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Zach Gaskin is presenting "The DNA Witness" at the California Association of Criminalists Semi-Annual Seminar, which is being held from October 7-11 at the San Diego Sheriff Department's Crime Laboratory (where he used to work I believe):
http://www.cacnews.org/wordfiles/fall%202003seminarschedule.xls
Polite company and board monitors prevent me from saying what I think about the shenanigans this weekend! I still have all my shares and will be hopefully participating in the PP.
shenanigan
n. Informal
A deceitful trick; an underhanded act.
Remarks intended to deceive; deceit. Often used in the plural.
Here is another one that concludes that genetic profiles can define optimal platinum/paclitaxel-based chemotherapy - the GSTM1 and GSTT1 polymorphisms described are both mentioned in DNAP's Paclitaxel responsiveness patent.
Medeiros R, Pereira D, Afonso N, Palmeira C, Faleiro C, Afonso-Lopes C, Freitas-Silva M, Vasconcelos A, Costa S, Osorio T, Lopes C. Platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma: glutathione S-transferase genetic polymorphisms as predictive biomarkers of disease outcome. Int J Clin Oncol. 2003 Jun;8(3):156-61.
Unit of Molecular Oncology, Laboratorios-PISO 4, Instituto Portugues de Oncologia-Porto, R. Dr. Ant. Bernardino Almeida, 4200-072 Porto, Portugal. ruimmms@mail.com
BACKGROUND: The glutathione S-transferases (GSTs) are a group of multifunctional enzymes that catalyze the conjugation of glutathione with a variety of electrophilic compounds, including cytotoxic agents. A significant percentage of normal individuals exhibit genetic polymorphism with a homozygous deletion (null genotype) of the genes, leading to absence of the enzyme. METHODS: In the present study we analyzed GSTM1 and GSTT1 polymorphisms in the genomic DNA isolated from peripheral blood of patients with ovarian cancer treated with chemotherapy (paclitaxel and cisplatinum) after cytoreductive surgery and assessed its correlation with the clinical outcome of these patients. The median follow-up for the patients was 30 months. RESULTS: The estimated 3-year survival rate was 59.8% for all patients and 20.8% for carriers of GSTM1-wt/GSTT1-wt (wt indicates wild type) genotype combination (37.7% for GSTM1-wt alone) compared with 83.1% for non-GSTM1-wt/GSTT1-wt genotype carriers (100% for GSTM1-null). The mean survival time was significantly better in patients who are carriers of the GSTM1-null genotype (40.5 vs. 33.5; P=0.006) or carriers of non-GSTM1-wt/ GSTT1-wt genotypes (55.4 vs. 30.7; P=0.009). The progression-free interval was more favorable for GSTM1-null carriers (41.9 vs. 27.4; P=0.024). CONCLUSION: The study suggests that characterization of the drug-metabolizing genetic individual profile can be of great interest in clinical oncology. It can define the optimal chemotherapy for each patient, improve the efficiency, and reduce the incidence of drug toxicity and poor drug responses.
Here is a positive phase III clinical trial result for paclitaxel plus carboplatin (TC) in comparison with paclitaxel plus cisplatin (PT) - Ovanome is concerned with TC response.
du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S, Bauknecht T, Richter B, Warm M, Schroder W, Olbricht S, Nitz U, Jackisch C, Emons G, Wagner U, Kuhn W, Pfisterer J; Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003 Sep 3;95(17):1320-9.
Department of Gynecology and Gynecologic Oncology, Dr.-Horst-Schmidt-Kliniken, Wiesbaden, Germany. dubois.hsk-wiesbaden@uumail.de
BACKGROUND: Despite considerable improvement in the treatment of advanced ovarian cancer, the optimization of efficacy and tolerability remains an important issue. Therefore, we performed a randomized, phase III non-inferiority trial comparing paclitaxel plus cisplatin (PT) with paclitaxel plus carboplatin (TC) in patients with advanced ovarian cancer. METHODS: A total of 798 patients with International Federation of Gynecology and Obstetrics stage IIB-IV were randomly assigned to receive six courses of either PT or TC at 3-week intervals. The primary endpoint was the proportion of patients without progression at 2 years. Secondary endpoints included toxicity, response to treatment, quality of life, and overall and progression-free survival time. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30, version 2.0. Survival curves were calculated using the Kaplan-Meier method, and hazard ratios were estimated using the Cox proportional hazards model. RESULTS: The proportion of patients without progression at 2 years was not statistically significantly different between the two treatment arms (40.0% for PT versus 37.5% for TC, difference = 2.5%, one-sided 95% confidence interval [CI] = - infinity to 8.2%). Median progression-free survival time in the TC arm (17.2 months, 95% CI = 15.2 to 19.3 months) and the PT arm (19.1 months, 95% CI = 16.7 to 21.5 months) were also not statistically significantly different; the same was true of median overall survival time (43.3 months, 95% CI = 37.2 to 47.8 months versus 44.1 months, 95% CI = 40.2 to 49.4 months, for the TC and PT arms, respectively). The TC regimen was associated with a higher frequency of hematologic toxicity, but a lower frequency of gastrointestinal and neurologic toxicity, than the PT regimen. Mean global quality-of-life scores at the end of treatment were statistically significantly better in the TC arm than in the PT arm (65.25 versus 51.97, respectively; difference = -13.28, 95% CI = -18.88 to -7.68). CONCLUSION: The TC regimen achieved comparable efficacy to the PT regimen but was associated with better tolerability and quality of life, and should, therefore, be considered as an important alternative for standard first-line chemotherapy in patients with advanced ovarian cancer.
Bag, indeed - assuming that AIMs are a prerequisite for the MALD method of course. There seem to be a lot of papers floating about talking about non-AIM approaches, and of course we do not have the patent yet anyway...
Jack, would be delighted if there was any collaboration between Michael Smith and DNAP (and more so if it involved Stephen O'Brien who is also at the NCI).
Jack, it's related to the following paper from 2001:
Smith MW, Lautenberger JA, Shin HD, Chretien JP, Shrestha S, Gilbert DA, O'Brien SJ. Markers for mapping by admixture linkage disequilibrium in African American and Hispanic populations. Am J Hum Genet. 2001 Nov;69(5):1080-94.
The MALD Paper link on this page:
http://rex.nci.nih.gov/lgd/front_page.htm
Takes you here:
http://rex.nci.nih.gov/lgd/pubs/2001.htm
From where the MALD Index page is linked.
Bag
1988 actually!
Chakraborty R, Weiss KM. Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9119-23.
He has indeed been at it a long time. Mark Shriver is no spring chicken though:
Shriver MD. Ethnic variation as a key to the biology of human disease. Ann Intern Med. 1997 Sep 1;127(5):401-3.
Shriver MD, Smith MW, Jin L, Marcini A, Akey JM, Deka R, Ferrell RE. Ethnic-affiliation estimation by use of population-specific DNA markers. Am J Hum Genet. 1997 Apr;60(4):957-64.
OT: Do not know what happened to the email - a glitch in the Universe!
From the PR in which DNAP announced that it would serve as a subcontractor for a new National Institutes of Justice (NIJ) research grant:
http://biz.yahoo.com/prnews/030825/flm007_1.html
"DNAPrint will apply its expertise in the measurement of population structure and genome screening to assist the NIJ and the grantee map genetic markers of a certain forensics value, considered by the Company to be complementary to its DNAWitness efforts."
We previously looked at current NIJ projects which might be relevant in this context. Another way to analyze potential interested parties is to look at who the NIJ has previously awarded grants to that are concerned with things like "markers", "population structure", and "ethnicity" in a forensic context. For instance, the following details NIJ Awards in Fiscal Year 1996:
http://www.ncjrs.org/txtfiles/165701.txt
The following three awards were made in the "Forensic Sciences" category:
95-IJ-CX-0007
Estimation of Population Structure Parameters
North Carolina State University
Bruce S. Weir
$26,000
This project is estimating the standardized variance of allele frequencies in several types of DNA data to describe the extent of population substructuring and to show how substructuring affects estimates of DNA profile frequencies.
95-IJ-CX-0008
Isolation and Characterization of Population-Specific Alleles
University of Pittsburgh
Mark D. Shriver
$100,000
A data base is being developed for estimating the ethnic affiliation of unknown suspects by typing a random sample of African American, Caucasian, and Hispanic residents from Pennsylvania for the identified markers.
96-IJ-CX-0023
Validation of PCR-Based DNA Typing Data Bases for
Forensic Use
University of Texas, Houston
Ranajit Chakraborty
$147,000
This study will develop automated methods of multilocus genotype-frequency computations for PCR-based DNA testing to increase the capabilities of crime laboratories.
Two interesting articles from the latest edition of Genetics in Medicine about race-based pharmacogenomics.
Condit C, Templeton A, Bates BR, Bevan JL, Harris AT. Attitudinal barriers to delivery of race-targeted pharmacogenomics among informed lay persons. Genet Med. 2003 Sep-Oct;5(5):385-92.
University of Georgia, Athens, Georgia; Washington University, St Louis, Missouri; and the University of Nevada, Las Vegas, Nevada.
SUMMARY: OBJECTIVES To ascertain attitudes of prospective patients relevant to the delivery of race-based pharmacogenomics.METHODS Written anonymous survey and qualitative responses in two sets of reactance format focus groups over-sampled for minority groups in urban, suburban, and rural communities conducted from February through April, 2002 [N = 104] and August through November, 2002 [N = 120].RESULTS Participants do not associate "races" exclusively with continental clusters. They have incomplete knowledge of their recent ancestors (39.6% do not know all their biological grandparents). They would be highly suspicious of race-labeled drugs; with 47.5% saying they would be very suspicious of their safety and 40.6% indicating they would be very suspicious of their efficacy. A substantial minority of African-American participants (13.2%) would prefer to take the drugs designated for European Americans. Effect of discussion of race-based medicine on racial attitudes is ambiguous.CONCLUSIONS Patient knowledge of ancestry and suspicion of race-designated drugs constitute substantial barriers that need to be incorporated in judging the likely effectiveness of race-based pharmacogenomics.
Bevan JL, Lynch JA, Dubriwny TN, Harris TM, Achter PJ, Reeder AL, Condit CM. Informed lay preferences for delivery of racially varied pharmacogenomics. Genet Med. 2003 Sep-Oct;5(5):393-9.
Greenspun School of Communications, University of Nevada, Las Vegas; the Department of Speech Communication, University of Georgia, Athens, Georgia; and Gainesville College, Gainesville, Georgia.
SUMMARY: OBJECTIVES To understand public perceptions and opinions of three options for prescribing medicine: individualized genetic testing, race-based prescription, and traditional prescription.METHODS Focus groups in urban, suburban, and rural communities over-sampled for minority groups conducted from February through April, 2001 in Georgia.RESULTS Group members (N = 102) identified individualized genetic testing as providing the best quality of care (60% of talk turns; 75% in postdiscussion anonymous survey), but stipulated the need for protection from the invasion of privacy, discrimination, and prohibitive cost. Most individuals chose genetic testing because it provided individualized attention, and African-Americans indicated they would choose genetic testing even if the costs were high. Overall, individuals were suspicious of race-based prescription. Analyses for degree of suspicion revealed a main effect for race and an interaction effect for race and gender.CONCLUSIONS If issues of cost, discrimination, and privacy are addressed, lay individuals prefer genetic testing as the basis for prescription of medicines that exhibit racially patterned response variation.
ifida, probably - poor old Hector is a bit longer in the tooth than these guys!
Here's a new one from Ramin Mirhashemi, who looks to have been genotyping again (tumors this time):
Mirhashemi R, Ganjei-Azar P, Nadji M, Lambrou N, Atamdede F, Averette HE. Papillary squamous cell carcinoma of the uterine cervix: an immunophenotypic appraisal of 12 cases. Gynecol Oncol. 2003 Sep;90(3):657-61.
Harbor-UCLA Medical Center, David Geffen School of Medicine, Department of Obstetrics and Gynecology, Box 3, 1000 W. Carson St., 90502, Torrance, CA, USA
The objective was to evaluate the role of human papillomavirus (HPV) in the pathogenesis of papillary squamous cell carcinoma (PSCC) of the cervix and to determine cell proliferative activity and p53 abnormalities in these rare variants of cervical cancer.Twelve examples of PSCC of the cervix were diagnosed between 1990 and 1999. Formalin-fixed paraffin sections of each tumor were stained by immunoperoxidase method using antibodies to p53 gene product (CM-10) and Ki-67 (MIB-1). In situ hybridization for HPV DNA (ENZO) was used to detect specific sequences of DNA shared by most types of genital HPV, followed by confirmatory PCR analysis. The nuclear staining for Ki-67 was graded as minimal (<10% of cells), moderate (between 10 and 50% of cells), and high (>50% of cells).Fifty-percent of the tumors showed presence of HPV DNA. Three tumors (25%) showed nuclear accumulation of p53. Moderate and high proliferative activity was observed in four and eight of tumors, respectively. Eight patients presented with stage IB1 tumor (67%), 3 with stage IA1 tumor (25%), and 1 with stage IIIA tumor (8%). Eleven patients (92%) were alive as of last contact with a mean follow-up of 34.2 months (range: 5 days to 84 months).In this series of patient, PSCC of the uterine cervix had a low rate of HPV DNA in their genome and a low rate of p53 gene abnormality. These genotypic differences may explain the differences between the clinical behavior of PSCC and the common types of squamous cell carcinomas of the cervix.
Interesting in its own right given that he is a DNAP scientific advisor.
What interests me more is why are Mirhashemi, Ganjei-Azar, Nadji, Lambrou and Averette (who are all at the University of Miami) working with UCLA? Atamdede was/is Chief Division of Gynecologic Oncology at UCLA. He is also on the faculty here:
http://www.cdrewu.edu/com2002/departments/obstetrics/faculty.asp
Look who is immediately above his details in the faculty list.
Here's a new paper that Chakraborty was involved with:
Zhou X, Tan FK, Wang N, Xiong M, Maghidman S, Reveille JD, Milewicz DM, Chakraborty R, Arnett FC. Genome-wide association study for regions of systemic sclerosis susceptibility in a Choctaw Indian population with high disease prevalence. Arthritis Rheum. 2003 Sep;48(9):2585-92.
University of Texas-Houston Medical School.
OBJECTIVE: Systemic sclerosis (SSc) is a complex, multisystem connective tissue disease in which genetic factors contribute to disease susceptibility. The aim of this study was to localize chromosome regions associated with susceptibility to SSc in a relatively isolated and homogenous population of Choctaw Indians with a high prevalence of SSc. METHODS: A genome-wide microsatellite screen at 10 cM resolution (400 markers) was performed in 20 Choctaw patients with SSc and 76 ethnically matched controls. Based on the results of the initial screen, fine-scale microsatellite mapping at </=1 cM resolution was performed in 10 selected chromosome regions. Allele and marker haplotype frequencies were compared between SSc patients and controls. RESULTS: From the genome-wide screen, 12 markers showed evidence of highly significant associations with SSc in this population (P < 0.01), while 5 other markers showed significant associations (0.01 < P < 0.05). Among these markers, loci D5S410, D6S422, D15S978, and D20S107 are near the SPARC, MHC, FBN1, and TOPOI genes, respectively, confirming the results of our previous studies, which used different markers. D1S2800 and D14S63 have been reported to show linkage to systemic lupus erythematosus (SLE) in family-based studies, and D1S206, D6S422, and D6S264 are loci on 1p21.2, 6p22.3, and 6q23-27, respectively, which are in regions reported as showing linkage to SLE and other autoimmune diseases. Other markers showing unique associations with SSc were D7S510 (7p12-11), D7S661 (7q35), D8S514 (8q24.12), D19S221 (19p13.2), D19S220 (19q13.2), D22S423 (22q13.1), DXS1068 (Xp11.4), and DXS8055 (Xq21-23). Further analysis with fine-scale microsatellite mapping revealed at least 14 potential haplotypes associated with SSc. CONCLUSION: Our findings indicate that a number of genetic loci may contribute to the high prevalence of SSc in the Choctaw and are consistent with the paradigm that some autoimmune rheumatic diseases are likely to share genetic determinants.
The reason this one is interesting is that other people seem to work in the same area and the following words keep appearing together: autoimmune disease, arthritis, SLE (lupus), admixture, ethnicity. For example:
Molokhia M, Hoggart C, Patrick AL, Shriver M, Parra E, Ye J, Silman AJ, McKeigue PM. Relation of risk of systemic lupus erythematosus to west African admixture in a Caribbean population. Hum Genet. 2003 Mar;112(3):310-8.
Parsa A, Peden E, Lum RF, Seligman VA, Olson JL, Li H, Seldin MF, Criswell LA. Association of angiotensin-converting enzyme polymorphisms with systemic lupus erythematosus and nephritis: analysis of 644 SLE families. Genes Immun. 2002 Oct;3 Suppl 1:S42-6.
(Collins-Schramm HE, Phillips CM, Operario DJ, Lee JS, Weber JL, Hanson RL, Knowler WC, Cooper R, Li, H, Seldin MF. Ethnic-difference markers for use in mapping by admixture linkage disequilibrium. Am J Hum Genet 2002 Mar;70(3):737-50)
Molokhia M, McKeigue P. Risk for rheumatic disease in relation to ethnicity and admixture. Arthritis Res. 2000;2(2):115-25.
mahastock, sorry been busy hiking in the mountains. I do not know how much they raised in the first PP, but presumably this will be in one of the 10Ks? Obviously they were overtaken by events and the predictions they made at the time did not hold water. Interesting that they viewed an IPO or secondary funding opportunity as the means to acquire more dominant market share though.
How do I see this PP being played in the plans of the company? Personally I think that they will use the funds (already) raised via the PIPE for one or more of the following: interest earning deposits, operating funds, capital purchases (e.g. the dedicated clinical genotyping machine) and M&A. They have more or less told us that they are going to acquire the drug pipeline, so I would expect acquisition of an existing Nasdaq entity, or equivalent which would enable them to relatively quickly reach that level in their own right. I still think there are also opportunities to acquire existing marketing and distribution mechanisms for some of the products if they are interested in taking this route.
RoyalDutchy, an interesting site, thank you. eom
One of their projects is particularly interesting:
http://research.marshfieldclinic.org/pmrc/pmrc_statin.asp
Statin-Induced Muscle Damage Project
Russell A. Wilke, MD, PhD
This study has been designed to determine if there is a genetic underpinning to a specific adverse drug reaction seen in a subset of patients taking atorvastatin (Lipitor) in order to lower their cholesterol.
The association between elevated serum cholesterol levels and recurrent coronary artery disease is well established. According to current guidelines, patients with coronary artery disease should work toward lowering their LDL cholesterol to a level below 100 mg/dl. Those who do not succeed with dietary therapy usually require additional help from a class of cholesterol lowering drugs called HMG CoA reductase inhibitors, or "statins." Atorvastatin (Lipitor) is the most commonly prescribed agent within this class.
In general, atorvastatin is very well tolerated. The most potentially serious adverse effect, liver damage, is extremely rare. Although slightly more common, muscle damage still occurs quite infrequently. The incidence of muscle damage has been reported to vary from 1 to 5% in patients taking atorvastatin. Although this problem usually resolves with discontinuation of the drug, some cases can progress to a more serious complication called rhabdomyolysis. Rhabdomyolysis can cause kidney failure and even death.
Most HMG CoA reductase inhibitors are metabolized in the liver. Molecular studies have revealed that some patients have an abnormal (polymorphic) form of the gene which codes for the hepatic metabolizing enzyme resulting in altered enzyme function. It is plausible that patients expressing this abnormality would be at increased risk of developing muscle damage while taking atorvastatin.
We have therefore designed a number of studies to help determine if derangements in this gene structure predispose patients to the development of adverse drug events while taking atorvastatin.
Russell A. Wilke, MD, PhD is a physician in the Department of Internal Medicine, and Head of Pharmacogenetics in the Personalized Medicine Research Center. His MD was earned at the Medical College of Wisconsin, and he trained as an Internal Medicine Resident in the Clinical Investigator Pathway at the University of Wisconsin. Dr Wilke also has a PhD in Pharmacology and Toxicology. He has done postdoctoral research in both Physiology and Molecular Biology. His primary area of interest is in the field of preventive medicine.
The importance of craniofacial morphology (skull shape)
http://www.ornl.gov/ORNLReview/rev29_3/text/war.htm
The Face of Crime
Reconstructing a human from skeletal remains is a somber task for even hardened investigators. Skillful hands can never reassemble a lost life, but there is the chance that identifying an unknown victim could bring a killer to light and to justice.
In cases where no other identifying evidence can be found, forensic anthropologists can recreate the victim's face by modeling clay over the skull. Using pencil-eraser-sized rubber markers attached to the skull, an expert molds the clay into "average" cheeks, lips, and other features. With skill, some luck, and a victim who's close to "average," an identification can sometimes be made. Unfortunately, the odds are low and the cost is high: Only one in seven such reconstructions leads to a successful ID; on average, the work takes two months and costs $2500.
Dr. William Bass, Knoxville's well-known forensic pathologist, examines the skull of a murder victim. Bass has been with the University of Tennessee's Anthropology Department.
Murray Marks, associate director of the Forensic Anthropology Center at the University of Tennessee at Knoxville (UTK), figured advanced technology could improve the process. Professor Marks had good reason to trust technology: his predecessor at UTK, William Bass, spent years pioneering physical and chemical techniques for identifying skeletal remains. (In the process, Bass became something of a legend, eventually inspiring Patricia Cornwell's 1994 novel The Body Farm; in fact, two characters in the book are modeled after Bass and Bohanan, and the "body farm" in the book is UTK's Anthropological Research Facility.) The collaboration Marks proposed to ORNL was not physical or chemical, but computational.
"Over the years, anthropologists have identified the thickness of tissue on a limited number of places on the skull," explains Marks. "It was clear that if we had more measurements, we could do a better job of reconstructing a face. One of the things that a computer can do very well is take many measurements."
At ORNL Marks met up with biologist Richard Mural and computational biologists Reinhold Mann and Ed Uberbacher, who were working on the problem using ORNL's supercomputers. From the outset, the researchers knew they needed better data to work with. "Using average tissue thickness is not very accurate because there's a lot of variation around 'average,' " explains Uberbacher. "If you put an 'average' nose on someone like me, for instance, I'd be unrecognizable," he says. The tissue-thickness data typically used for facial reconstruction come from a limited number of measurements taken from cadavers a half-century ago. By taking measurements from hundreds of recent magnetic resonance imaging scans of living volunteers, the ORNL researchers began to develop detailed predictions that consider age, gender, and ethnic origins.
Next, instead of basing the reconstruction on only a dozen or so points, they used the computer to plot thousands of points so the surfaces of the face would be mathematically based on the shape of the entire skull, not just a few landmark points directly below the skin.
Even the computer became more accurate over time, learning from its experience how to better predict a face. "We can program the computer to combine information to predict an outcome in much the way a child learns," Uberbacher explains. "It's like learning the difference between a cat and a dog. A one-year-old child often gets the two confused. That's understandable—four legs, tail, fur, ears. With experience, though, the child gathers more information—shape, meow—and draws better conclusions." Using case-based reasoning, ORNL's computers can do the same thing, combining information from the database into a composite—matching this forehead and that jaw, say—to reach more accurate conclusions about the shape of the face of an unknown victim.
ORNL and the University of Tennessee are working together to apply advanced computing and artificial intelligence to rapidly and inexpensively reconstruct faces of murder victims from their skeletal remains. Starting with an unidentified skull, the new technology is expected to predict the most probable face for the victim; identify gender, race, and age; match police photo books; and factor in genetic markers or DNA sequences that could be used to predict the victim's appearance.
Today, it takes supercomputers like ORNL's Intel Paragon XP/S 150 to sift through gigabytes of data and create a three-dimensional image. But as the system is refined, Uberbacher, Mann, Mural, and Marks expect the time and cost of computerized reconstruction to drop dramatically: from a couple of months and $2500 to a couple of hours and $25. That would allow facial reconstruction to be widely used on unsolved crimes. New virtual reality features that allow forensics experts to add or subtract 20 years or 20 pounds with a keystroke should soon make results even more realistic. And remote access, by which scans of a skull can be e-mailed for face reconstruction, will make the technique available even to smaller police departments.
http://www.courttv.com/news/2003/0718/doesketches_ctv.html
Whereas police sketch artists often compile portraits from a laundry list of features — the type of nose, mouth, hair — artists who render the unknown dead in three dimensional busts typically work from the inside out, envisioning how muscles, tendons, fat and skin all sit together on a foundation of bone.
Tissue depth charts tailored to ethnicity, age and weight can help determine the rough structure of the Doe's head, but the fine shape of the face, which can be crucial for sparking recognition in a family member, friend or witness, is largely left to the artist's intuition.
That's the process that yielded the first sketch and clay bust of the Precious Doe. But none of the more than 1,000 leads panned out, and by 2003, the Doe's case had grown cold.
This July, however, the search for Precious Doe's identity was revived, in part because of the promise of a new effort from a pioneering Louisiana reconstruction laboratory armed with pinpoint data on tissue depths for black children.
"I still believe somebody out there somewhere knows this child," said Sergeant David Bernard of the KCPD. Bernard and his team have been frustrated by a series of near-matches, but remain hopeful that this reconstruction will trigger a recollection in the right person. "We'll keep going until we find the right one," he said.
At Louisiana State University's Forensic Anthropology and Computer Enhancement Services lab, or FACES, forensic anthropologist Mary Manhein uses computer animation techniques and engineering software that would normally be too expensive for police to wield themselves.
On July 14, Manhein flew to Kansas City for the exhumation of Precious Doe, and carried her skull back to her Louisiana lab to begin the analysis.
Manhein first scanned the exterior of the skull with lasers to produce a 3-D model in plastic resin. That model will serve as a framework for her artist, Eileen Barrow, who will apply clay to flesh out the model.
"This will be the fourth and, we hope, last image made of Precious Doe," said Manhein.
Barrow will have a lot more than just the model of the skull to work from. Manhein's lab, which has produced more than 40 reproductions, has researched tissue depth markers to more accurately gauge the skin contours that determine the person's outward appearance. Forensic artists rely heavily on tissue depth charts for clues on how the musculature and other tissues affect the surface structure of someone's face.
The set of data Manhein plans to apply to Precious Doe is the most comprehensive tissue depth database of its kind in the country. Taken with ultrasound tools from almost 1,000 black children, it marks a shift in the way that such data are collected.
Tissue depths were once harvested solely from cadavers, and in fact many of the most popular data sets still rely on those antiquated measurements.
Tissue depth sets are now being taken from volunteers using sophisticated medical techniques, however, and the subtle differences in skin tension and gravity that result from having a living, standing subject can make all the difference in a Doe's reconstructed appearance.
Not only is the data becoming more precise, researchers like Manhein are also tailoring it to particular ethnicities and ages. Most victims, including Precious Doe, can be placed in a particular group through flesh remaining on the skeleton or through DNA and dental records. The more precise the data, the more accurate the reproduction.
"Without those depths you're just applying clay onto a structure, you're blind," said Barbara Martin, a forensic artist with the Oakland County Sheriff's Department in Michigan. "Leonardo, Michelangelo and DaVinci did studies on how veins and muscles and flesh tie together across the structures. They managed to breathe life back into the face. And that's exactly what we try to do."
John and Jane Doe Go Hollywood
Sketching and sculpting has largely remained the same since Renaissance days, but a pioneering British lab is working to give facial reconstruction a 21st-century makeover.
"Instead of modeling muscles in clay we model them by computer, in virtual reality," said Martin Evison, a senior lecturer in forensic and biological anthropology at Sheffield College in England. "The artistic skills are the same, but the artist works with a computer, keyboard, and tablet rather than with a bag of clay."
After scanning a skull much like the FACES lab does, Evison uses his proprietary software program to digitally re-create the detailed cranio-facial anatomy, from tendons all the way up to the skin, hair, and eyes. He can then morph the computer portrait through different age progressions, different weight levels, and can even blend tissue depth data to accommodate Does with mixed racial ancestry.
The goal: Showing potential family members and acquaintances a range of versions, hoping that one will click.
Other computer systems, including one used by the National Center for Missing and Exploited Children, work in two dimensions, "connecting the dots" by matching tissue depth data to a database of images.
Evison's team has worked since the mid-90s to construct a flexible system that takes advantage of the same commercial modeling systems that are industry-standard software for rendering three-dimensional architectural structures and movie special effects. The group is also seeking to distribute the fully rotatable images via the Internet.
Their results only stand to improve: This year, the Royal Society of London presented Evison's lab with a grant to use magnetic resonance imaging, or MRI, to collect even more data on living volunteers. The whole system should be up and running—and available for police departments around the world—in two or three years, Evison says.
End of article
Two interesting articles. So if we have a physical skull and have some idea about age, weight, ancestry etc then it seems that the technology is almost there to draw an electronic representation of that person's face. Age, weight, and ancestry are of course determinable from DNA markers (or telomeres in the case of age). So, if we had DNA markers for skull dimensions then potentially we can just use that as the starting point rather than a physical skull.
This article has already been posted previously:
http://web.dailytimes.com/story.lasso?wcd=7201
On Friday, the Kerr County Sheriff’s Department and Sid Peterson Memorial Hospital facilitated a presentation by a DNA analyst from the Texas Department of Public Safety crime lab in Austin to update police, prosecutors, nurses and victims’ advocates on forensic DNA analysis procedures and explain how to handle evidence before sending it to the lab.
DNA analyst Karin Scalise began the presentation describing upcoming advances in the field. Determining eye color and races of suspects based on genetic markers were upcoming, she explained, as was building a digital "picture" of a person based on markers for skull dimensions.
Because of the Human Genome Project, the field is wide open, and the potential for it to revolutionize police work continues.
Scalise told of a case in Lousiana in which a rape victim described a white male suspect in his early 30s, but DNA tests showed a black man in his early 40s.
Note that Karin refers to MARKERS for skull dimensions. And where did Karin hear about these advances?
http://www.afdaa.org/mminutes5.html
"T. Frudakis of DNAPrint Genomics presented on 'New tests for genomics-based physical profiling: case study'. This presentation focused on the use of a genetic panel used to give investigative leads in cases based on genetic information. This type of testing is used for customizing medication to specific patients and could be used to produce a 'physical profile' of a suspect in cases where DNA has been left at the crime scene. This technique was recently used in the serial murder investigations in Louisiana."
"As the meeting resumed, the floor was opened for nominations for the office of Chair. Karin Scalise nominated..."
Early, you are right, it is pure supposition that 8 million has been placed. You would expect that some (if not most) of it has but there is no evidence of this.
Dick, I don't think they have let you down as such, but at the same time they certainly haven't bent over backwards on your behalf. I haven't sold any of my shares.
Chris, nothing has fundamentally changed. All of the things that W2P itemized are pending. The PP has already largely occured. At the end of the day DNAP are debt free with money in the bank and the luxury of X years to try to realize their business plan. The sort of delays that we have seen to some of the products are not untypical. At the same time there are things that the company could improve on, such as shareholder communication (notwithstanding the fact that there are possibly very good reasons why they cannot be too forthcoming at this exact point in time). They also operate in an environment where some very intelligent and high motivated people are working in a "competitive" manner - and good luck to them if they succeed in implementing things that are of medical benefit. In this context I personally think that there are potential opportunities and synergistic benefits in working with some of these people (especially the academic groups who are in the same spaces). As you know, things are not always entirely as they seem. Time will tell.
I am not sure whether this patent (which also refers to CETP in its current embodiment) is going to be a problem in the future:
http://l2.espacenet.com/espacenet/bnsviewer?CY=gb&LG=en&DB=EPD&PN=US2002164598&ID=US...
Method for evaluating and applying an individual’s genetic characteristics to determine response to cardiovascular medication therapy
DNAP are not the only people working on statin response classifiers.
Bernhard Winkelmann at the Cooperation Unit for Pharmacogenomics and Applied Genomics in Heidelberg seems to have some expetise in this area. The following article:
http://www.pharmaco-genomics.co.uk/admin/files/Winkelmann.pdf
Refers to this paper:
Winkelmann BR, Hoffman MM, Nauck M et al.: Haplotypes of the cholesteryl ester transfer protein (CETP) gene predict modifying response to statin therapy. Pharmacogenomics J. (2003) (In Press).
Another paper by Bernhard:
Marz W, Winkler K, Nauck M, Bohm BO, Winkelmann BR. Effects of statins on C-reactive protein and interleukin-6 (the Ludwigshafen Risk and Cardiovascular Health study). Am J Cardiol. 2003 Aug 1;92(3):305-8.
This report provides preliminary evidence that statins may lower C-reactive protein levels by interfering with the generation and/or release of C-reactive protein in the liver rather than by modulating inflammatory processes in the vessel wall.
So Bernhard seems to understand something of how statins work and says that haplotypes of the CETP gene predict statin response. By contrast, DNAP's approach can be ascertained from the WIPO patent COMPOSITIONS AND METHODS FOR INFERRING A RESPONSE TO A STATIN:
http://l2.espacenet.com/espacenet/viewer?PN=WO03002721&CY=gb&LG=en&DB=EPD
Methods for inferring a statin response of a human subject from a nucleic acid sample of the suject are provided, as are reagents such as oligonucleotide probes, primers, and primer pairs, which can be used to practice such methods. A method of inferring a statin response can be performed, for example, by identifying in a nucleic acid sample from a subject, a nucleotide occurrence of at least one statin response related single nucleotide polymorphism (SNP) and/or at least one statin response-related haplotype in a cytochrome P450 gene and/or and HMG Co-A reductase gene.
It seems that DNAP are not looking at the CETP gene?
OT: bag8ger, neither. From the following source are several definitions for iniquity:
http://dictionary.reference.com/search?q=iniquity
Gross immorality or injustice; wickedness.
A grossly immoral act; a sin.
Inequality, unfairness, injustice.
Absence of, or deviation from, just dealing; want of rectitude or uprightness; gross injustice; unrighteousness; wickedness; as, the iniquity of bribery; the iniquity of an unjust judge.
An iniquitous act or thing; a deed of injustice or unrighteousness; a sin; a crime.
A character or personification in the old English moralities, or moral dramas, having the name sometimes of one vice and sometimes of another.
A defect; a fault; an error; a blemish; an imperfection; as, the vices of a political constitution; the vices of a horse.
A moral fault or failing; especially, immoral conduct or habit, as in the indulgence of degrading appetites; customary deviation in a single respect, or in general, from a right standard, implying a defect of natural character, or the result of training and habits; a harmful custom; immorality; depravity; wickedness; as, a life of vice; the vice of intemperance.
Absence of moral or spiritual values; "the powers of darkness"
Morally objectionable behavior
An unjust act
Gurinder Shahi (DNA Phenomics Scientific Advisor) is a panelist at this conference at the end of October:
http://www.smu.edu.sg/oee/pdf/2003_IES_Managing_Emerging_Technologies.pdf
GURINDER SHAHI (CEO and Principal Consultant, BioEnterprise Asia) Gurinder Shahi is a physician with training in molecular biochemistry and in international health policy and management. He is a leading expert on change management and strategic program implementation in healthcare and the life sciences. He has played a key role in the development of several major international initiatives including the International Vaccine Institute (now based in Seoul, Korea) and the Asia-Pacific International Molecular Biology Network, and has served as advisor and consultant to leading international organizations, governments, corporations and foundations. He has also been actively involved in establishing and providing strategic and management input to a range of start-up enterprises including Lynk Biotechnologies, Asia Pacific Genomics, and DNA Phenomics, and in helping a growing number of US, European and Australian enterprises build their operations in Asia. Gurinder has authored over 50 articles, refereed journal papers and conference presentations, and served as lead editor for International Perspectives on Environment, Development and Health: Toward a Sustainable World (GS Shahi, BS Levy, A Binger, T Kjellstrom and RS Lawrence, Springer Publishing Company, New York, 1997). He is currently putting the final touches to his latest book, BioBusiness in Asia. [MBBS, PhD - National University of Singapore; MPH - Harvard University; Warren Weaver Fellow - The Rockefeller Foundation]
Linda, I agree with the view that the company has come up with a reasonable formula to raise funds and provide an opportunity for some large existing shareholders to avoid dilution. Not sure what the cut-off point is for participation in the placement, but clearly the small shareholders are not getting such a good deal - which illustrates the iniquity of this type of placement. I understand the reasons given for the way these things are done, but would personally prefer it if all shareholders were treated equally.
I would like to know how many shares were placed in the private placement prior to the offering to retail investors. Having read the executive summary I am still slightly disappointed at the (further) delay to Ovanome and Statinome (they now refer to it as Statinome rather than Statnome), and the seeming lack of any other products in the product pipeline beyond those that we already know about. I really think that it is time for a newsletter from the company.
Oh, and "OVANOME will be used to predict a patient’s genetic predisposition for response to the Taxol and Carboplatin drug combination." I rest my case.
Words of wisdom:
"If we have gone from 480 million shares to 530 million shares outstanding (the billion authorized is technically irrelevant until they are issued), then the market capitalization is 10% higher at the same share price.
Here is another anthropology initiative that DNAP is involved with - this one is concerned with researching the DNA of native peoples to see whether they have Chinese DNA:
http://www.1421.tv/pages/evidence/content.asp?EvidenceID=149
Use of haplotype analysis in muscular dystrophy
Bachinski LL, Udd B, Meola G, Sansone V, Bassez G, Eymard B, Thornton CA, Moxley RT, Harper PS, Rogers MT, Jurkat-Rott K, Lehmann-Horn F, Wieser T, Gamez J, Navarro C, Bottani A, Kohler A, Shriver MD, Sallinen R, Wessman M, Zhang S, Wright FA, Krahe R. Confirmation of the Type 2 Myotonic Dystrophy (CCTG)n Expansion Mutation in Patients with Proximal Myotonic Myopathy/Proximal Myotonic Dystrophy of Different European Origins: A Single Shared Haplotype Indicates an Ancestral Founder Effect. Am J Hum Genet. 2003 Sep 10
Section of Cancer Genetics, Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be approximately 200-540 generations.
Details for Ralph Krahe, the main author of the paper:
http://www3.mdanderson.org/~genedev/krahe.html
Ituccilnv, it is actually quite complicated, and I have yet to see a good summary of the process published anywhere! The "usual" process takes some 18 months, so we could say that some of our patent applications are getting close to the approval stage. However, this is a new area. At the risk of copyright infringement, Tony said the following in the TWST article about DNAP intellectual property:
"Yes, we have several patents that are in the process of review right now. The patent office doesn’t know how it is going to treat a lot of these patents. Some of our patents require a lot of DNA sequences and so we are not sure whether the final form of the patent will be a broad patent or whether it will be a patent that covers specific sequences. But we are starting broad and making the patent office restrict our focus."
"The patents we have written cover all of the little parts, the machinery of our platform. By the way, the platform is called AdmixMap and is composed of lots of little pieces, each of which is protected by a patent application."
Aha, they have had to refer to one of the "secret" ones!
There are various dates because the patents are added to over time, and so update previous versions, or claim the benefit of previous applications (as per 60/338,771 which was filed Dec. 3 2001). The two we see today are important (apart from any other reason) because, as W2P says, they are the first two visible on the US Patent & Trademark Office database.
OK, it was listed on the website but (presumably because it was provisional) it did not appear in any form anywhere else. This is of course presumably not one of the "other" patents that has been filed but the details of which are being kept secret at this time...
OT: W2P, perhaps just off the banana boat?
ifida, comprehensive is the word that comes to mind. I see that W2P has recognized the significance of this one - it is indeed the haploscope, and it was not listed anywhere previously.
4titudinous has posted details of two new patent applications on RB:
http://ragingbull.lycos.com/mboard/boards.cgi?board=DNAP&read=271840
In the first one (Methods for the identification of genetic features for complex genetics classifiers) a "systematic feature extraction process" is described (a haplotype hunter).
This patent application also contains the following phrase:
"Visually useful features such as nose shape, hair color and height are obvious to the lay person..."
This does not mean that they have a classifier for nose shape, but interesting that it is mentioned with hair color and height (rather than say eye color).
The second patent (Efficient methods and apparatus for high-throughput processing of gene sequence data) happens to mention topoisomerase 2a and 2b in one of the examples. They usually only mention things that they have worked on in examples. This particular one could relate to a number of things e.g. anti-tumor drugs.
OT GE it was a number of questions about SOPs, which have been answered subsequently courtesy of the Charlottesville Fire Department (who have their SOPs online):
http://www.cfdonline.org/sop.htm
mahastock, that is correct.
mahastock, no it has not been addressed to my knowledge. Options for addressing it would seem to include some sort of renegotiation to achieve a workable solution for both parties, or for DNAP to try to buy them out. There was a view that if Orchid were going to go bankrupt then the problem would disappear. This was always unlikely and is now definitely not going to happen so the problem remains. Orchid are not exactly getting anything for the premium they have paid so it must be in their interests to address this as well.
GE, we do not perform tests for Orchid. They have their own products (GeneScreen and Lifecodes) which they use for identification, paternity and forensic testing. Orchid paid DNAP for an option on certain of their products, which so far has not been exercised by Orchid (but has conversely has prevented prevented other deals being finalized with DNAP due to concerns by third parties about possible litigation by Orchid). A complicated situation and a lose-lose if ever I saw one. This option is one thing that still has to be addressed in some manner by the company.
GE, the SNP work is officially being done by Orchid e.g.
http://www.biomedcentral.com/news/20030909/04/
"So the team turned to other methods, such as mitochondrial DNA analysis, which is being performed by Celera Genomics, and single nucleotide polymorphism (SNP) analysis, which is being performed by Orchid Biosciences' GeneScreen."
However, this is utilizing SNP testing where traditional STR testing is not sufficient. At some stage, after concerted efforts with the various conventional testing approaches, there will still be a large number of unidentified DNA samples. I wonder whether DNAWitness might not be used for these to try to identify individuals based on ancestry and the other traits that are perhaps now available.