Mark Corson

By L. Tom. Seattle University.

Polymerase Enzyme that assembles nucleotides to produce new strand of nucleic acid cystone 60 caps with visa. Originally isolated from bacteriumThermus aquaticusin hot springs of Yellowstone National Park buy cystone 60 caps on-line. Annealing (hybridization) 50°–70°C/ Primers attach to both template strands by binding with complementary 20–90 sec order 60 caps cystone fast delivery. Housekeeping gene detected control) & unrelated target (house- Differentiates true neg from false keeping gene or other nucleic neg due to amplification failure. Final probe is branched & carries signal-generating enzymes that act on chemiluminescent substrate. Cleavage-based amplification Isothermal method that uses primary probe, invader Detection of cystic fibrosis, factor (Invader technology) probe, reporter probe. Labeled probe (signal-generating probe) that anneals to different site on target added. Hybridized typing,Mycobacteriaspeciation complexes visualized with Biotin-Streptavidin method. Liquid-phase hybridization Target nucleic acid & probe interact in aqueous solution. After cancers/diseases, classification of amplification, sample & control nucleic acids labeled with leukemias, tumor staging, determi- 2 different fluorescent dyes & loaded onto chip. Single-stranded fragments transferred (blotted) to solid support medium by capillary action. Sequencing ladder 4-lane gel electrophoresis pattern obtained from dideoxy chain termination sequencing. Restriction site (recognition site) Nucleotide sequence recognized by restriction endonuclease. Band furthest from origin is smallest, fastest migrating fragment & ends in the 1st nucleotide in the sequence, e. Controlling Defining standards of performance, developing a reporting system, & taking corrective action when necessary. Organizational goals Administrator Runs organization within framework of policies given to him/her. Work environment Supervisor Oversees activities of others to help them accomplish specific tasks. Must be available on as-needed basis to provide on-site, telephone, or electronic consultation. Clinical consultant Consultation regarding appropriateness & interpretation of tests. Testing personnel Specimen processing, test performance, & reporting of test results. Measurement instrument Instrument to compare actual performance with desired performance. Evaluator Person trained in use of instrument, familiar with intricacies of job, time to dedicate to process. Feedback mechanism Plan for sharing results of review, taking corrective action, planning for future. Contrast error An individual is rated lower than justified because of comparison with another exceptional individual. Reverse halo effect Poor performance in one area influences evaluation in other areas. Recency phenomenon Judgments are made based on recent events or unusual incidents. Lean System developed by Toyota to improve quality by improving workflow & eliminating waste. Focuses on equipment layout, standardization of processes, cross-training, inventory management. Turnaround times are improved by grouping automated analyzers in core lab & replacing batch processing with single-piece flow. Tracer Methodology Internal audit tool to evaluate quality of patient care by following a specimen through preanalytic, analytic, & postanalytic phases of testing. Should delineate responsibilities for implementation/oversight & establish time lines. Considerations Cost, performance specifications, ease of use, turnaround time, impact on quality & cost of patient care, data management/connectivity/interface capabilities. Perform; demonstrate; explain; list; outline; label C Criteria Under what conditions? Following the directions in the Blood Bank Procedure Manual; after a lecture, demonstration, & practice session; without use of notes; within 30 min; without coaching D Degree Expected standard of performance. Psychomotor Physical skills Observe & imitate a Practice a skill Adapt existing skills to meet skill new demands or originate new procedures. Affective Attitudes, feelings, Receive & respond to Assess attitudes/feelings Organize & internalize values values information about into system that guides behavior. His together a variety of elements into a meaningful serum agglutinated A1cells & B cells. Management & Test-Taking Tips Education Review 595 • Set a study schedule & stick to it.

Depending on the defini- except that of the articulating surfaces in joints cheap 60caps cystone overnight delivery, tion purchase cystone 60caps overnight delivery, it starts at the 20th to 28th week of gestation which is covered by a synovial membrane discount cystone 60 caps on-line. For example, peripheral vision is the type of vision that allows a person to see objects that are peritoneum The membrane that lines the not in the center of his or her visual field. Peritonitis can result from infection, as nervous system that is outside the brain and spinal by bacteria or parasites; injury and bleeding; or dis- cord. The peritonitis, acute Sudden inflammation of the peripheral nerves include the 12 cranial nerves, the peritoneum that results in abrupt abdominal pain spinal nerves and roots, and the autonomic nerves. The most serious causes of acute The autonomic nerves are concerned with auto- peritonitis include perforation of the esophagus, matic functions of the body, specifically with the reg- stomach, duodenum, gallbladder, bile duct, bowel, ulation of the heart muscle, the tiny muscles that appendix, colon, rectum, and bladder; trauma; line the walls of blood vessels, and glands. Symptoms of peripheral neuropathy may include numbness, weakness, burning pain (especially at peritonitis, chronic Longstanding inflammation night), and loss of reflexes. Causes of chronic peritonitis include repeated attacks of infection such as from peripheral T cells See T cell, peripheral. Peripheral vascular disease can lead to pain in the legs when walking peritonsillar abscess A collection of pus (claudication) that is relieved by resting. A peritonsillar abscess is generally very painful and is usually associated with a periphery 1 The outside or surface of a structure decreased ability to open the mouth. In the stomach, this motion mixes food with gastric juices, turning it into a thin liquid. Personality disorders are enduring and dialysis catheter is surgically placed through the persistent styles of behavior and thought, not atypi- abdominal wall, into the abdominal cavity. The personality disorders encompass fluid is then flushed into the abdominal cavity and a group of behavioral disorders that are different washed around the intestines. The intestinal walls and distinct from the psychotic and neurotic disor- act as a filter between this fluid and the blood- ders. By using different types of solutions, waste defines a personality disorder as an enduring pat- products and excess water can be removed from the tern of inner experience and behavior that differs body. This form of dialysis can be done either markedly from the expectations of the individual’s manually or by machine at home, thereby avoiding culture, is pervasive and inflexible, has an onset in http://www. When teenagers and adults get pertussis, it the location of the metabolic process. For example, appears first as coughing spasms and then as a stub- glucose combined with a radioisotope shows where born dry cough that lasts up to 8 weeks. Symptoms seen right after birth in newborns and after violent may include communication problems such as vomiting or coughing. A person with petechiae using and understanding language; difficulty relat- should see a physician because they may be of ing to people, objects, and events; unusual play with major consequence. See also autism; Asperger’s like spots on the lips, mouth, and fingers and benign syndrome; Rett’s syndrome; childhood disinte- polyps in the intestines. The polyps may occur in any part of the gastrointestinal tract, but polyps in the pes cavus A foot with an arch that is too high. See also phantom limb syndrome; drome have affected parents and the other half have phantom tooth pain. Phantom p53 A specific protein with a mass of 53 kilodal- tooth pain may last for months and can spread tons that is produced by a tumor-suppressor gene. If p53 is physically lost or functionally inactivated, cells can grow with- phantom vision A phenomenon that involves out restraint. The pH number is from a is also concerned with the differences in the metab- scale where a pH of 7 is neutral, numbers less than olism of medications among children, adults, and a pH of 7 are increasingly more acidic, and num- senior citizens; men and women; and people with bers greater than a pH of 7 are increasingly more various medical conditions. A pharmacologist is usually especially in which the lens with the cataract is broken up by knowledgeable about new and obscure medications ultrasound, irrigated, and suctioned out. Pharmacologists usually act as consultants to primary care physicians or specialists. There are generally three phalanges (distal, lish official pharmacopeias, as do some medical middle, proximal) for each digit except the thumbs groups and health maintenance organizations and large toes. A pharmacy is constantly supervised phantom limb syndrome The perception of by a licensed pharmacist. Phantom pharmacy, compounding A place that both limb syndrome is relatively common in amputees, makes and sells prescription medications. A com- especially in the early months and years after limb pounding pharmacy can often concoct drug formu- loss. The leukapheresis, the leukocytes (white blood cells) pharynx serves as a vestibule or entryway for the tra- are removed; in plateletpheresis, the thrombocytes chea and esophagus. PhDs are involved in pheromone An agent secreted by an individual clinical care, biomedical research, health adminis- that produces a change in the sexual or social tration, teaching, and other areas of medicine. This translocation occurs in a cell in the bone phenomenon, Babinski See Babinski reflex. On a molec- phenomenon, phantom limb See phantom ular level the Philadelphia chromosome transloca- limb syndrome. Understanding this process led to the development of the drug ima- person’s genetic makeup and his or her environ- ment. By contrast, the genotype is merely the genetic tinib mesylate (brand name: Gleevec), the first in a constitution (genome) of an individual. Most philtrum The area from below the nose to the of the phe that is ingested is transformed (hydroxy- upper lip. In fetal lated) to form tyrosine, which is used in protein alcohol syndrome, the philtrum is flat. Too little phe does not permit normal phimosis A condition in which the foreskin of physical and intellectual growth.

The distribution of the residuals can be explored in more detail using standard tests of nor- mality in Analyze → Descriptive Statistics → Explore as shown in Box 2 buy cystone 60caps on-line. The descriptive statistics and the tests of normality show that the standardized resid- uals are normally distributed with a mean residual of zero and a standard deviation very close to unity at 0 generic cystone 60caps overnight delivery. For an approximately normal distribution generic 60caps cystone mastercard, 99% of standardized residuals will by def- inition fall within three standard deviations of the mean. In this sample size of 550 children, it would be expected that 1% of the sample, that is five children, would have a standardized resid- ual outside the area that lies between −3and+3 standard deviations from the mean. The Extreme Values table shows that residual scores for three children are more than three standard deviations from the mean and the largest standardized residual is 3. Analysis of variance 157 3 High leverage 2 Low discrepancy 1 0 High leverage High discrepancy Low leverage –1 High discrepancy 0. In addition, all three outliers have values that are just outside the cut-off range and therefore are not of concern. Leverage measures how far or remote a data point is from the remaining data but does not indicate whether the remote data point is on the same line as other cases or far away from the line. Thus, leverage does not provide information about the direction of the distance from the other data points. Cook’s distances are a measure of influence, that is, a product of leverage and discrep- ancy. Influence measures the change in regression coefficients (see Chapter 7) if the data point is removed. Therefore in practice, Cook’s distances above 1 should be investigated because these cases are regarded as influential cases or outliers. A leverage value that is greater than 2(k + 1)/n,wherek is the number of explanatory variables in the model and n is the sample size, is of concern. As with Cook’s distance, this leverage calculation is also influenced by sample size and the number of explanatory variables in the model. Leverage is also related to Mahalanobis 158 Chapter 5 distance, which is another technique to identify multivariate outliers when regression is used (see Chapter 7). Deciding whether points are problematic will always be context specific and several factors need to be taken into account including sample size and diagnostic indicators. If problematic points are detected, it is reasonable to remove them, rerun the model and decide on an action depending on their influence on the results. Possible solutions are to recode values to remove their undue influence, to recruit a study sample with a larger sample size if the sample being tested is small or to limit the generalizability of the model. In addition, it is important to report how any univariate or multivariate outliers were treated in the analysis and which interactions were tested. Other statistics to report are the total amount of variation explained and the significance of each factor in the model. Time is commonly measured as weeks, months or years but may be represented by other estimates such as age or school grade. When the outcome variable is continuous, two of the statistical methods that can be used to investigate changes in outcome and trends over time, both within and between study groups are: i. For analyzing data from cohort studies, models which offer the ability to compare differences at time points and/or between-exposure groups are ideal. In general, the sample size should be calculated on the basis of the number of vari- ables to be tested in the model including the outcome (dependent) variable. The number of participants needs to be much larger than the number of repeat measures because when the number of measurements exceeds the number of participants, the model used to analyze the data will have low statistical power. Calculation of the sample size required for repeated measures and linear mixed models can be complex and there are a few computing packages available (see Useful Websites). However, the calculation of power and sample size is not available for all types of mixed models. Generally the information that is required to calculate sample size for repeated measures or longitudinal analysis is an estimated effect size, the num- ber of repeated measures and an estimate of the correlations among pairs of the repeated measures. Cell size, that is the number of participants in each group of a fixed factor or in each sub-group if there are two or more factors, is an important consideration. Groups with small numbers may need to be combined with other groups if the theory is logical. If combining cells is not logical, groups with small cell sizes can be omitted from the model, although this may reduce the generalizability of the results. When the sample size is small, alternative outcome measurements such as area under the curve or average values should be considered rather than using a repeated measures or longitudinal analysis. Including all potentially predictive variables into a single model may introduce multicollinearity and may result in a number of small or empty cells and therefore reduce the statistical power. A sequential approach in which variables are Analyses of longitudinal data 163 added into the model one at a time in order of clinical importance or univariate evidence of effect conserves power because variables can be removed from the model if they are not significant predictors. At each step, the model can be examined for fit and signs of mulitcollinearity which can provide important insights into relationships between explanatory variables and developmental pathways. Any degree of error in measuring a variable is likely to increase variance and reduce statistical power. On the other hand, variables that explain a significant proportion of the variance and improve the fit of a model increase statistical power. There is obviously a trade-off between including all variables that improve the fit of a model and reducing the number of variables in order to maximize cell sizes and the precision that can be gained from the sample size. For example, when weight increase of infants is mod- elled, body length is an important covariate. In longitudinal data sets in which the covariate is measured at each time point the measurements may be highly correlated, and a time varying covariate such as age will also increase with time. In linear mixed models, if a covariate such as body length is included for each time point, the default option is that the mean value of the covariate across the model will be used. If the assumption of normality of residuals is not met, the direction of bias is not always clear.

Examples of evaluative tools include the use and verification of pathophysiological and/or descriptive biomarkers for patient selection for clinical trials and/or use as surrogate endpoints buy cystone 60 caps low price. Included among those are Genentech’s trastuzumab (Herceptin) trusted cystone 60caps, which requires that patients be tested for particular genetic characteristics and the results be considered before the drug is administered cheap cystone 60caps otc. It analyzes the activities of 21 genes in a sample of breast tumor and then computes a score that is said to be predictive of whether a patient’s cancer will recur and whether she would benefit from chemotherapy. While there are only a few such complex tests on the market now, their number is expected to grow. Therefore, the agency needs to look at the data on which these tests are developed. Some might have to come off the market until the developer can provide enough data for approval. Government agencies have been criticized for not doing more to clamp down on questionable genetic tests that are being sold directly to consumers. Three components are needed to ensure the safety and quality of genetic tests: (1) the laboratories that conduct the tests must have quality control and personnel stan- dards in place to prevent mistakes; (2) the tests themselves must be valid and reli- able – i. Once these mechanisms are in place, uses and outcomes also must be evaluated over time in order to pinpoint any problems that may require attention, particularly as new tests enter wider use. However, the requirement could also discourage the development of diagnostics by raising the costs of introducing them. The requirement could discourage gradual improvements of tests because each change in a test might require a new regulatory submission. The process for reviewing such tests is “contingent on the intended use of the device” therefore, design of studies and data sets required will be influenced Universal Free E-Book Store 674 22 Regulatory Aspects of Personalized Medicine by a particular use. In this instance, a test for the prognosis of breast cancer would require different data than a test used to diagnose the disease. The ultimate goal of the project is to guide the choice of targeted therapy so that patients receive the most effective treatments. The development of therapeutic products that depend on the use of a diagnostic test to meet their labeled safety and effectiveness claims has become more common. For example, if a therapeutic product is only safe and effective in a patient subpopulation identi- fied by a diagnostic test, the Indications and Usage section of the labeling must define the patient subpopulation. Likewise, if a diagnostic test is essential for moni- toring beneficial or adverse effects, the Warnings and Precaution section must iden- tify the type of test. When appropriate, the labeling can name a class of therapeu- tic products, rather than specific products within the class. In addition, it supports the evaluation of qualitative results for a specific clinical analyte, including: • Preparation of control transcripts • Design of primers and amplicons • Quality control • Use in final experimental or clinical test application • Analysis and interpretation of data obtained This document is intended to help ensure comparable within-platform assay per- formance to enable comparisons of gene expression results. The protocols will enable research and clinical laboratories, regulatory agencies, accrediting agencies, reference laboratories, as well as test, microarray, and reagent manufacturers to assess the performance of these expression assays. Regulation of Direct-to-Consumer Genetic Testing Various states are beginning to tackle the problem of uncontrolled personal genetic services. In 2008, New York State, warned 23 companies that they must have per- mits to offer their services to New Yorkers. New York’s warning letter was a blow not only to new companies such as Navigenics (now acquired by Life Technologies) and 23andMe that entered into the field of consumer genomics in 2007, but also to Universal Free E-Book Store Regulation of Direct-to-Consumer Genetic Testing 677 technology suppliers Affymetrix and Illumina, which make the tools the testing companies use. In 2008, Department of Health of the State of California, in an effort to prevent consumer genetic testing companies from offering their services to the state’s residents, sent letters to 13 firms saying they are violating state law. One offense that genetic testing companies could commit would be to sell their products to California citizens over the Internet without the request or counsel of a physician. Another problem is that the companies’ tests have not been validated for accuracy or for clinical utility, which is required under California law. The Genetic Alliance, a nonprofit health advo- cacy organization committed to transforming health through genetics, has suggested that informed decisions must be made on the basis of analytic and clinical validity, clinical utility, and individual usefulness, as well as an understanding of oversight, regulation, and reimbursement (Zonno and Terry 2009). Accurate, reliable, and vali- dated information must be available to individuals and providers as they make deci- sions about testing and the information gained through the testing process. Education regarding basic genetics and the testing process; professional society recommendations and guidelines, infor- mation for patients and providers on risk or diagnosis; and referral networks for spe- cialists, researchers, and disease-specific organizations could all be built into or linked with the registry. Such a system would be transparent and coordinated with all stake- holders and agencies to balances safety, innovation, ethical and social issues. Not doing so runs the risk of dangerously reassur- ing some and needlessly aggravating the already worried. In 2010, Navigenics (acquired by Life Technologies in 2012) received a license to offer its personal genomics services to residents of New York State. There are three important issues that consumer genomic testing needs to address before it can become part of medical care: • Analytic validity. A small error rate in sample can result in hundreds of misclas- sified variants for any individual patient. Many complex diseases are caused by multiple gene variants, and interactions between variants and environmental factors, which are not known yet. Few observational studies and almost no clinical trials demon- strate the risks and benefits associated with screening for individual gene variants. Universal Free E-Book Store 678 22 Regulatory Aspects of Personalized Medicine Ensuring that the public has information adequate to making informed choices about genetic testing is a prerequisite to realizing the public health benefits that have been promised from genetic medicine. The issues being studied relate particularly to the ways in which offering genotyping tests and services directly to customers by com- panies such as Decode Genetics, and 23andMe, differs from genetic testing offered by healthcare providers. The center also will conduct some legal analysis that supports coordinated efforts to protect consumers. Although they did not advocate an unregulated genomics market, the authors urged regulators to wait until information is available on the effects of such tests before introducing regulation. For instance, the team noted that personal genomics is pushing the individualization of responsibility for health one step further, without necessarily providing clear information about how genetics ties into health and individual choices.