By O. Karmok. Franciscan University of Steubenville.

The distributions of three continuous variables in the data set order 150 mg fildena visa erectile dysfunction vacuum pump demonstration, that is buy fildena 150 mg on line erectile dysfunction treatment in uae, birth weight, gestational age and length of stay can be examined using the commands shown in Box 2. This option provides information about each variable independently of missing values in the other variables and is the option that is used to describe the entire sample. The default setting for Options is Exclude cases listwise but this will exclude a case from the data analysis if there are miss- ing data for any one of the variables entered into the Dependent List. Multivariate statistics refers to the analysis of mul- tiple variables at the same time. Therefore, the information for these 126 babies would be important for describing the sample if multivariate statistics that only include babies without missing data are planned. The characteristics of these 126 babies would be used to describe the generalizability of a multivariate model but not the generalizability of the sample. The Case Processing Summary table with the Exclude cases pairwise option shows that two of the 141 babies have missing birth weights, eight babies have missing gestational age and nine babies have missing length of stay data. This information is important if bivariate statistics (when only two variables are analysed at the same time) will be used in which as many cases as possible are included. In the table, all statistics are in the same units as the original variables, that is, grams for birth weight, weeks for gestational age and days for length of stay. The exceptions are the variance, which is in squared units, and the skew- ness and kurtosis values, which are in units that are relative to a normal distribution. Case Processing Summary Cases Valid Missing Total N Per cent N Per cent N Per cent Birth weight 139 98. Many measurements such as height, weight and blood pressure may be normally distributed in the community but may not be normally distributed if the study has a selected sample or a small sample size. It is also important to identify the position of any outliers to gain an understanding of how they may influence the results of any statistical analyses. A quick informal check of normality is to examine whether the mean and the median values are close to one another. From the Descriptives table, the differences between the median and the mean can be summarized as shown in Table 2. The percent difference is calcu- lated as the difference between the mean and the median as a percentage of the mean. That is, most data values should lie in the area that is approximately two standard deviations above and below the mean. A good approximate check for normality is to double the standard deviation of the variable and then subtract and also add this amount to the mean value. The estimated range should be slightly within the actual range of data values, that is the minimum and maximum values. For birth weight and gestational age, the estimated 95% range is within or close to the minimum and maximum values from the Descriptives table. However, for length of stay, the estimated 95% range is not a good approximation of the actual range. The estimated lower value is invalid because it is negative and the estimated upper value is significantly below the maximum value. If the two estimated values are lower than the actual minimum and maximum values, as in this case, the distribution is usually skewed to the right, indicating positive skewness. If the two estimated values are much higher than the actual minimum and maximum values, the distribution is usually skewed to the left indicating negative skewness. A perfectly standard normal distribution has skewness and kurtosis values equal to zero. Skewness values that are positive indicate a tail to the right and skewness values that are negative indicate a tail to the left. Values between −1and+1 indicate an approximate bell-shaped curve and values from −1to−3orfrom+1to+3 indicate that the distribution is tending away from abellshapewith>1 indicating moderate skewness and >2 indicating severe skewness. Any values above +3orbelow−3 are a good indication that the variable is not normally distributed. The Descriptives table shows that the skewness values for birth weight and gestational age are between −1and+1 suggesting that the distributions of these variables are within the limits of a normal distribution. As for skewness, a kurtosis value between −1and+1 indicates normality and a value between −1and−3 or between +1 and +3 indicates a tendency away from normality. For birth weight and gestational age, the kurtosis values are small and are not a cause for concern. In practice, dividing a value by its standard error produces 32 Chapter 2 Table 2. Extreme Values Case number Value Birth weight Highest 1 5 3900 2 54 3545 3 16 3500 4 50 3500 5 141 3500 Lowest 1 4 1150 2 103 1500 3 120 1620 4 98 1680 5 38 1710 Gestational age Highest 1 85 41. However, the valuesin the Extreme Values table are the minimum and maximum values in the data set and these may not be influential outliers. A uni- variate outlier is a data point that is very different to the rest of the data for one variable. An outlier is measured by its distance from the remainder of the data in units of the stan- dard deviation, which is a standardized measure of the spread of the data. A multivariate outlier is a case that is an extreme value on a combination of variables. For example, a boy aged 8 years with a height of 155 cm and a weight of 45 kg is very unusual and would be a multivariate outlier. It is important to identify values that are univariate and/or multivariate outliers because they can have a substantial influence on the distribution and mean of the variable and can influence the results of analyses and thus the interpretation of the findings. For a continuously distributed variable with a normal distribution, about 99% of scores are expected to lie within three standard deviations above and below the mean value. Sometimes a case, that is, a univariate outlier for one variable will also be a univariate outlier for another variable. Multivariate outliers can be detected by inspecting the residuals around a model or by using statistics called leverage values or Cook’s distances, which are discussed in Chapter 5, or Mahalanobis distances, which are discussed in Chapter 7. Outliers may be errors in data recording, incorrect data entry values that can be corrected, or genuine values. When outliers are from participants from another population with different characteristics to the intended sample, they are called contaminants. This happens, for example, when a participant with a well-defined illness is inadvertently included as a healthy participant. Occa- sionally, outliers can be excluded from the data analyses if they are contaminants or biologically implausible values. However, deleting values simply because they are out- liers is usually unacceptable and it is preferable to find a way to accommodate the values without causing undue bias in the analyses. It is important that the methods used to accommodate outliers are reported so that the generalizability of the results is clear. The Tests of Normality table provides the results of two tests: a Kolmogorov–Smirnov statistic with a Lilliefors significance correction and a Shapiro–Wilk statistic. A limitation of the Kolmogorov–Smirnov test of normality without the Lilliefors correction is that it is very conservative and is sensitive to extreme values that cause tails in the distribu- tion.

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Skin testing for allergies solved purchase fildena 100mg free shipping erectile dysfunction treatment options-pumps, he states that “the cold moved to my chest” about E order fildena no prescription erectile dysfunction louisville ky. A 46-year-old man is brought to your office by his but these are less frequent now. He is reluctant to admit that he has any health prob- been coughing that awakens him from sleep at night and lems. His wife, on the other hand, is adamant that some- ultimately has resulted in progressive fatigue. Specific triggers for his cough include eating frequently sleepy at work and falls asleep while watching cold foods, especially ice cream. He has no history of television at night, but he attributes this to stress on the asthma or prior history of prolonged cough. She describes loud snoring at night that begins almost symptoms of gastroesophageal reflux disease. He breathes immediately when he falls asleep, punctuated by long peri- easily through his nose and does not have seasonal rhi- ods of no breathing at all. He does not recall his vaccination history, normal oropharynx and has a short, squat neck. His lung but thinks he has not had any vaccinations since gradu- sounds are clear, and he has a protuberant, obese abdo- ating from high school. He is 190 cm amination, the patient’s wife demands to know what is tall and weighs 95. What are the piratory rate of 14 breaths/min, heart rate of 64 beats/ next steps in diagnosis and treatment? He and his wife should be reassured that his symp- nose, and throat examination reveals no enlargement of toms will improve as his work stress lessens. He should be prescribed a therapeutic trial of No forced expiratory wheezes are present. Which test is most likely to establish the diagno- plaint of cough and dyspnea on exertion that has gradu- sis correctly? Before 3 months ago the patient had no limita- systemic lupus erythematosus except tion of exercise tolerance, but now she reports that she A. A 68-year-old man presents to the emergency room has scattered rhonchi and faint expiratory wheezes bilat- with fever and productive cough. There is associated left-sided pleuritic chest chiectasis to explain his recurrent infections. Positive Gram stain or culture of the pleural fluid chiectasis in a patient with this history. A 45-year-old female is seen in the clinic for evalua- the following is the most common cause of mortality? She reports a cough that began in her early twenties that is occasionally productive of yel- A. Bronchiolitis obliterans innumerable courses of antibiotics, all with brief im- C. Posttransplant lymphoproliferative disorder that she has asthma, and her only medications are flutica- E. A 52-year-old alcoholic man presents to a local cal examination is notable for normal vital signs and an emergency room with purulent, productive cough, short- oxygen saturation of 92% on room air. He lungs have dullness in the upper lobes bilaterally and dif- thinks his symptoms started a few days ago. There is multiple positive cultures for Pseudomonas aeruginosa dullness to percussion over the right lower lung field, and and Staphylococcus aureus. A chest radiograph shows eral chest radiography shows bilateral upper lobe infil- a right-sided opacity in the superior portion of the right trates. Which of the following tests is the most important lower lobe with an air-fluid level present. Subsequent management should include scribes the symptoms as “ants crawling in her veins. A 72-year-old male with a long history of tobacco very hot bath to alleviate the symptoms. During sleep, use is seen in the clinic for 3 weeks of progressive dyspnea her husband complains that she kicks him throughout on exertion. She has no history of neurologic or renal dis- anorexia but denies fevers, chills, or sweats. She currently is perimenopausal and has been expe- examination, he has normal vital signs and normal oxy- riencing very heavy and prolonged menstrual cycles over gen saturation on room air. The physical examination, in- normal, and cardiac examination shows decreased heart cluding thorough neurologic examination, is normal. Serum ferritin is 22 nary examination, the patient has dullness over the left ng/mL. Which is the most appropriate initial therapy for lower lung field, decreased tactile fremitus, decreased this patient? None of the above have fallen because whenever he tries to read he finds himself drifting off. Which of the following is the most common under- exercising or brief naps of 10–30 min. Because of this, he lying medical condition of patients undergoing lung states that he takes 5 or 10 “catnaps” daily. Sarcoidosis once weekly, he awakens from sleep but is unable to move for a period of about 30 s. A 34-year-old woman complains of cough produc- of consciousness but states that whenever he is laughing, tive of green sputum, malaise, and headache over the past he feels a heaviness in his neck and arms. She notes that two of her children recently had lean against a wall to keep from falling down. His mean sleep latency on tion, she is afebrile, with a heart rate of 125 beats/min and five naps is 2. She has pronounced use of her acces- ings of this patient is most specific for the diagnosis of sory respiratory musculature. Increased risk of lung cancer intensive care unit with pneumonia secondary to Pneu- B. All of the fol- increased incidence of sepsis in the United States except lowing are important supportive measures for this pa- tient except A. A 68-year-old woman is brought to the emergency ment with complaints of 1–2 days of fever, malaise, room for fever and lethargy. Her son feels that He is uncomfortable but alert with temperature of she has had periods of waxing and waning mental status. On examination, she is lethargic breath sounds in the right lower lobe, and chest radio- but appropriate. Piperacillin/tazobactam blood cell count of 24,200/µL with a differential of 82% E. A 68-year-old woman comes to the emergency de- blood cells with gram-negative bacteria on Gram stain. She is a 1 pack per day ministration of 2 L, the patient has a blood pressure of cigarette smoker and works in a retail store.

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This will integrate multidisciplinary research order fildena canada erectile dysfunction caused by ptsd, with the goal of understanding the complex phenotypic consequences of genetic mutations at the level of the organism buy cheap fildena line erectile dysfunction pumps buy. Hardware and software engineers, as well as behavioral (and other) neuroscientists will co- develop test paradigms and equipment that will enable investigators to cope with the demands set by the increasing number of mutants generated by such techniques as transgenics or chemical mutagenesis. Phenomics will be a crucial approach in aca- demic, as well as industrial, research and could lead to a significant paradigm shift both in the genetic analysis of brain function and in drug development. It will be used to identify individuals who are incompatible with certain drug treatments before the drugs are prescribed and damage is done. It will be used to tease out important genetic determinants associated with complex genetic diseases, so that drugs can be developed to target these genes. Universal Free E-Book Store 130 4 Pharmacogenetics Limitations of Genotype-Phenotype Association Studies Although genotype-phenotype association studies are seemingly simple, in practice, they are prone to potential difficulties and problems. Plausible biologic context con- sistent with allele function, low P values, independent replication of an initial study, rigorous phenotypic assessment and genotyping, selection of appropriate and suffi- ciently large populations, and appropriate statistical analysis are all critical to the confidence that can be placed in a proposed association. Because such criteria are not always met, the risk of false-positive or false-negative errors is always possible. Some of the disparities between genotype and phenotype clarified by metabolomics as described in Chap. Molecular Toxicology in Relation to Personalized Medicines The term molecular toxicology covers the use of molecular diagnostic methods for studying the toxic effects of drugs. During preclinical testing, pharmacogenetics methods can be applied to determine drug toxicity at the molecular level during animal stud- ies or to provide an alternative to in vitro/in vivo assays. A number of assays have been developed to assess toxicity, carcinogenicity, and other genetic responses that arise when living cells are exposed to various chemical compounds. Two important categories of molecular toxicology are: toxicogenomics (use of genomic technolo- gies for the study of toxicology) and toxicoproteomics (see Chap. The object of these studies is to detect suitable drug candidates at an early stage of the discovery process and to reduce the number of failures in later stages of drug development. Toxicogenomics Toxicogenomics is the application of genomic technology to toxicology to study how the entire genome is involved in biological responses of organisms exposed to environmental toxicants/stressors. Researchers use toxicogenomic data to determine how human genes respond and interact with each other during different states of health, disease and challenges from toxicants. Technologies to measure and compare gene expression levels are being increasingly applied to in vitro and in vivo drug toxicology and safety assessment. Use of microarray technologies for toxicogenomics will be described later in this chapter. Universal Free E-Book Store Role of Pharmacogenetics in Pharmaceutical Industry 131 Increasingly, genetic polymorphisms of transporter and receptor systems are also recognized as causing interindividual variation in drug response and drug toxicity. However, pharmacogenetic and toxicogenetic factors rarely act alone; they produce a phenotype in concert with other variant genes and with environmental factors. Genomics is providing the information and technology to analyze these complex situations to obtain individual genotypic and gene expression information to assess the risk of toxicity. Biomarkers of Drug Toxicity This topic is discussed in detail in a special report on biomarkers (Jain 2015). Clinical chemistry endpoints for routine animal toxicity testing and clinical trial safety monitoring have been used for over 25 years. Drug-induced damage to the liver is the most common type of toxicity that results in withdrawn of a drug from clinical trials or from further marketing. Similarly, cardiotoxicity is a frequent occurrence in patients undergoing cancer chemotherapy. However, the currently available biomarkers for these common types of drug-induced toxicities have lim- ited sensitivity or predictive value. The proteomic tools available today are enabling us to tap into the wealth of genome sequence information to discover and carefully investigate associations of thousands of proteins with drug-induced toxicities. Methods for earlier, more accurate prediction and detection of toxicity can save lives by increasing the window for successful medical treatment, while identifying the best treatment methods for each patient. Drug-Induced Mitochondrial Toxicity Mitochondria are recognized as the producers of the majority of energy cells need for their normal activity. Because drugs can produce toxic effects through damaging mitochondrial bioenergetics, use of the organelle can be an effective and reliable bio-sensor to predict drug safety. Classic methods used to test the toxicity of a wide range of compounds on isolated mitochondrial fractions were later replaced by novel high-throughput methods to investigate the safety of a very large number of new molecules. The assessment of “mitochondrial safety” for new discovered mol- ecules is of interest for pharmaceutical companies, which can now select com- pounds lacking mitochondrial toxicity for further trials, thus avoiding the possibility of discontinuation of clinical trials later on due to mitochondrial toxicity (Pereira et al. Many drugs used to treat these diseases can cause toxic side effects that are often due to inhibition of mitochondrial function. MitoSciences’ MitoTox line of assays can identify drug toxicity before symptoms start to appear. Gene Expression Studies Gene expression is used widely to assess the response of cells to various substances. Two technologies will be described to illustrate the use in molecular toxicology studies. Transcript profiling technology has been used to pre- dict adverse toxicity for novel or untested compounds. Such arrays allow comprehensive coverage of genes associated with entire pathways (such as oxidative stress, signal transduction, stress response, epithelial biology) and enable simultaneous measurement of more several thousand gene expression events. Advantages of this format are the lower amount of sample needed and much easier handling. Cytotoxicity assays were among the first in vitro bioassay methods used to predict toxicity of drugs to various tissues. Xenometrix offers a broad range of cyto- toxicity assays for the in vitro evaluation of cells in response to pharmaceutical or chemical compounds. They are based on well established, sensitive and reliable endpoints of cytotoxicity and growth inhibition and are adapted for high throughput in microtiter plates. Pharmacogenetics in Clinical Trials Currently, the most significant polymorphisms in causing genetic differences in phase I drug metabolism are known and therapeutic failures or adverse drug reac- tions caused by polymorphic genes can be predicted for several drugs. Further investigations need to be done on the consequences of each pharmacogenetic phe- nomenon. Pharmacokinetic or pharmacodynamic changes my determine drug selec- tion or dose adjustment. Application of benefit of this approach in needs to be verified in prospective clinical trials using the parameters of Universal Free E-Book Store Role of Pharmacogenetics in Pharmaceutical Industry 133 reduction in adverse drug reactions, improved outcome and cost-effectiveness. Candidate Gene Approach This approach involves generation of specific hypoth- eses about genes that cause variations in drug responses, which are then tested in responders and non-responders. Candidate drugs that are selectively metabolized by polymorphic enzymes can be dropped early in drug screening. Based on the results of clinical trials, pharmacogenetic genotyping can be introduced into routine clinical practice. This provides significant opportunities to enhance current drug surveillance systems by collecting data that would enable rare serious adverse events to be predicted in subsequent patients before the medicine is prescribed.

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Remember: In the Type I situation order fildena canada xeloda impotence, H0 is really true (the variables are not related in nature) purchase fildena with mastercard erectile dysfunction treatment without medicine. Second, if you don’t make one type of error, then you are not automatically making the other error because you might be making a correct decision. Therefore, look at it this way: The type of error you can potentially make is determined by your situation—what nature “says” about whether there is a relation- ship. Then, whether you actually make the error depends on whether you agree or dis- agree with nature. As in the upper row of the table, sometimes H0 is really true: Then if we reject H0, we make a Type I error (with a p 5 ). In any experiment, the results of your inferential procedure will place you in one of the columns of Table 10. The most serious error is a Type I, concluding that an independent variable works when really it does not. For example, concluding that new drugs, surgical techniques, or engineering procedures work when they really do not can cause untold damage. For this reason, researchers always use a small to minimize the likelihood of these errors. Not only have we avoided any errors, but we have learned about a relationship in nature. This ability has a special name: Power is the probability that we will reject H0 when it is false, correctly concluding that the sample data represent a relationship. Power is important because, after all, why bother to conduct a study if we’re unlikely to reject the null hypothesis even when there is a relationship present? Therefore, power is a concern anytime we do not reject H0 because we wonder, “Did we just miss a relationship? To avoid this doubt, we strive to maximize the power of a study (maximizing the size of 1 2 ). We’re confident that if the relationship was there, we would have found it, so it must be that the relationship is not there. We can’t do anything to ensure that we’re in this situation (that’s up to nature), but assuming we are, then the goal is to have significant results. Therefore, we increase power by increasing the likelihood that our results will be significant. Results are significant if zobt is larger than zcrit, so anything that increases the size of the obtained value relative to the critical value increases power. Errors in Statistical Decision Making 229 We influence power first through the statistics we use. It is better to design a study so that you can use parametric procedures because parametric procedures are more power- ful than nonparametric ones: Analyzing data using a parametric test is more likely to produce significant results than analyzing the same data using a nonparametric test. Then, in case we’re in the situation where H0 is false, we won’t miss the relationship. Also, when we can predict the direction of the relationship, using a one-tailed test is more powerful than a two-tailed test. Together, these strategies minimize our errors, regardless of whether or not there is really a relationship. Power is increased by increasing the size of the obtained value relative to the critical value so that the results are more likely to be significant. Failing to conclude that an independent variable works although in nature it does is a ____ error. To be confident in a decision to retain , our decrease the likelihood of this, we keep alpha small. We would have no idea if this had occurred, nor even the chances that it had occurred. After finding a significant result, however, we are confident that we did not make a Type I error because the probability of doing so is less than. You then compute something like a z-score for your data on the sampling distribution when H0 is true. If the z-score is larger than the critical value, the results are unlikely to represent the populations described by H0, so we reject H0 and accept Ha. The results are called significant, meaning essentially that they are “believable“: The relationship depicted in the sample data can be believed as existing in nature rather than being a chance pattern resulting from sampling error. Inferential statistics are procedures for deciding whether sample data represent a particular relationship in the population. Parametric inferential procedures require assumptions about the raw score populations being represented. Nonparametric inferential procedures do not require stringent assumptions about the populations being represented. The alternative hypothesis 1Ha2 is the statistical hypothesis that describes the population s being represented if the predicted relationship exists. The null hypothesis 1H02 is the statistical hypothesis that describes the population s being represented if the predicted relationship does not exist. A two-tailed test is used when we do not predict the direction in which the dependent scores will change. The z-test is the parametric procedure used in a one-sample experiment if (a) the population contains normally distributed interval or ratio scores and (b) the standard deviation of the population 1σX2 is known. If zobt lies beyond zcrit, then the corresponding sample mean is unlikely to occur when sampling from the population described by H0. This is a significant result and is evidence of the predicted relationship in the population. If zobt does not lie beyond zcrit, then the corresponding sample mean is likely to occur when sampling the population described by H0. This is a nonsignificant result and is not evidence for or against the predicted relationship. Why does the possibility of sampling error present a problem to researchers when inferring a relationship in the population? Describe the experimental hypotheses and the independent and dependent variables when we study: (a) whether the amount of pizza consumed by college students dur- ing finals week increases relative to the rest of the semester, (b) whether breathing exercises alter blood pressure, (c) whether sensitivity to pain is affected by increased hormone levels, and (d) whether frequency of day-dreaming decreases as a function of more light in the room. For each study in question 11, indicate whether a one- or a two-tailed test should be used and state the H0 and Ha. We ask whether attending a private school leads to higher or lower performance on a test of social skills. Foofy claims that a one-tailed test is cheating because we use a smaller zcrit, and therefore it is easier to reject H0 than with a two-tailed test. If the independent variable doesn’t work, she claims, we are more likely to make a Type I error. Poindexter claims that the real cheating occurs when we increase power by increasing the likelihood that results will be significant. He reasons that if we are more likely to reject H0, then we are more likely to do so when H0 is true. Researcher A finds a significant relationship between increasing stress level and ability to concentrate. A report indicates that brand X toothpaste significantly reduced tooth decay rela- tive to other brands, with p 6.

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