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Ann
This topic was the subject of this question on the list for the shareholders meeting:
9.b) Is there any update on the FAMRI sponsored project on genetic susceptibility to cervical cancer in second hand smokers in conjunction with the University of Miami that was the subject of the press release in February 2003?
Here is the original press release:
http://www.dnaprint.com/2003/pressreleases/pr_02_20_03.htm
Robert, the key thing is:
"The new offering is designed to accelerate the already encouraging rate of adoption by law enforcement of DNAWitness service technology."
Of course ultimately STRmap will itself be ASCLD accredited, at which point we might well see this product priced accordingly. For the time being it is a device to increase DNAWitness take-up (and revenue) which offers potential time advantages to investigators.
I don't think we knew previously that DNAWitness was being used in Canada...
Not to my knowledge. If there was an acknowledgement it would have gone to frog as he submitted the list, and I am sure that he would have told us if there was.
I would guess SNPs on the basis that you take a cheek swab rather than performing a biopsy to get a tumor sample (probably more "efficient" from the patient's perspective as well).
Another promising step. If you can correlate TP levels to drug metabolism and you can find markers that relate to TP expression, then you should be able to perform the same predictive test using SNPs rather than looking at tumor composition.
Ancestry Informative Markers again:
Seldin MF, Morii T, Collins-Schramm HE, Chima B, Kittles R, Criswell LA, Li H. Putative ancestral origins of chromosomal segments in individual african americans: implications for admixture mapping. Genome Res. 2004 Jun;14(6):1076-84.
Rowe Program in Human Genetics, Departments of Biological Chemistry and Medicine, University of California at Davis, Davis, California 95616-8669, USA.
Theoretically, markers that distinguish European from West African ancestry can be used to examine the origin of chromosomal segments in individual African Americans. In this study, putative ancestral origin was examined by using haplotypes estimated from genotyping 268 African Americans for 29 ancestry informative markers spaced over a 60-cM segment of chromosome 5. Analyses using a Bayesian algorithm (STRUCTURE) provided evidence that blocks of individual chromosomes derive from one or the other parental population. In addition, modeling studies were performed by using hidden real marker data to simulate patient and control populations under different genotypic risk ratios. Ancestry analysis showed significant results for a genotypic risk ratio of 2.5 in the African American population for modeled susceptibility genes derived from either putative parental population. These studies suggest that admixture mapping in the African American population can provide a powerful approach to defining genetic factors for some disease phenotypes.
I mentioned this article before:
Bonilla C, Parra EJ, Pfaff CL, Dios S, Marshall JA, Hamman RF, Ferrell RE, Hoggart CL, McKeigue PM, Shriver MD. Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping. Ann Hum Genet. 2004 Mar;68(Pt 2):139-53.
Now there is a letter pending in the Journal of Medical Genetics:
http://jmg.bmjjournals.com/future/
Relation of type 2 diabetes to individual admixture and candidate gene polymorphisms in the Hispanic-American population of San Luis Valley, Colorado
Esteban J Parra, Clive J Hoggart, Carolina Bonilla, Sonia Dios, Jill M Norris, Julie A Marshall, Richard F Hamman, Robert E Ferrell, Paul M McKeigue, and Mark D Shriver
Looks like this group is continuing their research in the San Luis Valley.
ifida, yes rings a bell.
"Of note, 18 patients treated with carboplatin were unable to move onto the next phase of the study because of hematologic toxicity, progressive disease, or other adverse events. For the same reasons, 6 patients on arm A, 10 patients on arm B, and 15 patients on arm C withdrew during the course of the randomized portion of the study. The researchers also discerned that shortness of breath was markedly increased (P = .001) in the gemcitabine arms and much more so in the weekly arm of the protocol."
Relatively high percentages of the patient populations concerned. Of course one of the projects underway in conjunciton with Moffitt is "taxanes". I wonder which ones.
New cancer treatments are coming made to order
http://www.usatoday.com/news/health/2004-06-02-cancer-treatments_x.htm
New cancer treatments are coming made to order
By Liz Szabo, USA TODAY
When Cecily Harris was diagnosed with lung cancer in 1998, the outlook was grim. A tumor near her shoulder grew so big that it broke a rib. Chemotherapy left her too sick to see her grandchildren. She was given nine months to live.
Today, Harris is alive, well and working full time. With her cancer stabilized, her doctor says, the disease has been transformed from a death sentence into a chronic disease.
"I feel as well as a 76-year-old can feel," says Harris, who is from Englewood, N.J. "I'm one of the lucky ones."
Indeed, few cancer patients are as fortunate as Harris. Fewer than 5% of those diagnosed with advanced lung cancer survive five years or more. And only 10% of those taking the same cancer drug, Iressa, see dramatic benefits.
But doctors hope one day to see more patients like Harris.
Experts say her story illustrates the profound changes taking place in cancer research as scientists strive to perfect the new field of personalized cancer treatment. Researchers plan to share the latest news about such "targeted therapies" at the meeting of the American Society of Clinical Oncology beginning today in New Orleans.
"Patient-specific therapy might be the only way we will make inroads into this disease," says Harris' doctor, Roy Herbst, chief of thoracic oncology at M.D. Anderson Cancer Center in Houston. "Every patient's cancer is a little bit different."
The new drugs aren't cures.
But with therapies such as Iressa, researchers are beginning to tailor cancer drugs based on the genetics of a patient's tumor cells. And in a new field called "pharmacogenomics," doctors are developing ways to predict which patients might benefit — and which might suffer serious side effects — from therapies.
It could take five years or so before a wide array of such treatments is available to the average patient, Herbst says. Some might not work out. Yet many experts presenting research at the cancer meeting are optimistic.
By individualizing cancer treatments, doctors say they hope to help patients and avoid some of the grueling side effects of broad-based chemotherapy. Herbst compared Iressa — which Harris began taking in 1999 — to a "laser-guided bomb."
Targeting tumors
Iressa is one of a growing number of drugs which — rather than kill growing cells throughout the body — binds to an enzyme called the epidermal growth factor receptor, or EGFR, and turns it off. The enzyme, which is common in many kinds of cancer, acts as a switch that tells cells to divide and spread without dying.
Recently, researchers discovered one reason why Iressa works so well for some patients, but not for others. Certain tumors have mutated versions of that growth switch, which are particularly vulnerable to Iressa. Doctors are developing tests for the mutation so they can give Iressa to patients who will benefit most, or give the drug earlier.
EGFR also might play a key role in tumors of the breast, colon, ovary, head and neck.
The EGFR enzyme, researchers believe, sets in motion a complicated chain reaction that leads cells to multiply, invade surrounding tissue, develop their own blood supply and spread to organs without dying.
Drugs such as Iressa attack the EGFR molecule on the inside of the cell.
Another drug approved this year, Erbitux, blocks part of the EGFR molecule on the surface of tumor cells.
Doctors say they hope to put together "cocktails" of such drugs, attacking vulnerable links throughout the chain.
'Right drug for the right person'
Scientists might never have expected chronic myeloid leukemia — a cancer of the blood — to have much in common with a rare digestive tract cancer called gastrointestinal stromal tumors, says Harmon Eyre, chief medical officer at the American Cancer Society. As it turns out, however, both diseases respond to a drug called Gleevec, one of the first targeted therapies.
Instead of classifying cancers by organ, doctors are beginning to group them — and develop drugs — based on molecular structures, Eyre says. Because doctors already know so much about EGFR, many new therapies focus on that enzyme, although there are probably dozens of pathways and potential targets.
At the New Orleans conference, doctors plan to reveal the results of combining Tarceva with a drug called Avastin, approved in February, that starves tumors by cutting off their blood supplies.
Doctors note that targeted therapies, like all drugs, have limitations.
Some patients have become resistant to Gleevec, for example. Many promising therapies have not lived up to expectations. And experts note that even with so many new drugs, doctors still don't have enough options for patients.
Doctors say they wish they had more to offer the majority of patients who don't respond to Iressa. "We're just touching the tip of the iceberg," Eyre says.
"The real test will be when we have the right drug for the right person for the right disease."
FDA, NIH Drive Clinical Genomics -- Is Widespread Application in the Near Future?
http://biz.yahoo.com/prnews/040602/new023_1.html
FDA, NIH Drive Clinical Genomics -- Is Widespread Application in the Near Future?
Wednesday June 2, 9:41 am ET
Emerging Opportunities and Strategies to Implement Genomics in Clinical Practice Are Analyzed in a New Cambridge Healthtech Report
NEWTON UPPER FALLS, Mass., June 2 /PRNewswire/ -- The promise of clinical genomics for improving drug development and enhancing health care is enormous, both from a medical and market perspective. Genomics offers the potential to improve both drug development and the practice of medicine by elucidating the mechanisms of drug action and response, predicting adverse drug reactions, and identifying compound failure earlier in the product cycle.
While implementation of genomics in clinical trials and medical practices continues to face significant hurdles from regulatory, technical, and sociological issues, recent events suggest that genomics may finally be poised to make a significant contribution to clinical practice in the near future. In 2003, the Human Genome Project completed the sequence of all human genetic material, providing an essentially complete catalogue of all human genes. Since the practice of genomics relies on large-scale, comprehensive analyses of genes, this information will prove very valuable in speeding the implementation of genomics in clinical settings. Furthermore, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) have each recently issued documents making clear that increased use of genomics in the practice of medicine and drug development is both anticipated and encouraged.
In a new Cambridge Healthtech study, Clinical Genomics: The Impact of Genomic Technology on Clinical Trials and Medical Practice, industry experts such as Geoffrey S. Ginsburg, M.D., Ph.D., Vice President of Molecular Medicine at Millennium Pharmaceuticals, Inc., express their views on the prospects for incorporating genomic technologies in clinical settings.
"Today, we are seeing only the tip of the iceberg of the full potential of clinical genomics," Dr. Ginsburg states. "I believe over the next decade, we are going to see a tsunami of genetic information entering the clinical arena ... As the technology becomes more validated and reproducible, it will become more standardized, and I think it will become increasingly incorporated into clinical decision-making. Another factor driving genomics into clinical decision-making is that the timeline for developing predictive tests based on genomics, in my mind, is much shorter than the timelines for developing a drug, because of the prerequisites for Phase I, II, and III studies in drug development."
Clinical Genomics: The Impact of Genomic Technology on Clinical Trials and Medical Practice assesses the challenges and future prospects for incorporating genomics technologies into standard clinical practice. The report examines some of the ways in which genomics could directly contribute to clinical practice, evaluates the scientific, technological, legal, and regulatory issues that will have a significant impact on the future adoption of genomics in clinical settings, and discusses the emerging business opportunities that will arise as the widespread application of genomics in clinical drug development, diagnostics, and medical practice comes to fruition.
For more information about Clinical Genomics: The Impact of Genomic Technology on Clinical Trials and Medical Practice, please visit the Cambridge Healthtech Advisors Web site at http://www.chadvisors.com/services/Clinical%20Genomics/overview.cfm.
Cambridge Healthtech Life Sciences Reports highlight areas where biotechnologies meet the demands of a shifting competitive landscape. Clients find these reports to be rich with the "highest-caliber" analysis available. Visit http://www.chadvisors.com to learn more, or contact Cindy Ohlman at 617- 630-1334 or at cohlman@chadvisors.com.
Call to bring cancer genomics from the lab bench into large-scale clinical trials
http://www.news-medical.net/view_article.asp?id=1816
It is time to bring cancer genomics from the lab bench into large-scale clinical trials, a leading Cancer Research UK scientist will tell delegates at the charity's Senior Researchers Meeting in Harrogate today.
Professor Patrick Johnston is one of a number of pioneering scientists exploring how intimate genetic knowledge from individual tumours could help doctors predict which treatments will benefit their patients best. Major trials of this approach – which has shown considerable success in the lab – are needed to test its full predictive potential.
Progress towards this goal has been too slow to date, according to Professor Johnston. He believes that large-scale trials could lead to a paradigm shift in the way doctors approach treating their patients, as well as providing new medical facilities to enable this complex but potentially revolutionary area of research to reach cancer patients across the UK.
Tumours are often resistant to individual chemotherapy drugs. Identifying patients who are not likely to benefit from a particular treatment would enable doctors to pursue other lines of treatment – freeing patients of the side effects of drugs that are unlikely to help them and improving their chances of survival.
Genomics allows scientists to obtain the detailed genetic 'fingerprints' of tumours. These fingerprints group tumours into specific types with much greater accuracy than is possible using traditional features such as tumour size, location and cellular make-up – and make it possible to predict which type of treatment will be most potent against them.
Professor Johnston, who is Director of the Centre for Cancer Research at Queens University Belfast and Belfast City Hospital, says: "Cancer genomics could really change the way doctors treat cancer.
"But turning that hope into reality will require a bold acceleration in clinical research. Using genomics in treating cancer is new, and potentially very expensive. Clinical trials will tell scientists and doctors how accurately the use of genomics can target treatments to patients, and confirm whether it is safe and cost-effective.
"Clinical trials for cancer are still very much focussed on testing new drugs. We believe an integrated approach to treatment using detailed genetic information about tumours and patients needs to become a priority."
One barrier to targeting treatment in this way is the risk of false negatives – meaning that patients could be selected not to receive a drug that they actually needed.
Dr Richard Sullivan, Cancer Research UK's Head of Clinical Programmes, says: "Cancer doctors know that many of the drugs they use will only benefit some patients – but they have no clear way of knowing which ones.
"Well-run clinical trials integrating genetic technologies could lead to predictive tests to make treatment a more exact science.
"This will require linking genetic information from patients' tissue samples to high quality data on whether or not they benefit from the treatment, and for how long that benefit lasts."
The specialised equipment and expertise required to uncover a tumour's genetic fingerprint mean that trials will be expensive to run. But scientists believe the end result could be hugely improved efficiency in the prescribing of cancer treatments, improved survival and a large reduction in the number of patients who are over treated.
Professor Johnston adds: "Research has already yielded a large selection of treatments for cancer. The challenge before us now is to find ways to use this growing arsenal effectively."
"This means demonstrating the true clinical value of the tests we have developed in the lab through large-scale clinical trials. Otherwise the full potential of this research may never be realised."
Professor Robert Souhami, Cancer Research UK's Director of Clinical and External Affairs, says: "Professor Johnston is one of a number of Cancer Research UK researchers looking for genetic and other markers that can predict the best treatment for an individual patient's cancer.
"We actively encourage and support research aimed at turning this technology into a clinical reality.
"Many institutions do not yet have the expertise or the equipment needed to run clinical trials involving complex genetic tests on large numbers of samples. Cancer Research UK has set up a specialised funding route to ease the way for scientists and doctors setting up appropriate trials in this exciting area of research." http://www.cancerresearchuk.org
Those folks at Harvard know a thing or two:
http://www.newswise.com/articles/view/505269/
Most genes carry out their tasks by making a product–a protein or enzyme. The new gene, found in yeast, does not produce a protein. It performs its function, in this case to regulate a nearby gene, simply by being turned on.
JUNK DNA YIELDS NEW KIND OF GENE
Regulates Neighboring Gene Simply By Being Switched On
BOSTON-Newswise — In a region of DNA long considered a genetic wasteland, Harvard Medical School researchers have discovered a new class of gene. Most genes carry out their tasks by making a product-a protein or enzyme. This is true of those that provide the body's raw materials, the structural genes, and those that control other genes' activities, the regulatory genes. The new one, found in yeast, does not produce a protein. It performs its function, in this case to regulate a nearby gene, simply by being turned on.
Joseph Martens, Lisa Laprade, and Fred Winston found that by switching on the new gene, they could stop the neighboring structural gene from being expressed. "It is the active transcription of another gene that is regulating the process," said Martens, HMS research fellow in genetics and lead author of the June 3 Nature study .
"I cannot think of another regulatory gene such as this one," said Winston, HMS professor of genetics. The researchers have evidence that the new gene, SRG1, works by physically blocking transcription of the adjacent gene, SER3. They found that transcription of SRG1 prevents the binding of a critical piece of SER3's transcriptional machinery.
The discovery raises tantalizing questions. How does this gene-blocking occur? Do other regulatory genes work in this fashion? Does the same mechanism occur in mammals, including humans?
At the same time, SRG1 provides clues to a recent puzzle. Researchers have lately begun to suspect that the long stretches of apparently useless, or junk, DNA might possess a hidden function. In the past year, evidence has been pouring in, not just from yeast but from mammals, that these apparently silent regions produce RNAs, which are associated with transcriptional activity (see Focus, March 5, 2004 http://focus.hms.harvard.edu/2004/March5_2004/biological_chemistry.html). Yet no one has found associated protein products. "For us it is easy to look at those findings and say, 'Well maybe those are examples of what is going on here in yeast,'" said Martens.
If so, the findings would carry an important message for the post-human genome era-namely, that researchers' attempts to turn the masses of data churned out by the Human Genome Project into an understanding of what actually happens in the human body may be even more complex than they anticipated. One of the main challenges for that effort is to figure out how and when genes are turned on and off during normal development and disease. Rather than look only at how genes are regulated by proteins, they would have to turn their attention to a new, and possibly more-difficult-to-detect form of control. And given that junk DNA makes up 95 percent of chromosomes, the mechanism could be fairly common.
"I think if nothing else, this sends up an alert that this likely occurs in other cases," said Winston. "When people are looking to understand regulation of genes from whatever organism-humans, flies, mice, yeast-they cannot just look for proteins that are acting there. It might be that it is simply the act of transcribing that is causing regulation."
Like many researchers, Winston and his colleagues may have known in the back of their minds that someday they would have to contend with junk DNA, but it was not their intention to map a new gene in those wild and relatively uncharted regions of the chromosome. If anything, the yeast SER3 gene was their lodestar. What intrigued them about the gene, which is involved in the synthesis of the amino acid serine, was its unusual expression pattern. To be turned on, genes must first be bound by an activator molecule. A common activator in yeast is a molecule called Switch/Sniff. While most genes are turned on by Switch/Sniff, SER3 is turned off by the complex.
In the course of exploring how this repression happens, Martens came across an even more surprising result. "The usual story when a gene is transcriptionally repressed is that RNA polymerase, TATA binding protein and a host of other factors associated with active transcription, will not be there," he said. He, Laprade, a research associate, and Winston conducted a series of experiments and found that the factors were all present and active, and they were located just upstream of the SER3 promoter-as was a jot of DNA needed for the onset of transcription, the TATA element.
Thinking that the TATA element might signify the beginning of a new gene, one associated with both the active RNA polymerase and SER3 repression, Martens mutated it. "We no longer saw the RNA, and we found transcription of SER3 was de-repressed," he said. "That is when we thought, 'OK, we have got a new regulatory gene.'" After characterizing SRG1, which turned out to be 550 base pairs long, they tackled the question, How is it regulating SER3? They put the question on the table during a lab retreat atop a downtown skyscraper. "Everybody talks, and they are not allowed to show any data," said Winston. Out of that intellectual free-for-all, three models emerged.
The first held that RNA transcripts produced from SRG1 were being recruited to SER3 and were somehow repressing transcription. The researchers assumed that if this were true, it would not matter where the RNA came from. As it turned out, SER3 was repressed only when the RNA was produced by an adjacent SRG1. The second model, which proposed that the SRG1 promoter outcompeted the SER3 promoter for transcription factors, also did not hold up to experimental scrutiny.
There had been hints all along favoring the third model. In this one, transcription of the nearby SRG1 somehow prevents an activator from binding the SER3 promotor. Using chromatin immunoprecipitation, a powerful method for imaging the location of molecules in living cells, the researchers found that this was exactly what happened: a well-known activator fell off the SER3 promotor when SRG1 was turned on. In fact, when SER3 was replaced by a reporter gene, the same thing happened-the turning on of SRG1 prevented the activator from binding to that gene as well.
As for how this interference actually occurs, one possibility is that the machinery required to transcribe SRG1 -RNA polymerase, TATA-binding proteins and other factors-somehow spills over to the nearby SER3 promotor, physically preventing it from being approached by an activator. "It is also possible that active transcription alters chromatin structure and modifies things in other ways," said Winston.
As for the molecule that got them started in the first place, Switch/Sniff, the researchers now think it may activate SRG1 and in that way bring about SER3's anomalous repression. "That is our current thinking," Winston said. It is a view he expects will be revised. "Every time we thought we understood everything going on here, we have been wrong. There are additional layers of complexity."
Here's a USA Today article on the same subject:
http://www.usatoday.com/news/health/2004-06-02-junk-dna-usat_x.htm
'Junk' DNA may simply be in a jam
By Elizabeth Weise, USA TODAY
Scientists at Harvard Medical School may have unraveled some of the mystery about why up to 95% of all chromosomes are apparently non-functioning — otherwise known as "junk" DNA.
If the team is right, it may be that some of that DNA has been busily working all along, but researchers just didn't realize it.
That's because these genes don't do what classic genetic theory tells us they should. It has generally been accepted that there are two kinds of genes: structural genes that make the raw materials that cells need and regulatory genes that control the activities of other genes.
Both do their work by first making a copy of themselves called messenger RNA. That RNA produces the proteins and enzymes that do the work of building and regulation .
What geneticist Fred Winston and his co-workers discovered is a gene in yeast called SRG1 that regulates its next-door neighbor without the use of either proteins or enzymes. Instead, this gene keeps its neighbor from turning on — and thus getting anything done — by pouring out a steady stream of messengers that physically block the gene next door from sending out its own RNA messages.
"It's like the freeway at rush hour. There are so many cars coming down the highway that you can't get on," Winston says.
To turn the neighboring gene back on, Winston and his colleagues Joseph Martens and Lisa Laprade put in a molecular "roadblock" that stopped the SRG1 gene from pumping out RNA. The silenced gene next door immediately turned back on. "Now the cars could get on the highway with no problem," Winston says.
The study is published in Thursday's issue of the journal Nature.
Winston notes that it has long been known that there is a lot more RNA being made in humans than is accounted for. It could be that the missing RNA is being produced by these silenced genes, he says. This type of regulation could be what some of that RNA is actually doing, he says.
Grateful, hopefully not! eom
Variations In DNA Repair Genes May Predict Survival In Non-small Cell Lung Cancer Patients
http://www.sciencedaily.com/releases/2004/06/040602063128.htm
http://www.asco.org/ac/1,1003,_12-002112-00_15-002104-00_18-0034139-00_19-0034218-00_20-001,00.asp
Variations in DNA Repair Genes May Predict Survival in Non-Small Cell Lung Cancer Patients
June 1, 2004 at 6 p.m. (ET)
CONTACT: Carrie Housman(703) 519-1423
Elizabeth Milbank (212) 584-5014
Study Points to the Prospect of “Individualized” Cancer Treatment
Alexandria, VA - Genetic variations in an individual’s ability to repair DNA damage may help predict survival in lung cancer patients treated with the common chemotherapy drugs cisplatin or carboplatin, a new study shows. The findings, if verified in larger studies, may help oncologists tailor chemotherapy to patients based on their genetic make-up. The study and an accompanying editorial will be published online June 1 in the Journal of Clinical Oncology (JCO).
“The concept of selecting a chemotherapy drug based on a patient’s genetic make-up is relatively new and very exciting,” said lead investigator Sarada Gurubhagavatula, MD, of Massachusetts General Hospital. “We hope that this type of research will one day enable doctors and patients to make more informed decisions about chemotherapy treatments.”
Study investigators evaluated genetic variations (also called polymorphisms) in two DNA repair genes – XPD and XRCC1 – in 103 patients diagnosed with stage III or IV non-small cell lung cancer who were treated with cisplatin or carboplatin.
The XPD and XRCC1 genes are involved in correcting mistakes that sometimes occur when DNA is copied in preparation for cell division. Researchers suspected that the inability to repair DNA damage may lead to more aggressive lung tumors that spread more rapidly to other organs, thereby decreasing survival.
By comparing combinations of variations in both genes, researchers found that more variations were associated with decreased median survival. Patients with a total of three variations in the XPD and XRCC1 genes survived a median of 6.8 months, while those with no variations survived a median of 20.4 months. Patients with two variations survived a median of 11 months, and those with one variation survived 16.6 months.
The presence of genetic variations independently predicted survival even after researchers took into account patients’ ability to carry out daily activities, their stage of disease, and the type of chemotherapy they received.
While other researchers have investigated the link between XPD and XRCC1 gene variations in patients with other cancers, particularly those with colorectal cancer, this is the first study to look at variations in these genes in patients with lung cancer.
Researchers noted that the retrospective nature of the study presented certain limitations. Because evaluation of clinical response and time to disease progression is often imprecise in the retrospective setting, the study focused on overall survival, the most objective outcome. However, they noted that future studies measuring clinical outcome and time to disease progression may be critical to further understand the mechanism by which DNA repair affects patient outcome.
An accompanying editorial by Heinz-Josef Lenz, MD, Associate Professor of Medicine and Preventive Medicine at the USC Norris Comprehensive Cancer Center discusses the application of polymorphisms in clinical oncology and the potential for including analyses of germline (inherited) polymorphisms known to have an effect on the efficacy and toxicity of certain common chemotherapeutic agents into clinical trials, and eventually into clinical practice.
“This paper is a good example of the potential future using these polymorphisms in the clinic but at the same time of the limitations and the need for a better functional understanding in our quest to elucidate the role of germline polymorphisms in clinical oncology,” said Dr. Lenz.
"XPD and XRCC1 Genetic Polymorphisms are Prognostic Factors in Advanced Non-Small Cell Lung Cancer Patients Treated with Platinum Chemotherapy.” Sarada Gurubhagavatula et al, Massachusetts General Hospital Cancer Center, Boston, MA.
The Journal of Clinical Oncology is the semi-monthly peer-reviewed journal of the American Society of Clinical Oncology (ASCO), the world’s leading professional society representing physicians who treat people with cancer.
W2P, yes from the last AFFX 10K:
"As a result of this financing, our collective equity ownership in Perlegen (including that of our affiliates) was reduced to less than 45%..."
Of course, AFFX still enjoys certain rights in this relationship:
In March 2001, we contributed to Perlegen the rights to use certain intellectual property with no cost basis and we have rights to use and commercialize certain data generated by Perlegen in the array field. Using access to whole-wafer technology developed by Affymetrix, Perlegen focuses on identifying the millions of genetic variations (known as single nucleotide polymorphisms or "SNPs") among individuals, and finding patterns in those variations that might be predictive of disease susceptibility or drug response. In January 2003, we obtained accelerated access to Perlegen's SNP database which will further our efforts to develop these next generation arrays. In addition, our collaborative arrangement with Perlegen provides us with access and commercialization rights to certain whole genome technologies, including 248,000 chip-optimized, long-range polymerase chain reactions (or "PCRs") across the human genome that we intend to make available to our customers through our GeneChip® CustomSeq™ Resequencing Array program which offers high-quality arrays for large-scale resequencing of the human genome.
It occurs to me that people may not be aware that Perlegen is a subsidiary of Affymetrix...
W2P, I was going to mention AFFX's mysterious absence from the list of competitors in the 10K. It certainly seems that there might well be something going on here but quite how and where (or if) DNAP fits into the picture is the key question. Perhaps this is indeed related to one of those "significant moves".
mahastock
My speculative opinion is that, like others, Perlegen have some basic technology that might ultimately be competitive with DNAP. They might also be infringing on our intellectual property. There is a lot of collaboration going on, for instance:
http://www.perlegen.com/newsroom/2004_01_26_Galileo_Press_Release.html
However, there do not seem to be any actual products based on Perlegen's technology. Here is a description of Perlegen's approach from their website:
http://www.perlegen.com/science/scanning.html
At Perlegen, we have developed a set of over 1.5 million SNPs that we use in genetic association studies to provide a powerful approach for identifying combinations of common trait-associated variants. This resource was generated using high-density oligonucleotide array technology to sequence dozens of ethnically-diverse human genomes. By comparing the sequences of these individual genomes, we were able to identify over 1.5 million widely distributed SNPs.
Approximately 1.1 million of these SNPs were found to be common in the ethnically-diverse population (i.e. present in at least 10% of the individuals of the population), making them extremely useful for identifying the genetic causes of complex diseases, including those that affect different ethnic groups. Across our entire set of 1.5 million SNPs, the average spacing is one SNP per two kilobases (kb), making for a very high-density SNP marker set.
We also have shown that there is strong linkage disequilibrium between neighboring SNPs in the Perlegen SNP panel i.e., the SNPs are often associated with each other. We identified ~ 175,000 regions (called haplotype blocks) within which SNPs were in strong linkage disequilibrium. In addition to the close association between neighboring SNPs, we found that for each haplotype block, the SNPs within the block fell into one of only a few possible combinations (called haplotype patterns).
This combination of high density common SNP markers, strong linkage disequilibrium exhibited between neighboring SNPs, and the limited number of haplotype patterns allows us to use the Perlegen SNP set to perform statistically powerful association studies. We can identify genes contributing even a small amount to complex traits, such as susceptibility to common diseases and drug responses.
Perlegen
Somebody sent me a private message about this and I thought that I would reply publicly. Perlegen look superficially to have compelling technology that is in DNAP's domain. Here is what DNAP said about competition in the last 10K:
"Our expertise finding and modeling AIMs form the cornerstone of our strategy to penetrate the consumer products, forensic and pharmacogenomics markets with our genomic testing products. We are one of the first companies to develop infrastructure for this purpose. Due to limited competition in the field of complex genomics classification to date, these market opportunities remain attractive. Other companies and researchers seeking to develop genomic classification or diagnostic products to bring to market are currently screening hundreds of thousands to millions of markers across the genome. This process is not commercially viable for many markets, due to cost."
"By developing unique genome maps, however, we allow researchers to efficiently and cost effectively discover and decipher complex, common genetic traits. Our AIMs are novel because they allow a genome screen to be accomplished with as few as 2,000 markers, making it cost effective to develop genomic based tests."
"We compete against a limited number of companies in pharmacogenomics, including Gennaissance, Seryx, Variagenics, and Genset; deCODE Genetics, Celera Genomics, Incyte Genomics, Orchid BioSciences, and Sequenom. The latter two principally offer tools and services for sequencing and scoring SNPs, while Celera and Incyte are involved primarily in creating SNP databases. DeCODE Genetics focuses on gene discovery, drug target validation, as well as pharmacogenomic analysis through use of its proprietary informatics system and its Icelandic Health Sector Database. Genset also has an interest in pharmacogenomics through its development of genomic markers using its proprietary technology platform; however, it has dedicated its resources to internal drug discovery and development in the areas of central nervous system and metabolic disorders."
Note that Perlegen are not listed as a competitor.
Wayne Joseph was offered and declined a retest.
Frog, I have posted the latest list. I have included W2P's proposed wording for question 1.d in the absence of any feedback to the contrary. I previously supplied a suggested covering mail. Would you be so good as to send the final list to the company at the appointed hour. I would hope that there are not too many additions or revisions to the list that are contentious between now and then! I shall trust you to exercise your judgement.
Thanks
Ming
Shareholders Meeting Questions (Draft) - Version 0.4
1 Company
1.a) In the 10K the company stated that it plans to move from its current 7,000 square foot building to a new 20,000 square foot building at a cost of approximately $1,000,000. DNAP has 12 full-time employees as per the last 10K and not much equipment. Can you explain why the additional space if needed and confirm the timescale?
1.b) Does the company intend to relocate to the new research facility being constructed at the USF, as indicated by having signed a letter of intent to do so? If not, has the company selected alternative premises? What is the timescale to finalize this decision and move to the new location? Will the existing offices at Cocoanut Avenue be retained?
1.c) Can you confirm the current number of employees, their function, and whether they are full time or part time or employed on a contract basis? Do all employees work at the company offices? What are the current plans for expanding the workforce in terms of numbers and functions of prospective employees?
1.d) In the January 2003 letter to shareholders, Dr. Frudakis intimated that shareholders would be able to participate in a warrants plan that the company intended at that time to implement. There was never any explanation given for the withdrawal of the plan even though it was stated quite plainly that such a plan would have a higher priority than pursuing an agreement with a venture capital firm. Would you address the issue and provide an explanation as to the circumstances that led to the withdrawal of the warrants plan?
1.e) In the January 2003 letter to shareholders, Dr. Frudakis stated that the common shareholders would be given the right to vote on any further issuance of shares. Since that letter was released, DNAP has issued over 200,000,000 shares. Why have shareholders not received proxies from the company in relation to these issuances?
1.f) What is the current status of the agreement with Genomedics Inc (GMED)? Is the agreement still in force and what are the implications (if any) of this for DNAP?
1.g) Early in the companies history there was much discussion of the Orchid option agreement. It was described as a six month window of opportunity in which Orchid could obtain the exclusive rights to the first completed product. Mention was made in newsletters that the terms of the option created some hesitation on the part of potential partners/customers as they did not wish to lose their negotiated rights should Orchid chose to exercise their option. Since then we have heard that the rights to the option have transferred to Beckman and there has been very little said in regards to it lately. Does the option still exist? If not, what completed product was used to trigger the six month window and in what time frame did it occur? If it still exists, what are the ramifications in terms of any approaching project completions? Since Ancestry and DNAWitness were developed under different circumstances we are under the impression that the option agreement does not apply to them, is that a correct assumption?
1.h) Much has been made of the technology and innovation of the company and the potential value that can result from exploiting them, but in terms of material value, what are the tangible assets of the company? We are aware that the building is leased and that the actual ownership of the major piece of equipment (Orchid UHT) is questionable. Aside from the office and lab equipment, is there any other capital equipment that is the property of the company? The products themselves (Ancestry and DNAWitness) can be considered assets, but as they are 'service based' there is very little inventory associated with them (swabs, plastic bags, printed material etc.). The major asset of the company is presumably the 'platform' from which the various products are derived, what exact form does the platform take? Is it a program/database and associated documentation resident on a computer? Is it a documented and archived set of CD-ROMS? Is it a collection of various parts that coalesces into a functional entity under the careful management of a trained individual? Is it therefore a tangible object that can be described, backed-up or duplicated at will, or is it an intangible collection of expertise and knowledge that requires the involved participation of a single, or set of, individuals? The patent applications are a growing repository of potential value that will perhaps provide a tangible asset if they are ever granted, until they are however, they must be considered intangible. What Safeguards are in place to protect the assets of the company?
1.i) Presumably the platform is protected from competitive duplication by patent application. We can see where this would prevent a competitor from reading the patent application and duplicating the platform and going into business with a competing service. How would it prevent a major pharmaceutical company, for instance, from duplicating the platform and using it in the privacy of their own lab to develop new drugs. Drugs that would come out of the drug pipeline just like countless others before them. The drugs themselves would not be in competition with DNAP so what would be the path for litigating the patent rights? How would anyone know, by what mechanism would the use of a duplicate platform be revealed?
1.j) Given that the assets of the company, while potentially valuable, are knowledge based and therefore somewhat intangible, are there any particular safeguards in place to protect shareholder value in the event of unforeseen business failure? Are the assets documented and archived such that they can be reconstituted by knowledgeable individuals? Are they listed on an asset sheet so that they can be tracked by auditors? Are there by-laws in place that would require a shareholder vote before such key assets could be transferred or licensed?
1.k) What is the legal status of the Orchid device if the company entered bankruptcy?
1.l) Can the company confirm the status of the NIH and the NIJ grant applications?
1.m) Can the company confirm the status of the company's application for forensic laboratory accreditation?
1.n) What happened to the proposed private placement?
1.o) Can the company provide an update on the civil case in the Florida circuit court involving a former employee?
1.p) Are there are other current or pending legal actions involving the company?
1.q) Has the company been, is it currently, or will it potentially be involved with DNA Phenomics in Malaysia? If not, has the company identified another partner(s) for product distribution in the Asia Pacific market?
1.r) Are there any initiatives underway or planned in relation to partner(s) for product distribution in Europe?
1.s) If the company share price reaches .025 will funding under the La Jolla Cove agreement be discontinued, be suspended until the share price recovers, or will funding continue?
1.t) Can the company provide an update in relation to its previous indications about becoming a drug company?
1.u) The company previously indicated that it would at some future stage make license fee payments to Genetic Technologies. Can you explain the context, and anticipated magnitude and timescale of these payments?
2 Management
2.a) Can you explain and justify the level of management compensation and how this changed upon expiration of the original one year employment agreements for the management team?
2.b) Can you explain why it is necessary to have a Chief Financial Officer/Chief Operating Officer role at the present time? Would it have been possible to outsource these functions, possibly as an interim measure?
2.c) In previous SEC quarterly and annual filings, the company stated that the performance conditions necessary to award Dr. Frudakis' 30,000,000 performance shares had not been met, and were not likely to be met. The Board changed its position sometime during the second quarter of 2003. Can you provide the criteria the Board determined had been met to merit award of those shares?
2.d) What is Dr. Frudakis's involvement with the Biometrics Council (renamed to Biological Threats Council)? Are there any implications for the company as a result of his involvement with this initiative?
2.e) Can you provide an update on the status of the search for a Director of Marketing that was mentioned in the TWST article?
2.f) How do you justify the wide margin between revenues ($709,638), administrative costs (i.e. payroll is approximately $3,857,925) and net loss ($7,789,905)?
3 Scientific Advisory Board
3.a) Can you confirm the current composition of the SAB? Some individuals were previously listed in SEC returns and on the company website as being SAB members, e.g. Ramin Mirhashemi, Fernando Arena and DC Rao, but these individuals no longer appear to be SAB members. For any people who are no longer SAB members can you provide an explanation as to why they are not?
3.b) Can you explain the role of the SAB and the services that are typically performed by SAB members?
3.c) Can you explain how the remuneration level of 50,000 shares of common stock per annum was arrived at? In the Company's opinion is this sufficient to attract and retain the type of individual that the company would want as SAB members?
3.d) As per the last 10K the company has initiated plans to expand the SAB to include "other scientists who will actively contribute to our effort in increasing the number of BGA sub-categories from our current four, to as many as 20." Can you provide an update on how these efforts are progressing? Are there any current plans to expand the SAB to include scientists in disciplines other than biogeographical ancestry?
3.e) Can you explain the difference between the SAB and the Board of Consultants, which was also mentioned in the last 10K?
4 Investor Relations
4.a) A fundamental element to attracting and retaining capital investment in a public company is the need for professional Public Relations, Investor Relations and Marketing. This is an area of particular frustration for existing investors. How does the company plan to address these needs and when will we see improvements in these areas?
4.b) Does the company intend to provide newsletters on a regular basis in the future?
5 Website
5.a) Why are the “DNAP in the Press” and the “Conferences/Trade Shows/Presentations” sections of the company website not updated on a regular basis?
5.b) Why is the January 2003 letter to shareholders the only publicly released document from the company not available on the website?
6 Science
6.a) What relevance do the new AIMs in version 3.0 of ABD have in relation to DNAP's existing platform? The original ADMIXMAP impacted every part of DNAP's business and every dollar that went into finding those AIMs was maximized. Can the same be said for the new AIMs? Are they only relevant to genealogy and forensics or to all of the products? Do some of them “fine-tune” the ADMIXMAP platform?
6.b) Do AIMs related to pigmentation genes have any special significance in drug metabolism and associated pharmacogenomic classifiers?
6.c) Is the company’s intellectual property in any way affected by the provisional US patent application number 20040072217 titled "Methods of analysis of linkage disequilibrium", which is assigned to Affymetrix, Inc.?
7 Services/Products
7.a) The two major products in the market today are AncestryByDNA (ABD) and DNAWitness. We have heard positive things about both. Since the two products have been on the market for a number of months now can you share any market analysis that you have obtained. We have heard some fairly large estimates for the size of the market for DNA testing as it relates to the forensic space, but those estimates include such unrelated to DNAWitness categories as CODIS testing of convicted felons and backlogged rape kits. Do you have any market analysis that focuses on the specific number of applications available for the DNAWitness product? What is your projection for the growth curve for ABD, is it still growing, at what rate? Is the curve showing signs of exponential growth, linear growth or is it flattening out?
7.b) Can you confirm the current status of the development of ABD 3.0?
7.c) What kind of pricing is anticipated for the version 3.0 test bearing in mind the need to strike a balance between profit and affordability? Will current 2.0/2.5 customers get a significant discount on 3.0? If not will this not potentially have a detrimental effect on demand from these customers? Will DNAP honor its original promise to give free 3.0 tests to 2.0 customers from before 10/8/02?
7.d) Can you give any details about the parental populations used in the development of the AIMs? Specifically, what is the parental population for the Indo-European category? From what ethnic groups/part of Europe were these people from?
7.e) Is it possible that some of the admixture estimates that are derived are overestimated due to their being compared to a small (narrow) parental population?
7.f) What will the 20 categories be in ABD 3.0? Who is this product being developed in conjunction with and what are their aims for the project(s)? Is there an agreed taxonomy of racial categories and what correlation is there between any such taxonomy and the categories that the company intends to use?
7.g) Can the company provide any details of the scope and progress of the project to “date” admixture? How would such work result in new products or impact current products?
7.h) What is the company’s current anticipation of the likely adoption of DNA Witness for routine use by US and foreign Police Departments and/or Governmental agencies?
7.i) Can the company provide any details on the development of additional classifiers for traits such as hair color and facial features that would be components of DNA Witness?
7.j) Why has genotyping not been provided as a service to other companies to date? What are the current plans for offering this as a service? Why did the $1,000 genome scan appear not to generate market interest?
7.k) Will the company be providing so-called “validation genotyping” services for (GMED)?
7.l) Has any interest been expressed in the paternity testing service that was recently introduced by the company?
7.m) What is the status of Retinome? This was ostensibly 75% finished over two years ago. We then heard that the data was inconsistent due to ‘self reporting’ errors introduced by the participants, but a more sophisticated data set was obtained using digital equipment. We heard in a magazine article last summer Retinome would be introduced by the end of 2003. It is now mid 2004 and we have heard nothing lately. Could you clarify? What is the anticipated timetable for completion of this product and its launch in the market?
7.n) What is the status of Statinome? What is the anticipated timetable for completion of this product and its launch in the market? There has been some indication that competitors are working on similar projects, can you give us any indication of DNAP’s advantages or disadvantages in regards to these competing approaches?
7.o) What is the status of Ovanome? What is the anticipated timetable for completion of this product and its launch in the market?
7.p) Are there any other products currently in development or planned by the company?
8 Patent Applications
8.a) What is the current status of the various patent applications? What issues if any) have been encountered in practice during the patent application review process? What is the company's expectation that any or all of these patents will be granted in due course?
8.b) Have all the inventions and patent applications been assigned to DNAP as the sole owner and assignee of those assets? If not, then who owns the inventions and patent applications?
8.c) Do all the employees of DNAP, including officers and staff members, and outside contract researchers have a written obligation to assign all of their inventions to the company as a condition of their employment or contract? If not, then how is ownership determined?
N.B. As utilized here, the term “inventions” comprise only those pertinent to the science, technology and business objectives of DNAP.
9 Collaborative Research
9.a) Can the company confirm the current status of the collaborative relationship with the University of Miami? Are Drs. Mirhashemi and Arena still employed by the University and are they participating in research with the company?
9.b) Is there any update on the FAMRI sponsored project on genetic susceptibility to cervical cancer in second hand smokers in conjunction with the University of Miami that was the subject of the press release in February 2003?
9.c) Can the company provide any update about the work that has been underway with New York University aimed at developing a transplant classifier?
9.d) Can the company explain what happened with the proposed collaboration with GeneLink which is apparently now not going forward?
9.e) Can the company provide more details about the relationship with H. Lee Moffitt (Moffitt) over and above what is contained in the 10K?
9.f) What is the nature of the relationship with Moffitt? Equal partners, both sharing in the costs of resources and materials of the various projects and then sharing equally in the resulting assets? Is DNAP acting as a service provider to Moffitt, being paid for their services and their expertise, but then Moffitt is the owner of any assets developed from the project. Is DNAP providing the project management or is it acting as a subcontractor taking direction from Moffitt? Is there some other form for the relationship? How does the company see the process of co-development and co-commercialization working in practice with Moffitt?
9.g) Can the company provide any detail on the due diligence work that was undertaken by Moffitt before collaborating with DNAP and confirm when the projects actually started?
9.h) Can the company confirm that the following projects are currently underway in conjunction with Moffitt: Colon Cancer, Multiple Myeloma, Cyclophosphamide, Taxanes? Is it possible to provide any additional detail on the scope and anticipated timetable for these projects? Are there any other projects currently in progress or planned to be undertaken with Moffitt?
9.i) Can the company explain why they terminated the license agreement with the Penn State Research Foundation? Does this have any affect on the company’s intellectual property or on other work underway, or future work planned, in conjunction with Dr. Shriver?
9.j) Is there any update on the National Institutes of Justice Funded Project that was the subject of the press release in August 2003?
9.k) Can the company confirm the scope and status of any projects underway in conjunction with Senecio Inc?
10 Listing
10.a) Can the company confirm that it has applied to be delisted from the Berlin Exchange and also confirm the status of the listing on the Frankfurt Exchange? Does the company have plans to list on other foreign exchanges?
10.b) Has the company considered possible courses of action to address potential naked short-selling of its stock? These could include delisting from exchanges, removing its stock from the DTCC system and issuing physical certificates, and recalling all of its stock and re-issuing it to shareholders of record.
10.c) Does the company intend ultimately to list on NASDAQ or AMEX (or some other exchange)? Is there any timetable for such a listing?
10.d) Approximately one year ago Dr. Frudakis stated in the TWST interview, that DNAP needed to get off the OTCBB and to the NASDAQ. He also stated that it would happen via a couple dramatic steps rather than several little changes. Have any of the "dramatic" steps taken place yet? If they have, can you identify the dramatic step? If not, can you give us an indication of what a “dramatic step” might entail?
11 Miscellaneous
11.a) Does the company intend to implement a reverse split of its stock in the foreseeable future? If not, how does the company think that the existing level of authorized shares will be perceived by the market? Is so, what would the ballpark split ratio be?
11.b) How does DNAP Utah impact/affect its wholly-owned operating subsidiary, DNAP Florida? What's the role/structure of the Utah parent company? Do they interact with DNAP Florida? If so, in what capacity do they interact? Is there overhead to DNAP Florida for this entity? Is Utah involved in the day-to-day operations of Florida? Do they handle employment contracts, etc? How many shares does Utah hold? Based on the above, what's the float?
Manti, I though I had picked them all up. Which ones can you still see? I am not including spurious things that the Microsoft Word grammar checker finds as a lot of these are just plain wrong.
mahastock, did you have any questions you wanted to add?
mahastock, I suggested 17:00 EST on Monday.
cgr, indeed there was:
9.c) Can the company provide any update about the work that has been underway with New York University aimed at developing a transplant classifier?
Here's more information related to Affymetrix's work involving AIMs and linkage disequilibrium. I have not added any analysis but merely highlight the potential overlap wth DNAP, and the "co-incidental" use of the term "ancestry informative markers". Note that DNAP's patent application COMPOSITIONS AND METHODS FOR INFERRING ANCESTRY was first filed in August 19, 2002.
Based on this I have already included the following question in the "Science" category in the list of shareholder questions:
"Is the company's intellectual property in any way affected by the provisional US patent application number 20040072217 titled "Methods of analysis of linkage disequilibrium", which is assigned to Affymetrix, Inc.?"
United States Patent Application 20040072217
Title: Methods of analysis of linkage disequilibrium
Assignee Name and Adress: Affymetrix, INC.
Filed: June 17, 2003
Last Update: April 15, 2004
Abstract
Methods and kits for analyzing a collection of target sequences in a nucleic acid sample are provided. A sample is amplified under conditions that enrich for a subset of fragments that includes a collection of target sequences. Methods are also provided for analysis of the above sample by hybridization to an array, which may be specifically designed to interrogate the collection of target sequences for particular characteristics, such as, for example, the presence or absence of one or more polymorphisms. Methods of estimating the extent of linkage disequilibrium in a region or population by determination of the ancestral and non-ancestral alleles are also provided.
...
27. A method to identify at least one ancestry informative marker comprising: a. determining the allele frequency for each of a plurality of SNPs in each of two populations; b. calculating an F.sub.ST value for at least one SNP in said plurality of SNPs; and c. identifying at least one SNP whose F.sub.ST value is greater than 0.3.
...
FIELD OF THE INVENTION
[0002] The invention relates to methods for enrichment and amplification of sequences from a nucleic acid sample and highly parallel methods of determining the genotypes of SNPs. In many embodiments a generic method of complexity reduction is combined with an array of probes to a collection of SNPs to determine genotype. In one embodiment, the invention relates to determining regions of low or high linkage disequilibrium across the whole genome. In another embodiment the invention relates to identification of ancestral alleles of human polymorphisms. The methods may be used to identify human chromosomal regions of low linkage disequilibrium and to determine haplotype maps. The present invention relates to the fields of molecular biology and genetics.
SUMMARY OF THE INVENTION
[0003] In one embodiment a method for identifying the ancestral allele of a human single nucleotide polymorphism is provided. Genomic DNA samples from at least two higher primate species are amplified by a method to reduce complexity, for example amplification with a single primer, and hybridized to a nucleic acid array comprising allele specific probes to at least 5,000 human SNPs. Hybridization patterns for the primates are analyzed to identify at least one human SNP that is homozygous for the same allele in both of the higher primate species. The allele present in both higher primate species is assigned as the ancestral allele state of that human SNP.
[0004] In another embodiment the extent of linkage disequilibrium in the chromosomal region near at least one human SNP is estimated by determining the ancestral allele for a plurality of human SNPs, identifying at least one human SNP allele that is the ancestral allele; and predicting low linkage disequilibrium across the chromosomal region near the SNP allele that is the ancestral allele or predicting low linkage disequilibrium across the chromosomal region near a non-ancestral allele. The non-ancestral allele is any allele that is not the ancestral allele. The higher primate species may be, for example, chimpanzee, gorilla or orangutan. The region may include the region 1, 10, 100 or 200 kb from the SNP in either direction.
[0005] In another embodiment the extent of linkage disequilibrium in the chromosomal region near a plurality of human SNPs is estimated by determining the ancestral allele for a plurality of human SNPs according to the method of claim, identifying the ancestral and non-ancestral alleles for each human SNP and predicting low linkage disequilibrium across the chromosomal region near each ancestral allele and high linkage disequilibrium across the chromosomal region near each non-ancestral allele.
[0006] In another embodiment a pattern of regions of high linkage disequilibrium across a chromosome is established by identifying at least one non-ancestral allele in a chromosome of an individual, determining the ancestral state of the human SNP in a population of individuals, identifying at least one human SNP that is found to be non-ancestral in a population of individuals with a frequency greater than 0.3, predicting regions of high linkage disequilibrium near a frequent non-ancestral allele on a chromosome of the population; and establishing a pattern of regions of high linkage disequilibrium across a chromosome. In another embodiment a pattern of regions of high linkage disequilibrium is established across a plurality of chromosomes by establishing a pattern of regions of high linkage disequilibrium across one chromosome and repeating for at least one other SNP located on a second chromosome.
[0007] In another embodiment a linkage disequilibrium map is established across human chromosomes by identifying at least one non-ancestral allele of a first human SNP, identifying chromosomal regions localized less than 200 kilobases from the at least one non-ancestral allele, identifying at least one other human SNP within this region; grouping the first SNP and the SNP or SNPs identified into blocks, and predicting high linkage disequilibrium between SNPs within these blocks. This may be used to establish a haplotype map. In another embodiment a computer and computer code are used to estimate haplotype diversity within blocks of SNPs and may be used to establish a haplotype map.
[0008] In another embodiment a haplotype map across a human chromosome is established by identifying human SNPs that are non-ancestral, identifying chromosomal regions localized less than 200 kb from the non-ancestral allele, identifying human SNPs within these regions, grouping the SNPs into blocks of high linkage disequilibrium, estimating haplotype diversity within these blocks via an haplotype estimation software and establishing an haplotype map.
[0009] In another embodiment the haplotype map that is established is used to search for complex disease genes.
[0010] In another embodiment the extent of linkage disequilibrium in the human genome is estimated by determining the allele frequencies for a first plurality of SNPs in a population, determining the ancestral allele for a second plurality of SNPs contained in the first plurality of SNPs, comparing the allele frequency of a SNP to the frequency of the ancestral allele for that SNP for a plurality of SNPs from the second plurality of SNPs in the population sample to generate a correlation coefficient for the population; determining high frequency for an ancestral allele if the correlation coefficient is greater than 0.8, identifying a chromosomal region nearby a frequent ancestral allele; and inferring low linkage disequilibrium across the region.
[0011] Populations that may be compared include any distinct populations, for example, geographically distinct human populations. The methods may be used to determine which population is more ancient.
[0012] In another embodiment at least one ancestry informative marker is identified by determining the allele frequency for each of a plurality of SNPs in each of two populations, calculating an F.sub.ST value for at least one SNP in the plurality of SNPs and identifying at least one SNP whose F.sub.ST value is greater than 0.3 or greater than 0.4.
[0013] In another embodiment a haplotype is identified in a region of high linkage disequilibrium in a first population of individuals, wherein a haplotype comprises at least two linked SNP alleles, by identifying a non-ancestral allele of a first SNP in the first population wherein the non-ancestral allele is not present in a second population, genotyping at least one additional SNP that is within 100 kb of the first SNP; and determining which allele of the additional SNP is linked to the non-ancestral allele of the first SNP.
...
[0142] 3. Discovery of Ancestry-Informative Markers (AIMs)
[0143] In one embodiment the F.sub.ST statistic is calculated and used to identify SNPs that are ancestry-informative markers (AIMs), F.sub.ST is an estimate of the geographic structure between two populations, for each SNP. F.sub.ST values vary from 0 to 1; as allele frequency differences between populations become more pronounced, F.sub.ST values increase. When calculating 0.061, 0.094 and 0.065 for SNPs in an African-American versus Caucasian population, African-American versus Asian populations and Caucasian versus Asian populations the mean F.sub.ST values are typically less than 0.1 indicating that the majority of markers show very small inter-population frequency differences. However, there is a subset of SNPs whose allele frequencies differ significantly in one population versus the other two. These SNPs, called ancestry-informative markers, or AIMs, can be used to map complex diseases using admixture-generated linkage disequilibrium, or MALD. See Collins-Schramm, H. et al., Am. J. Hum. Genet. 70, 737-750 (2002), Briscoe, D. et al., J. Hered. 85, 59-63 (1994), Parra, E. J. et al., Am. J. Hum. Genet. 63, 1839-1851 (1998), and McKeigue, P. M. et al., Ann. Hum. Genet. 64, 171-186 (2000) each of which is incorporated herein by reference in its entirety.
DNAWitness fuzzy photograph
This is an extremely complicated and challenging problem for the company. There are a couple of academic efforts underway that I am aware of attempting to elucidate SNP markers that relate to facial morphology phenotypes. Here is a recent paper that illustrates how face morphology changes with age in one ancestral population, the authors noting that admixture provides additional challenges in providing more reliable guidelines for therapy.
Anthropometric Measurements of the Facial Framework in Adulthood: Age-Related Changes in Eight Age Categories in 600 Healthy White North Americans of European Ancestry From 16 to 90 Years of Age. Farkas LG, Eiben OG, Sivkov S, Tompson B, Katic MJ, Forrest CR. J Craniofac Surg. 2004 Mar;15(2):288-298.
Toronto, Ontario, Canada; From the *Center for Craniofacial Care and Research, The Hospital for Sick Children, and the Division of Plastic Surgery, University of Toronto, Department of Orthodontics, The Hospital for Sick Children, University of Toronto, and Department of Research Design and Biostatistics, Sunnybrook Hospital and Women's Health Sciences Center, University of Toronto, Ontario, Canada; Department of Biological Anthropology, Eotvos Lorand University, Budapest, Hungary; and Department of Anatomy and Histology, Higher Medical Institute, Plovdiv, Bulgaria.
The aim of this cross-sectional anthropometric study was to determine the age-related changes in the facial framework during adulthood in healthy white North Americans of European ancestry (261 male subjects and 339 female subjects). Five measurements, four horizontal and one vertical, defining the framework were taken from the skin and bony surface of the face in the maturation period (16-20 years) and in 10-year age categories of adulthood (21-90 years). As well, the thickness of the soft-tissue cover between these two anatomical levels was measured. The categories between 21 and 40 years represented early adulthood, those between 41 and 70 years represented middle adulthood, and those between 71 and 90 years represented late adulthood. The forehead width in both sexes increased significantly on the skin and bony surface from the maturation period to early adulthood. In middle adulthood, the changes were significant only sporadically. In late adulthood, the upper and lower jaw showed a harmonious change with age, mostly increasing on both the skin and bony surface. The face width proved to be the most stable measurement and had the thinnest soft-tissue cover. No consistent pattern emerged during adulthood in increases or decreases within the facial framework; however, an unexpected harmony was noted between the values of the measurements in early and late adulthood in both sexes on both the skin and bony surface. The thickness of the soft-tissue cover at the bony landmarks was greatest in the midface, with a moderately decreasing tendency in both sexes. In the lower jaw, the soft tissue showed significant increases in thickness in early adulthood and moderate to large decreases in late adulthood. Anthropometric analysis of the facial framework in adulthood marks only the first step in establishing the morphological changes of the aging face. Quantitative evaluation of changes within the facial framework of the aging population must be carried out in more detail. Increased worldwide migration results in a mixing of people of various racial/ethnic origins and necessitates a general anthropometric analysis of the aging face to provide more reliable guidelines for therapy.
Shareholders Meeting Questions (Draft) - Version 0.3
1 Company
1.a) In the 10K the company stated that it plans to move from its current 7,000 square foot building to a new 20,000 square foot building at a cost of approximately $1,000,000. DNAP has 12 full-time employees as per the last 10K and not much equipment. Can you explain why the additional space if needed and confirm the timescale?
1.b) Does the company intend to relocate to the new research facility being constructed at the USF, as indicated by having signed a letter of intent to do so? If not, has the company selected alternative premises? What is the timescale to finalize this decision and move to the new location? Will the existing offices at Cocoanut Avenue be retained?
1.c) Can you confirm the current number of employees, their function, and whether they are full time or part time or employed on a contract basis? Do all employees work at the company offices? What are the current plans for expanding the workforce in terms of numbers and functions of prospective employees?
1.d) In the January 2003 letter to shareholders, Dr. Frudakis intimated that shareholders would be able to participate in a warrants plan that the company intended at that time to implement. Why did the company not ultimately proceed with the warrants plan as initially envisaged?
1.e) In the January letter to shareholders, Dr. Frudakis stated that the common shareholders would be given the right to vote on any further issuance of shares. Since that letter was released, DNAP has issued over 200,000,000 shares. Why have shareholders not received proxies from the company in relation to these issuances?
1.f) What is the current status of the agreement with Genomedics Inc (GMED)? Is the agreement still in force and what are the implications (if any) of this for DNAP?
1.g) Early in the companies history there was much discussion of the Orchid option agreement. It was described as a six month window of opportunity in which Orchid could obtain the exclusive rights to the first completed product. Mention was made in newsletters that the terms of the option created some hesitation on the part of potential partners/customers as they did not wish to lose their negotiated rights should Orchid chose to exercise their option. Since then we have heard that the rights to the option have transferred to Beckman and there has been very little said in regards to it lately. Does the option still exist? If not, what completed product was used to trigger the six month window and in what time frame did it occur? If it still exists, what are the ramifications in terms of any approaching project completions? Since Ancestry and DNAWitness were developed under different circumstances we are under the impression that the option agreement does not apply to them, is that a correct assumption?
1.h) Much has been made of the technology and innovation of the company and the potential value that can result from exploiting them, but in terms of material value, what are the tangible assets of the company? We are aware that the building is leased and that the actual ownership of the major piece of equipment (Orchid UHT) is questionable. Aside from the office and lab equipment, is there any other capital equipment that is the property of the company? The products themselves (Ancestry and DNAWitness) can be considered assets, but as they are 'service based' there is very little inventory associated with them. (swabs, plastic bags, printed material etc.). The major asset of the company is presumably the 'platform' from which the various products are derived, what exact form does the platform take? Is it a program/database and associated documentation resident on a computer? Is it a documented and archived set of CD-ROMS? Is it a collection of various parts that coalesces into a functional entity under the careful management of a trained individual? Is it therefore a tangible object that can be described, backed-up or duplicated at will, or is it an intangible collection of expertise and knowledge that requires the involved participation of a single, or set of, individuals? The patent applications are a growing repository of potential value that will perhaps provide a tangible asset if they are ever granted, until they are however, they must be considered intangible. What Safeguards are in place to protect the assets of the company?
1.i) Presumably the platform is protected from competitive duplication by patent application. We can see where this would prevent a competitor from reading the patent application and duplicating the platform and going into business with a competing service. How would it prevent a major pharmaceutical company, for instance, from duplicating the platform and using it in the privacy of their own lab to develop new drugs. Drugs that would come out of the drug pipeline just like countless others before them. The drugs themselves would not be in competition with DNAP so what would be the path for litigating the patent rights? How would anyone know, by what mechanism would the use of a duplicate platform be revealed?
1.j) Given that the assets of the company, while potentially valuable, are knowledge based and therefore somewhat intangible, are there any particular safeguards in place to protect shareholder value in the event of unforeseen business failure? Are the assets documented and archived such that they can be reconstituted by knowledgeable individuals? Are they listed on an asset sheet so that they can be tracked by auditors? Are there by-laws in place that would require a shareholder vote before such key assets could be transferred or licensed?
1.k) What is the legal status of the Orchid device if the company entered bankruptcy?
1.l) Can the company confirm the status of the NIH and the NIJ grant applications?
1.m) Can the company confirm the status of the company's application for forensic laboratory accreditation?
1.n) What happened to the proposed private placement?
1.o) Can the company provide an update on the civil case in the Florida circuit court involving a former employee?
1.p) Are there are other current or pending legal actions involving the company?
1.q) Has the company been, is it currently, or will it potentially be involved with DNA Phenomics in Malaysia? If not, has the company identified another partner(s) for product distribution in the Asia Pacific market?
1.r) Are there any initiatives underway or planned in relation to partner(s) for product distribution in Europe?
1.s) If the company share price reaches .025 will funding under the La Jolla Cove agreement be discontinued, be suspended until the share price recovers, or will funding continue?
1.t) Can the company provide an update in relation to its previous indications about becoming a drug company?
1.u) The company previously indicated that it would at some future stage make license fee payments to Genetic Technologies. Can you explain the context, and anticipated magnitude and timescale of these payments?
2 Management
2.a) Can you explain and justify the level of management compensation and how this changed upon expiration of the original one year employment agreements for the management team?
2.b) Can you explain why it is necessary to have a Chief Financial Officer/Chief Operating Officer role at the present time? Would it have been possible to outsource these functions, possibly as an interim measure?
2.c) In previous SEC quarterly and annual filings, the company stated that the performance conditions necessary to award Dr. Frudakis' 30,000,000 performance shares had not been met, and were not likely to be met. The Board changed its position sometime during the second quarter of 2003. Can you provide the criteria the Board determined had been met to merit award of those shares?
2.d) What is Dr. Frudakis's involvement with the Biometrics Council (renamed to Biological Threats Council)? Are there any implications for the company as a result of his involvement with this initiative?
2.e) Can you provide an update on the status of the search for a Director of Marketing that was mentioned in the TWST article?
2.f) How do you justify the wide margin between revenues ($709,638), administrative costs (i.e. payroll is approximately $3,857,925) and net loss ($7,789,905)?
3 Scientific Advisory Board
3.a) Can you confirm the current composition of the SAB? Some individuals were previously listed in SEC returns and on the company website as being SAB members, e.g. Ramin Mirhashemi, Fernando Arena and DC Rao, but these individuals no longer appear to be SAB members. For any people who are no longer SAB members can you provide an explanation as to why they are not?
3.b) Can you explain the role of the SAB and the services that are typically performed by SAB members?
3.c) Can you explain how the remuneration level of 50,000 shares of common stock per annum was arrived at? In the Company's opinion is this sufficient to attract and retain the type of individual that the company would want as SAB members?
3.d) As per the last 10K the company has initiated plans to expand the SAB to include "other scientists who will actively contribute to our effort in increasing the number of BGA sub-categories from our current four, to as many as 20." Can you provide an update on how these efforts are progressing? Are there any current plans to expand the SAB to include scientists in disciplines other than biogeographical ancestry?
3.e) Can you explain the difference between the SAB and the Board of Consultants, which was also mentioned in the last 10K?
4 Investor Relations
4.a) A fundamental element to attracting and retaining capital investment in a public company is the need for professional Public Relations, Investor Relations and Marketing. This is an area of particular frustration for existing investors. How does the company plan to address these needs and when will we see improvements in these areas?
4.b) Does the company intend to provide newsletters on a regular basis in the future?
5 Website
5.a) Why are the “DNAP in the Press” and the “Conferences/Trade Shows/Presentations” sections of the company website not updated on a regular basis?
5.b) Why is the January 2003 letter to shareholders the only publicly released document from the company not available on the website?
6 Science
6.a) What relevance do the new AIMs in version 3.0 of ABD have in relation to DNAP's existing platform? The original ADMIXMAP impacted every part of DNAP's business and every dollar that went into finding those AIMs was maximized. Can the same be said for the new AIMs? Are they only relevant to genealogy and forensics or to all of the products? Do some of them “fine-tune” the ADMIXMAP platform?
6.b) Do AIMs related to pigmentation genes have any special significance in drug metabolism and associated pharmacogenomic classifiers?
7 Services/Products
7.a) The two major products in the market today are AncestryByDNA (ABD) and DNAWitness. We have heard positive things about both. Since the two products have been on the market for a number of months now can you share any market analysis that you have obtained. We have heard some fairly large estimates for the size of the market for DNA testing as it relates to the forensic space, but those estimates include such unrelated to DNAWitness categories as CODIS testing of convicted felons and backlogged rape kits. Do you have any market analysis that focuses on the specific number of applications available for the DNAWitness product? What is your projection for the growth curve for ABD, is it still growing, at what rate? Is the curve showing signs of exponential growth, linear growth or is it flattening out?
7.b) Can you confirm the current status of the development of ABD 3.0?
7.c) What kind of pricing is anticipated for the version 3.0 test bearing in mind the need to strike a balance between profit and affordability? Will current 2.0/2.5 customers get a significant discount on 3.0? If not will this not potentially have a detrimental effect on demand from these customers? Will DNAP honor its original promise to give free 3.0 tests to 2.0 customers from before 10/8/02?
7.d) Can you give any details about the parental populations used in the development of the AIMs? Specifically, what is the parental population for the Indo-European category? From what ethnic groups/part of Europe were these people from?
7.e) Is it possible that some of the admixture estimates that are derived are overestimated due to their being compared to a small (narrow) parental population?
7.f) What will the 20 categories be in ABD 3.0? Who is this product being developed in conjunction with and what are their aims for the project(s)? Is there an agreed taxonomy of racial categories and what correlation is there between any such taxonomy and the categories that the company intends to use?
7.g) Can the company provide any details of the scope and progress of the project to “date” admixture? How would such work result in new products or impact current products?
7.h) What is the company’s current anticipation of the likely adoption of DNA Witness for routine use by US and foreign Police Departments and/or Governmental agencies?
7.i) Can the company provide any details on the development of additional classifiers for traits such as hair color and facial features that would be components of DNA Witness?
7.j) Why has genotyping not been provided as a service to other companies to date? What are the current plans for offering this as a service? Why did the $1,000 genome scan appear not to generate market interest?
7.k) Will the company be providing so-called “validation genotyping” services for (GMED)?
7.l) Has any interest been expressed in the paternity testing service that was recently introduced by the company?
7.m) What is the status of Retinome? This was ostensibly 75% finished over two years ago. We then heard that the data was inconsistent due to ‘self reporting’ errors introduced by the participants, but a more sophisticated data set was obtained using digital equipment. We heard in a magazine article last summer Retinome would be introduced by the end of 2003. It is now mid 2004 and we have heard nothing lately. Could you clarify? What is the anticipated timetable for completion of this product and its launch in the market?
7.n) What is the status of Statinome? What is the anticipated timetable for completion of this product and its launch in the market? There has been some indication that competitors are working on similar projects, can you give us any indication of DNAP’s advantages or disadvantages in regards to these competing approaches?
7.o) What is the status of Ovanome? What is the anticipated timetable for completion of this product and its launch in the market?
7.p) Are there any other products currently in development or planned by the company?
8 Patent Applications
8.a) What is the current status of the various patent applications? What issues (if any) have been encountered in practice during the patent application review process? What is the company's expectation that any or all of these patents will be granted in due course?
8.b) Have all the inventions and patent applications been assigned to DNAP as the sole owner and assignee of those assets? If not, then who owns the inventions and patent applications?
8.c) Do all the employees of DNAP, including officers and staff members, and outside contract researchers have a written obligation to assign all of their inventions to the company as a condition of their employment or contract? If not, then how is ownership determined?
N.B. As utilized here, the term “inventions” comprise only those pertinent to the science, technology and business objectives of DNAP.
9 Collaborative Research
9.a) Can the company confirm the current status of the collaborative relationship with the University of Miami? Are Drs. Mirhashemi and Arena still employed by the University and are they participating in research with the company?
9.b) Is there any update on the FAMRI sponsored project on genetic susceptibility to cervical cancer in second hand smokers in conjunction with the University of Miami that was the subject of the press release in February 2003?
9.c) Can the company provide any update about the work that has been underway with New York University aimed at developing a transplant classifier?
9.d) Can the company explain what happened with the proposed collaboration with GeneLink which is apparently now not going forward?
9.e) Can the company provide more details about the relationship with H. Lee Moffitt (Moffitt) over and above what is contained in the 10K?
9.f) What is the nature of the relationship with Moffitt? Equal partners, both sharing in the costs of resources and materials of the various projects and then sharing equally in the resulting assets? Is DNAP acting as a service provider to Moffitt, being paid for their services and their expertise, but then Moffitt is the owner of any assets developed from the project. Is DNAP providing the project management or is it acting as a subcontractor taking direction from Moffitt? Is there some other form for the relationship? How does the company see the process of co-development and co-commercialization working in practice with Moffitt?
9.g) Can the company provide any detail on the due diligence work that was undertaken by Moffitt before collaborating with DNAP and confirm when the projects actually started?
9.h) Can the company confirm that the following projects are currently underway in conjunction with Moffitt: Colon Cancer, Multiple Myeloma, Cyclophosphamide, Taxanes? Is it possible to provide any additional detail on the scope and anticipated timetable for these projects? Are there any other projects currently in progress or planned to be undertaken with Moffitt?
9.i) Can the company explain why they terminated the license agreement with the Penn State Research Foundation? Does this have any affect on the company’s intellectual property or on other work underway, or future work planned, in conjunction with Dr. Shriver?
9.j) Is there any update on the National Institutes of Justice Funded Project that was the subject of the press release in August 2003?
9.k) Can the company confirm the scope and status of any projects underway in conjunction with Senecio Inc?
10 Listing
10.a) Can the company confirm that it has applied to be delisted from the Berlin Exchange and also confirm the status of the listing on the Frankfurt Exchange? Does the company have plans to list on other foreign exchanges?
10.b) Has the company considered possible courses of action to address potential naked short-selling of its stock? These could include delisting from exchanges, removing its stock from the DTCC system and issuing physical certificates, and recalling all of its stock and re-issuing it to shareholders of record.
10.c) Does the company intend ultimately to list on NASDAQ or AMEX (or some other exchange)? Is there any timetable for such a listing?
10.d) Approximately one year ago Dr. Frudakis stated in the TWST interview, that DNAP needed to get off the OTCBB and to the NASDAQ. He also stated that it would happen via a couple dramatic steps rather than several little changes. Have any of the "dramatic" steps taken place yet? If they have, can you identify the dramatic step? If not, can you give us an indication of what a “dramatic step” might entail?
11 Miscellaneous
11.a) Does the company intend to implement a reverse split of its stock in the foreseeable future? If not, how does the company think that the existing level of authorized shares will be perceived by the market? Is so, what would the ballpark split ratio be?
11.b) How does DNAP Utah impact/affect its wholly-owned operating subsidiary, DNAP Florida? What's the role/structure of the Utah parent company? Do they interact with DNAP Florida? If so, in what capacity? Is there overhead to DNAP Florida for this entity? Is Utah involved in the day-to-day operations of Florida? Do they handle employment contracts, etc? How many shares does Utah hold? Based on the above, what's the float?
The next post contains the amended list of questions. I have reflected all the changes suggested to date with the exception of the further numbering breakdown suggested by Robert, for which I still await a statement on consensus.
There appears to be some cynicism about whether the company will answer the questions. If we do not provide questions I can guarantee that the company will not answer them! We can only submit them and see. I have no reason to believe that the company would not find such a list useful input and indeed provide answers, unless they felt there was a good reason for not doing so (which I hope could also be communicated). If the company were not to provide any answers then IMO charges of lack of communication would indeed have some basis. Let's submit the list and see what happens.
Bag8ger was concerned about the appropriateness of questions relative to the potential newsletter and shareholder meeting. My view is that if the company has the superset of questions they can determine which will be covered by the proposed newsletter, or could be added to the end of this document in a Q&A section, and which it is more appropriate to address in another manner e.g. at the shareholder's meeting.
Can I suggest that Frog sends the final list by email to investor relations at 17:00 EST on Monday? I suggest a covering note similar to the following:
Dear Sir/Madam
Please find attached a list of questions that have been prepared and reviewed by posters on the Investors Hub and Raging Bull boards. We would be grateful if the company would consider these as input to the proposed shareholder meeting and/or to any newsletter (or similar communication) that the company might issue.
Frog, agreed. Perhaps the most pragmatic way to ensure that the individual question authors approve of W2P's suggested changes is to invite them to speak out if they do NOT approve. In the absence of any objections we can then de facto approve the proposed changes.
Frog, are you happy with W2P's comments and suggested changes?
Mike, still time to add questions. I suggested end of Monday as a cut-off. Your questions are IMO more client-oriented than shareholder-oriented, but are of interest as they have a bearing on revenue associated with ABD.
Miss Scarlet, OK if people would like this format I will reverse the version 0.3 changes into your text. If people further want to adopt Robert's breakdown then we can do that as well. If you can all reach a consensus I will make the changes.
66fan, an interesting question. I'll put it in the "listing" category for now. It might be an idea to add the rider: "if not, can you give us an indication of what a 'dramatic step' might entail"?
Nice article summarizing some of the issues with pharmacogenomics.
http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/05-27-2004/0002183055&....
Pharmacogenomics Could Replace 'Trial-and-Error' With Science From the Human Genome to Optimize Drug Therapy
Nature article from St. Jude points to challenges ahead and approaches that will be required to individualize drug therapy based on a patient's genetic make-up
MEMPHIS, Tenn., May 27 /PRNewswire/ -- The future use of a gene-based technology called pharmacogenomics could lower the cost of health care by decreasing the occurrence of adverse drug effects and increasing the probability of successful therapy. These findings are published by investigators at St. Jude Children's Research Hospital in the May 27 issue of Nature.
According to the authors, the significant potential for improving health and reducing cost will not be achieved unless three things happen. First, more studies must be undertaken to identify the network of genes that govern most drug responses. Second, systems must be developed to assist physicians and pharmacists in interpreting genetic tests for selecting drug therapy. Finally, legal protections must be put in place to preclude the misuse of genetic information from patients.
The science and technology of pharmacogenomics, which bases the choice of medications and their dosages on the patient's specific genetic makeup, is the basis of "individualized medicine," according to the article's co-authors, William E. Evans, Pharm.D., St. Jude Scientific director, and Mary V. Relling, Pharm.D., chair of St. Jude Pharmaceutical Sciences.
The key to pharmacogenomics is its ability to predict how a patient will respond to medications by identifying individual polymorphisms, or variations, in specific genes that contribute to that response. Pharmacogenomics can also help investigators discover more effective drugs, such as anti-cancer agents.
"Some genes are over-expressed in cancer cells that are either sensitive or resistant to anticancer agents, while other genes are under-expressed, or relatively inactive," Evans said. "Drugs designed to target the genes that are over-expressed in drug-resistant cancer cells would make logical targets for new anti-cancer drugs in an attempt to reverse this resistance."
Pharmacogenomic studies could also save potentially valuable new drugs from being abandoned during clinical trials because the medications are toxic to a small percentage of patients. Identifying the tell-tale "signature" of responses of specific genes known to occur in patients with toxic responses would allow clinicians to determine which individuals should not take the drug. This would protect patients from toxicity while allowing an otherwise effective -- and perhaps life-saving -- drug to be approved for use in patients who are at low risk of toxicity.
The use of pharmacogenomics in routine medical care will depend on a change in thinking among most clinicians, the authors say. Clinicians are generally educated to start treatment using an "average dose" rather than considering whether the patient might represent an exception to this rule.
"The medical and pharmaceutical communities tend to avoid trying to individualize therapy even using such simple patient characteristics as age or kidney function," Relling said. "So we've become accustomed to designing treatments using a "trial-and-error" approach. Incorporating pharmacogenomics into prescribing decisions will represent a major change for the health care community. Clinicians are reluctant to incorporate genetic information into the medical record, as long as it is not clear whether health insurance companies might discriminate against patients at high genetic risk for adverse health events."
The authors also warn that it is difficult to conduct clinical trials that prove that individualized drug therapy based on genetics actually improves outcomes. Such trials could be complicated by several factors: multiple genes might influence patient response to the drug; there might be interaction with other drugs given simultaneously; and the seriousness or rate of progression of the disease as well as diet and activities such as smoking might affect treatment outcome.
"Despite the enthusiasm researchers have for advancing biomedical technology and exploring the human genome, there is little willingness to incorporate pharmacogenomics into clinical trials," Evans said.
What is needed, according to the authors, are large-scale clinical trials that incorporate comprehensive pharmacogenomic studies. In order to bring the significant potential benefits of pharmacogenomics to the public, medical practice has to evolve from the trial-and-error approach. For that to happen, society must institute protections against misuse of genetic information.
Groups with a stake in better, affordable health care must also support the initial investment needed to develop the field of pharmacogenomics and incorporate it into daily clinical practice.
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay.
St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org .
SOURCE St. Jude Children's Research Hospital
Web Site: http://www.stjude.org
Miss Scarlet, we seem to be talking at cross purposes slightly. I understand the convention that you want to adopt. If we do that we essentially dispense with the current categories and each question that currently relates to a specific theme (i.e. keyword) becomes a category in it's own right. So, rather than "Products/Services" (or sub-divisions such as "Forensic", "Genealogy", "Paternity", "Genotyping", "Pharmacogenomics", etc.) we have "categories" like "DNAWitness", "ABD", "Statnome", Ovanome, etc. (which are essentially sub-sub-divisions) each of which has a new number.
Now a couple of points. The existing categories were used to try to make it easy and intuitive to locate topics. Merely giving a "category" such as "Statnome" a number (such as 27) does not per se achieve that objective. I could understand a convention that used the keywords themselves which would achieve this objective. This is what I was trying to intimate with my previous example. In your scheme you can add new questions to existing "categories" (using a,b,c, etc.); however if you have a new "category" you cannot add it to the list next to existing "categories" which it relates to without undertaking the renumbering exercise which we are trying to avoid. It would have to be appended to the end of the list, which means you lose the ability to organize the list by subject. In total I suspect we will end up with something like a hundred questions - even allowing for decomposing existing "multi-part" questions as per Robert's example. Looking at the current list you will end up with a lot of questions with the format "<number>.a" - because a lot of the questions are not multi-part. I am not sure this makes things clearer. Do you see what I am getting at?
I can certainly see an argument for precising some of the more verbose questions so that they are easier to understand. Some of Frog's questions perhaps fall into this category, although I perfectly understand why he has been as specific as he has with his questions - especially those that are dealing with complex issues such as the Orchid option agreement.
I would be interested in Frog's and other's views on this. I am perfectly happy to do whatever you like with the list (short of providing multiple choice answers to questions for the company's benefit) but we should not lose sight of the fact that the overall intent is to quickly agree a list of questions to forward to the company so that there is shareholder input to the pending newsletter and meeting. We should therefore perhaps not become too concerned with "format" rather than "content".
Regards
Ming
Miss Scarlet, OK but the sections are currently things like "Products/Services" (to deliberately match the organization of the company website). For say three statinome questions within this section (statinome being the first sub-section) would you therefore expect to see a numbering convention like PS.1.a, PS.1.b, and PS.1.c; or do you want the entire list to be reworked so that the existing sections are dispensed with and each sub-section becoming a number?
frog, this seems to be the only change that has been made - in which case I will append it to the Management section.
I see that Cosmic suggested a numbering system. We could do this but if you do not have a long list where you just add new questions on the end it is difficult as you have to keep renumbering questions if you insert any in the middle. It seems more useful to have the sections that currently appear in the list, as this makes things easier to find. You could use a numeric sequence within each section, but I am not sure this is necessary. I will include it if you REALLY want it Robert.