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In our exam- ple discount 160mg fenofibrate otc cholesterol ratio average, the null hypothesis states that there is no difference in death rate due to myocardial infarction between those patients who took aspirin daily and those who did not purchase fenofibrate 160 mg amex tasty cholesterol lowering foods. By starting with the proposition that there is no association purchase fenofibrate 160mg visa cholesterol chart webmd, statis- tical tests estimate the probability that an observed association occurred due to chance alone fenofibrate 160mg mastercard cholesterol levels understanding the numbers. Rejecting the null hypothesis is a vote in favor of the alternative hypothesis, which is then accepted by default. The only knowledge that can be derived from statistical testing is the proba- bility that the null hypothesis was falsely rejected. Therefore the validity of the Hypothesis testing 111 alternative hypothesis is accepted by exclusion if the test of statistical signiﬁ- cance rejects the null hypothesis. For statisticians, the reference point for signiﬁ- cance of the results is the probability that the null hypothesis is rejected when in fact the null hypothesis is true and there really is no difference between groups. This appears to be a lot of double talk, but is actually the way statisticians talk. The letter P stands for the probability of obtaining the observed difference or effect size between groups by chance if in reality the null hypothesis is true and there is no difference between the groups. Sir Ronald Fisher, a twentieth-century British mathematician and founder of mod- ern statistics one day said it, and since he was the expert it stuck. He reasoned that “if the probability of such an event (falsely rejecting the null hypothesis) were sufﬁciently small – say, 1 chance in 20, then one might regard the result as signiﬁ- cant. How many tails in a row would you tolerate before beginning to sus- pect that the coin is rigged? Sir Ronald reasoned that in most cases the answer would be about four or ﬁve tosses. The probability of four tails in a row is (1/2)4 or 1 in 16, and for ﬁve tails in a row (1/2)5 or 1 in 32. There is always talk in biomedical research circles, usually by pharmaceutical or biotech companies, that the level of signiﬁcance of 0. This means that we would accept one chance in ten that the difference found was not true and only occurred by chance! This would be a poor decision, and the reasoning why will be evident by the end of this book. Errors in hypothesis testing The results of a clinical study are tested by application of a statistical test to the experimental results. The researcher asks the question “what is the probability that the difference between groups that I found was obtained purely by chance, 1 From G. The universal truth cannot always be determined, and this is what’s referred to as clinical uncertainty. Researchers can only determine how closely they are approaching this universal truth by using statistical tests. A Type I error occurs when the null hypothesis is rejected even though it is really true. In other words, concluding that there is a difference or association when in actuality there is not. There are many ways in which a Type I error can occur in a study, and the reader must be aware of these since the writer will rarely point them out. Often the researcher will spin the results to make them appear more important and sig- niﬁcant than the study actually supports. Manipulation of variables using tech- niques such as data dredging, snooping or mining, one-tailed testing, subgroup analysis, especially if done post hoc, and composite-outcome endpoints may result in the occurrence of this type of error. In other words, the researcher concludes that there is not a differ- ence when in reality there is. An example would be concluding there is no relationship between hyperlipidemia and coronary artery disease when there truly is a relationship. By convention the power of a study should be greater than 80% to be considered adequate. As the power of the microscope increases, smaller differences between cells can be detected. This is important Hypothesis testing 113 because a negative result may not be due to the lack of an effect but simply because of low power or the inability to detect the effect. This is fairly common in the liter- ature and includes studies of new drugs against placebo instead of older drugs. Studies of drugs for acute treatment of migraine headaches may be done against drugs that are useful for that indication, but in doses that are inadequate for the management of the pain. The reader must have a working knowledge of the stan- dard therapy and determine if the new intervention is being tried against the best current therapy. Studies of new antibiotics are often done against an older antibi- otic that is no longer used as standard therapy. But, since the current standard is prevention in the form of inﬂuenza vaccine, the correct study should in fact have been comparing the new drug against the strategy of prevention with vaccine. This is a much more complex study, but would really answer the question posed about the drugs. Any study of a new treatment should be com- pared to the effect of both currently available standard therapies and prevention programs. Effect size The actual results of the measurements showing a difference between groups are given in the results section of a scientiﬁc paper. The effect size, commonly called δ, is the magnitude of the outcome, association, or difference between groups that one observes. It often can be expressed as either an absolute difference or the percentage with the outcome in each group or the event rate. The effect size for outcomes that are dichotomous can be expressed as percentages that achieved the result of interest in each of the groups. When continuous out- comes are evaluated, the mean and standard deviations of two or more groups 114 Essential Evidence-Based Medicine can be compared. A statistical test will then calculate the P value for the difference between the two mean values, and will show the probability that the difference found occurred by chance alone. If the measure is an ordinal number, the median is the measure that should be compared. In that case, special statistical methods can be used to determine the P value for the difference found. The clinically signiﬁcant effect size is the difference that is estimated to be important in clinical practice. It is statistically easier to detect a large effect like one representing a 90% change than a small effect like one representing a 2% change. Therefore, it should be easier to detect a difference which is likely to be clinically important. However, if the sample size is very large, even a small effect size may be detected. This effect size may not be clinically important even though it is statisticallysigniﬁcant. Event rates In any study, researchers are interested in how many events of interest happen within each of two treatment groups. The outcome of interest must be a dichoto- mous variable for this set of calculations. The most common varilables are sur- vival, admission to the hospital, patients who had relief of pain, or patients who were cured of infection. The reader ought to be able to clearly determine the outcome being measured and the dif- ferences between the groups are usually expressed as percentages. The control group consists of those subjects treated with placebo, comparison, or the cur- rent standard therapy. The experimental group consists of those subjects treated with the experimental therapy.
Behavior of rabbit chondrocytes during tissue culture and subsequent allografting order 160mg fenofibrate visa food cholesterol chart singapore. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells generic fenofibrate 160 mg free shipping cholesterol deep conditioner. Region specific generation of cholinergic neurons from fetal human neural stem cells grafted in adult rat trusted fenofibrate 160 mg does cholesterol medication make you tired. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats 160 mg fenofibrate fast delivery bon cholesterol definition. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Human feeders support prolonged undifferentiated growth of human inner cell masses and embryonic stem cells. The challenges of cell-transplantation and genetic engineering for the treatment of diabetes and haemophilia. Insulin-secreting cell derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Mechanisms of immune suppression by interleukin-10 and transforming growth factor beta: the role of T regulatory cells. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane. Establishment of tendon-derived cell lines exhibiting pluripotent mesenchymal stem cell-like property. Tissue-engineered cartilage and bone using stem cells fromhuman infrapatellar fat pads. Bridging tendon defects using autologous tenocyte engineered tendon in a hen model. Bone marrow-derived mesenchymal stem cells influence early tendon-healing in a rabbit achilles tendon model. Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction. Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue-derived stromal cells. Chondrogenic potential of adipose tissue-derived stromal cells in vitro and in vivo. Multilineage cells from human adipose tissue: Implications for cell-based therapies. In vitro differentiation of human processed lipoaspirate cells into early neural progenitors. Transformation of adult mesenchymal stem cells isolated from the fatty tissue into cardiomyocytes. Differentiation of in vitro modified human peripheral blood monocytes into hepatocyte-like and pancreatic islet-like cells. Cultivation of rat marrow-derived mesenchymal stem cells in reduced oxygen tension: effects on in vitro and in vivo osteochondrogenesis. Incubation of murine bone marrow cells in hypoxia ensures the maintenance of marrow-repopulating ability together with the expansion of committed progenitors. Extensive in vivo angiogenesis following controlled release of human vascular endothelial cell growth factor: implications for tissue engineering and wound healing. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Role of vascular endothelial growth factor in bone marrow stromal cell modulation of endothelial cells. The role of bone grafting in the treatment of delayed unions and nonunions of the tibia. The osteogenic potential of culture-expanded rat marrow mesenchymal cells assayed in vivo in calcium phosphate ceramic blocks. Bone formation in vivo: comparison of osteogenesis by transplanted mouse and human marrow stromal fibroblasts. Culture expanded canine mesenchymal stem cells possess osteochondrogenic potential in vivo and in vitro. The effect of implants loaded with autologous mesenchymal stem cells on the healing of canine segmental bone defects. Autologous bone marrow stromal cells loaded onto porous hydroxyapatite ceramic accelerate bone repair in critical-size defects of sheep long bones. Healing of segmental bone defects with granular porous hydroxyapatite augmented with recombinant human osteogenic protein-1 or autologous bone marrow. Repair of large bone defects with the use of autologous bone marrow stromal cells. The use of percutaneous autologous bone marrow transplantation in non-union and concentration of progenitor cells. Percutaneous bone marrow grafting of delayed union and nonunion in cancer patients. The use of percutaneous autologous bone marrow transplantation in non-union and concentration of progenitor cells. Bensaid W, Oudina K, Viateau V, Potier E, Bousson V, Blanchat C, Sedel L, Guillemin G, Petite H. De novo reconstruction of functional bone by tissue engineering in the metatarsal sheep model. Analysis of ectopic and orthotopic bone formation in cell-based tissue-engineered constructs in goats. Successful healing of Refractory Tibial Non-union by combined Calcium Sulphate and Stromal Cell Implantation. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Microfracture technique for full- thickness chondral defects: technique and clinical results. Results after microfracture of full-thickness chondral defects in different compartments in the knee. Repair of human articular cartilage after implantation of autologous chondrocytes. Relationship between cell shape and type of collagen synthesized as chondrocytes lose their cartilage phenotype in culture. Mesenchymal cell- based repair of large, full-thickness defects of articular cartilage. Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports.
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The likelihood that ev¬ evidence as determinants of clinical de¬ knowledgeable with respect to current idence-based medicine can help amelio¬ cisions; the relevant literature may not therapeutic guidelines in the treatment rate these problems should encourage be readily accessible; and the time avail¬ of hypertension than were the gradu¬ its dissemination. While strategies for inculcat¬ Some solutions to these problems are tion of the evidence-based medicine ap¬ ing the principles ofevidence-based med¬ already available. Reference to literature over- dence ofits superiority in improving pa- practices into postgraduate medical ed- Downloaded from www. AnnIn- ical journals, V: to distinguish useful from useless interim results for symptomatic patients with se- tern Med. A a diagnostic market test: lessons from the rise and Outcome-based doctor-patient interaction analysis. Rapid advances in genomics, as demonstrated by the tangible use of gene diagnosis and targeted thera- pies indicate that the impact of genomics in healthcare is only going to increase. The debate is not “if genomic medicine will impact healthcare” as much as how rapidly it will impact healthcare. However, caution needs to be exercised with respect to three key enablers whose success is critical in order to fully harvest the potential of genomics and successfully integrate genomics in healthcare. Health service organizations and healthcare leaders will play a pivotal role in this regard, by beginning to strategize and plan for how they will incorporate genomics into healthcare delivery. IntroductIon The impact of genomic medicine on healthcare continues to generate healthy debate in the literature (Epstein 2004). The availability of over 1,500 genetic tests and several targeted therapies and the use of pharmacogenomic data for drug and dosage selec-1 2 tion suggest that genomics is already integrated into healthcare and that it will be a game changer. On the other hand, there is scepticism regarding the current and future impact of genomics in healthcare because of the lack of everyday use of such technolo- gies in clinical practice, the questionable clinical utility and validity of some genetic tests and the availability of only a handful of targeted therapies amidst others that have failed clinical trials. Regardless of which position one chooses to take, recent accomplishments in genomics demonstrate that healthcare stakeholders have a remarkable opportunity – an oppor- 1 A type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells. Targeted therapy may have fewer side effects than other types of cancer treat- ments (National Cancer Institute N. Data from a number of recent publications and websites affirm that the current use of genomics in everyday clinical practice represents only the tip of the iceberg. In the case of chronic diseases in particular, such data will lead to significant pre-emptive measures to prevent the onset of disease years in advance of symptoms appearing. This paper examines these enablers and outlines opportunities for health service organizations and health professionals to plan for the integration of genomics in healthcare. The genetic alphabet contains four nucleotides bases – adenine, guanine, cytosine and thymine – which chemically combine in pairs: adenine with cytosine and guanine with thymine. It is estimated that there are three billion base pairs in the human genome and approximately 20,000–25,000 protein-coding genes. Clearly, the billion-plus data elements needed to define even one person’s genetic signature are several orders of magnitude more complex than the few hundred to few thousand data points in a traditional medical record. Rather than dealing with diseases after they have manifested themselves, genomics allows clinicians to look into a person’s future and determine what diseases that person is susceptible to and which drugs and interventions hold the highest likelihood for success. It changes healthcare from retrospective, interventional care to prospective, preventative care that is highly personalized and pre-emptive. The true value of genomic medicine rests in understanding and incorporating genomic information, both from clinical and research outcomes, into a person’s health record. Genomics will become an integral part of a person’s medical record for the following reasons: • The cost of sequencing an individual complete genome will decrease from hundreds of thousands of dollars to under $1,000. Genomic medicine will also have a significant impact on healthcare delivery due to its intensely personal, predictive, ethical, legal and social dimensions and impacts. She would then face emotional upheaval on learning her risk for breast and ovarian cancer and a very personal choice regarding what to do with this information (e. Genomic testing therefore creates a new demand for people who can interpret and accurately and compassionately deliver such information. Genomics is already impacting healthcare, although mainly in specialized settings. Figure 1 depicts early successes in specific types of cancer, where genomics has already enabled pre-symptomatic diagnosis, personalized therapy and personalized drug dosages. Genomics enabled approach to specific cancers Pre-symptomatic or symptomatic Targeted therapy Pharmacogenomic gene test, risk, prediction testing for dosage Pre-symptomatic diagnosis Personalized therapy Personalized drug dosage e. These data provide a basis for diagnosis and, if possible, a determination of personalized treatment(s). However, the presence of mutations in these genes increases the lifetime “likelihood” of developing breast cancer and other cancers, such as ovarian cancer. Predisposition testing can also test for rarer gene disorders that manifest in adulthood (e. Pharmacogenomic testing enables an understanding of how an individual’s genetic variation for specific drug-metabolizing enzymes may affect the body’s response to the drug being administered (Epstein 2004; Johnson 2003). Using such profiles to adjust warfarin dosage can prevent complications of warfarin treatment. Most drugs produce a spectrum of responses in various people: from no effect in some, to a moderate effect in most, to an absolute cure in a few. Targeted therapy aims to identify those persons for whom a given drug is highly efficacious, and avoid giving the drug to those in whom it will have little or no effect. This not only provides a path to novel therapies, but also rehabilitates older drugs that have cured some people, but on average have had little effect or been overly toxic. The genomic approach toward drug-target isolation offers significant advantages over the tried and tested approaches that pharmaceutical companies have used. Such therapies are precise and hence possess high efficacy, but often only in a subset of individuals with a specific condition. For example, screening for and treating phenylketonuria provides net direct cost savings to society. In the case of imatinib, a first-line therapy for chronic myeloid leukemia, a six-year increased survival rate over interferon-alpha therapy has been noted, with a $43,100 per life-year saving (Reed et al. Prenatal genetic testing, genetic predisposition testing and pharmacogenomic testing are three categories of tests which are regularly being offered to healthcare consumers today. However, data from research studies detailing clinical outcomes based on pharmacogenomic testing and the appropriate dosage of specific drugs remain sparse. Similarly, data on clinical outcomes associated with genetic and genomic interventions are more the exception than the norm (Scheuner et al. The business of genetics – examples of molecular diagnostic testing three companies offering molecular diagnostic testing 5 Genomic Health Inc offers a molecular based test – OncotypeDx, which analyzes the expression patterns of a panel of 21 genes and provides a likelihood of breast cancer recurrence in women with newly diagnosed early stage breast cancer. In addition, this test is also able to predict the benefits from certain types of chemotherapy. Thus, based on the results of this test, it is possible to screen for and differentiate women with a specific type of breast tumour who may not benefit from chemotherapy. Genzyme offers a comprehensive menu of genetic testing for single gene disorders e. Navigenics offers a Health Compass package which includes 24/7 access to genetic counsellors ongoing, secure, personalized updates for an entire year, adding new condition predispositions, new markers, new clinical therapies, other wellness strategies, and easy-to-use, relevant health information. Gefitinib is an anti-cancer drug for patients with recurrent non-small-cell lung cancer who have specific mutations within a specific gene. Through genetic testing, candidates for gefitinib (instead of chemotherapy) can be identified. Imatinib is a drug therapy that affects the molecular cause of chronic myeloid leukemia.