CDT

Thanks to my mom for this one.  PLoS Hats rule.

Science Blogging 2008 [Sciencebase Science Blog]

Posted: 03 Sep 2008 09:02 AM CDT

sciblog-2008-logoFirst off, just to say thanks to everyone who made sciblog2008 possible, already looking forward to its successor ScienceOnline2009. It was fun to put faces to names of many of my fellow science bloggers and others out there who were at the Ri on Saturday. Quite amazing how so many look as young as their avatars! The conference, the breakouts and the unconference were fun and informative albeit if a certain keynote speaker was wont to use rather too many expletives (is that how conferences are these days?)

Anyway, speaking of how conferences are “these days” it was interesting to see just how much of the interaction at the conference went on online - through liveblogging - even between delegates sitting in the same room. Funny to see someone type and another raise an eyebrow in response. It was a bit like passing secret notes around the classroom, except the whole science blogosphere beyond the hallowed halls of the Royal Institution [why cerise seatcovers, why?] was reading those notes.

In particular, several bloggers were commentating on happenings via the sciblog08 FeedFriend room. Me, I didn’t even have my mobile phone switched on the whole day (it was Saturday, after all). I’ve no intention of duplicating the efforts of those Feedfriends nor of the various Nature bloggers and staff who have reported, blogged, and podcast the event and will soon be vidcasting it. Great logo by the way Euan, been there, done that, got the teeshirt.

However, I do want to raise the possibility of a mashup that occurred to me during the unconference thread on tracking conversations through the blogosphere. Cameron Neylon mentioned (previously known as, and their DOI-citation capture system. Egon Willighagen and others mentioned Chemical Blogspace (Cb) and Adie’s Postgenomic (Pg) together with the Zemanta plugin and Mozilla Ubiquity. Willighagen has already written a post-conference script to act as a handler for DOIs, I see.

But, it was
unconference discussion
that got me thinking
it was the unconference discussion that got me thinking that a science-specialised version of Zemanta and/or Ubiquity could monitor your latest blog post and on the basis of the names and keywords it sees as you type could suggest likely literature references. It would be a straightforward matter to display the titles of all relevant papers and as you blog you could add a star to the main paper about which you’re righting and tick any others that might be worth citing in the post.

A blog plugin could then fetch the formated reference and paste into the foot of the blog post automatically, perhaps flagging your post once you hit “publish” in Connotea too. This way you would not have to remember to visit nor have to be able to locate the DOI for pasting into their citation wizard the Science-based Zemanta tool would do the job for you.


Science Blogging 2008

Drug information for ordinary people in PubMed [Discovering Biology in a Digital World]

Posted: 03 Sep 2008 08:11 AM CDT

PubMed is an on-line database at the National Center for Biotechnology Information (NCBI) that contains information from scientific literature. Most of the information is related to medical research.

To search PubMed, you use a program called Entrez. You go to the NCBI, select PubMed from the menu, type words into the text box, and start the search. Sometimes that's all you need to do. Sometimes you get several million results and need to use more specific words to limit the results the ones that you really want.

Many scientists use PubMed on a daily basis. But the NCBI has noticed that ordinary people also use PubMed to find information. Last fall, they added a really nice feature that makes PubMed more useful and accessible for non-scientists.

Read the rest of this post... | Read the comments on this post...

A Presidential Candidate on Science Policy [Bitesize Bio]

Posted: 03 Sep 2008 05:53 AM CDT

Late last year, a handful of individuals spawned an idea, calling for a presidential debate on science in the United States. They started a website and called it Science Debate 2008, and received a vocal response.

For much of the last ~9 months since then, it seemed that the candidates from both parties were intent on ignoring such a call (or at least that was my cynical impression). It almost seems that one requisite for political advancement is to pander to opponents of scientifically-sound public health, science education, climate change mitigation, energy, environmental protection, and research policies. Even the Democratic candidates do so.

But lo and behold!, Barack Obama has responded to 14 ScienceDebate questions. And his answers are even halfway decent!

dr-presidentWhat do Obama’s responses tell us about him and his support of scientifically-sound policies? Well, not necessarily that he is personally good on science - but he does apparently know how to hire decent scientific advisers, and listen to them. That is huge.

Specifically, when asked about scientific integrity, he affirms that he will:

  • Appoint individuals with strong science and technology backgrounds and unquestioned reputations for integrity and objectivity to the growing number of senior management positions where decisions must incorporate science and technology advice. These positions will be filled promptly with ethical, highly qualified individuals on a non-partisan basis.
  • Establish the nation's first Chief Technology Officer (CTO) to ensure that our government and all its agencies have the right infrastructure, policies and services for the 21st century. The CTO will lead an interagency effort on best-in-class technologies, sharing of best practices, and safeguarding of our networks.
  • Strengthen the role of the President's Council of Advisors on Science and Technology (PCAST) by appointing experts who are charged to provide independent advice on critical issues of science and technology. The PCAST will once again be advisory to the president.
  • Restore the science integrity of government and restore transparency of decision- making by issuing an Executive Order establishing clear guidelines for the review and release of government publications, guaranteeing that results are released in a timely manner and not distorted by the ideological biases of political appointees. I will strengthen protection for "whistle blowers" who report abuses of these processes.

Not bad. But check the rest of Obama’s answers out… and also be sure to ask John McCain why he won’t take the same test.

reporter gene normalization [Reportergene]

Posted: 03 Sep 2008 03:27 AM CDT

Reporter gene normalization on google chrome browser

AKA, how to warp keywords to trap new visitors
(yes, today I'm evil)

PubSurg and HealthMash [ScienceRoll]

Posted: 03 Sep 2008 02:50 AM CDT

PubSurg is a dynamic Pubmed link collection for minimal invasive surgery created by Attila Dubecz, a surgeon currently working at University of Rochester.

HealthMash will be a medical metasearch engine:

“The mission of HealthMash Health Knowledge Base is to promote health and well being in the world by providing personally relevant information of high quality from trusted health sources on the Web.” HealthMash will be powered by an innovative Health Knowledge Base that captures the expertise of medical professionals as well as the wisdom of people everywhere practicing the art of living and healing. HealthMash will combine sophisticated Web 2.0 universal search and discovery technology with Semantic Web concepts in a simple yet highly informative user interface.

Processed Food Makers Cut Corners As Prices Rise [Highlight HEALTH]

Posted: 02 Sep 2008 09:19 PM CDT

Do you read labels at the supermarket? If you do, you may soon notice changes in the ingredients of some of the foods you buy. Food makers are quietly substituting cheaper ingredients in processed foods to offset the high price of commodities.

The Wall Street Journal took note of this trend last weekend, reporting that Food Makers Scrimp on Ingredients In An Effort to Fatten Their Profits [1]. However, that may be overstating their intentions. With high fuel prices driving up the cost of basic ingredients such as sugar and wheat, food companies are are forced to make a choice: raise prices or cut corners. Because competition in the industry is so strong, raising prices is the last thing food companies want to do. Instead, they look to the quality and quantity of the ingredients they use [2]. For example:

  • Kraft Miracle Whip now contains more water
  • Nestle snack products now contain less milk
  • Sara Lee has switched to cheaper wheat for some breads
  • Mars Inc. is reducing the size of its Funsize candy packs
  • Hamburger Helper products have reduced the number of spice and ingredient pouches
  • Some of Hershey’s chocolates are now being made with vegetable oil instead of cocoa butter
Food Label

While some companies are adding fillers or cheaper ingredients, others are simply trimming manufacturing costs to save money. Food makers that are changing ingredients insist that they aren’t sacrificing quality or nutritional value. That may be hard to swallow, given that they’re reducing ingredient quality and quantity. Although it’s not hard to imagine smaller quantities (and thus lower calories) making a positive impact on health, the WSJ article cited at least one change that doesn’t result in a healthier product: making chocolate with vegetable oil instead of cocoa butter. Indeed, by replacing cocoa butter with vegetable oil, Hershey’s is lowering the overall health benefit of chocolate. Why? Because a number of epidemiologic studies have shown that cocoa, rich in flavonoids, has a number of cardiovascular health benefits [4-5].

The question is, will consumers be sensitive to the nutritional affects of these kinds of changes?

Not really, according to Harry Balzer of the NPD group, a market research and industry tracking firm [3]:

Consumers read labels. About half of all Americans say they routinely read labels on food products. So, I’d say yes, but the question really is ‘are they going to alter their behavior because of the reading the label’. Our experience has been no. Health in this country is really a secondary issue, a secondary concern. The primary concerns are taste, cost and ease.

What can health-concious consumers do? Keep in mind that these changes are occurring in processed foods. Food processing tends to lower the nutritional value of food, and processed foods often have a higher ratio of calories to other essential nutrients than unprocessed foods. Simply by reading this article you’re aware that cheaper ingredients are being used in processed foods — review your labels carefully.

Your best bet? Stick with fresh fruits and vegetables. A diet rich in fresh fruits and vegetables is important for maintaining good health. When fresh produce isn’t available, frozen and canned fruits and vegetables are a good option. Canned vegetables don’t taste as good as fresh and typically aren’t as nutritious, but it’s better than not eating vegetables at all. Fruits and vegetables contain essential vitamins, minerals and fiber, and increased consumption lowers your risk of developing several cancers.

Additional resources can be found in the Nutrition category of the Highlight HEALTH Web Directory.


  1. Food Makers Scrimp on Ingredients In an Effort to Fatten Their Profits . The Wall Street Journal. 2008 Aug 23.
  2. Secret ingredient? A cheaper substitute. Marketplace Morning Report, Marketplace, American Public Media. 2008 May 9.
  3. ‘Marketplace’ Report: Check Your Spices. Day to Day, Marketplace, American Public Media. 2008 Aug 25.
  4. Engler and Engler. The emerging role of flavonoid-rich cocoa and chocolate in cardiovascular health and disease. Nutr Rev. 2006 Mar;64(3):109-18.
    View abstract
  5. Erdman et al. Effects of cocoa flavanols on risk factors for cardiovascular disease. Asia Pac J Clin Nutr. 2008;17 Suppl 1:284-7.
    View abstract
Thank you for subscribing by RSS or email. I work hard to make the articles on Highlight HEALTH engaging and I truly appreciate your interest and readership!

This article was published on Highlight HEALTH.

Other Articles You May Like

The Big Pimpin’ Gene []

Posted: 02 Sep 2008 09:16 PM CDT


New Scientist reports that researchers at the Karolinska Institute in Stockholm, Sweden have found that the number of copies of a gene called RS3 334 is linked to how well men bond with their mates. As it turns out, men can have none, one or two copies of RS3 334, and the less they have, the more likely they are to sleep around.


Okay, are we the only ones to see a huge market opportunity here? Anybody at 23andMe listening? Product idea: Fidelity Spit Kit. (Props: cool image quoted from David Cutter)

Science Poll [Bayblab]

Posted: 02 Sep 2008 09:16 PM CDT

By a show of hands, would you rather:

- Keep working on a problem even if you might never find the answer, because you like the pleasure of figuring things out yourself.

- Be given the answer to your problem that has eluded you for awhile, even if it means you'll have to admit defeat and work on something else.


No comments: