By Y. Jens. North Park University.
Long-acting injections are frequently prescribed in cases of poor adherence and for consumers on community treatment orders generic piroxicam 20 mg without a prescription, which permit the involuntary treatment of some consumers whilst they reside in the community discount piroxicam online visa. Community treatment orders are typically granted when consumers are non-adherent and experience frequent symptom relapses that place their own or others’ safety at risk 20 mg piroxicam with amex. Long-acting depot formulations work by distributing medication throughout the body on a constant basis over the following weeks and then gradually leave the body after the one to six weeks have elapsed order 20mg piroxicam free shipping. Thus, the perceived advantage of this method is that it guarantees consistent delivery of the medication (David & Adams, 2001). Whilst the exact mechanism of antipsychotic medications is unclear, it is frequently proposed that they block dopamine receptors, thereby targeting the positive symptoms of schizophrenia (Van Os & Kapur, 2009). Consistently, randomised control trials of medication have shown that the potency of different antipsychotic medications can be explained almost perfectly by the amount of dopamine in the brain that is blocked by that medication (Mueser & Gingerich, 2006). This theory is disputed by research which demonstrates 17 that newer (atypical) medications bind less than older (typical) medications to dopamine receptors, yet are as efficacious (or more so in the case of clozapine) (Jones & Buckley, 2006). Negative symptoms and cognitive symptoms are not consistently improved by antipsychotic medication treatment. Doses below the dopamine binding threshold (approximately 60% dopamine receptor occupancy) are clinically ineffective for treating schizophrenia. The atypical medications, in general, have a wider therapeutic window, meaning that the difference between therapeutic and toxic levels is larger (Jones & Buckley, 2006). Another hypothesis is that the new medications are more selective in the parts of the brain they affect (Weiden et al. For example, there is more than one type of dopamine receptor, and different antipsychotics may have different effects on each type (Mueser & Gingerich, 2006). It was originally termed a ‘major tranquiliser’ due to its calmative effects in addition to dramatically reducing psychotic symptoms amongst agitated patients (Jones & Buckley, 2006; Schulz & McGorry, 2000; Weiden et al. The introduction of Chlorpromazine represented the first effective medical management strategy for schizophrenia and was, thus, deemed one of the great medical advances of the twentieth century (Sharif et al. Typical antipsychotics were breakthrough medications, as they provided therapy for psychosis, which had previously been almost impossible to treat (Conley, 2000). The effectiveness of antipsychotics in reducing the intensity of consumers’ positive symptoms- has permitted the outpatient treatment of schizophrenia and was associated with a dramatic reduction in mental hospital populations (Freedman, 2005; Schulz & McGorry, 2000). The typical antipsychotic medications currently in use include: Haloperidol, Thieridaxine, Thiothixene, Fluphenazine, Trifluoperazine, Chlorpromazine and Perphenazine. Over one hundred clinical trials have demonstrated the effectiveness of typical antipsychotic medications, including a series of double-blind placebo studies (Sharif et al. Research that has not supported the effectiveness of typical medications is generally restricted to poorly designed studies that involved ineffective dosages (Sharif et al. Although typical antipsychotic medications substantially reduce the positive symptoms of schizophrenia in some people, they have been documented as having no appreciable effect on cognitive dysfunction, and as having only a limited effect on, and even worsening, negative and depressive symptoms (Conley, 2000; Jones & Buckley, 2006; 19 Mueser & Gingerich, 2006; Weiden et al. Contradictory evidence exists, however, which points to clinical trials that indicate that all symptoms associated with schizophrenia improve with typical antipsychotic medication although, in general, positive symptoms respond to a greater degree and more consistently than negative symptoms (Sharif et al. Extensive evidence indicates that typical antipsychotic medications are essentially similar in efficacy profiles, however, individual consumers may respond better to one drug than another due to their different side effect profiles (Sharif et al. For example, while Chlorpromazine is quite sedating, Haloperidol is not (Mueser & Gingerich, 2006). The side effects of typical antipsychotic medications are frequently distressing and prominent and in addition to sedation, include: slowed thinking, dizziness, sexual dysfunction and sensitivity to sunlight. Anticholinergic side effects are also associated with typical antipsychotics, which include dry mouth, blurry vision, constipation, difficulty urinating and memory problems (Mueser & Gingerich, 2006). Tardive dyskinesia typically 20 emerges several months after the commencement of treatment and is potentially a lifelong condition (Weiden et al. It usually consists of involuntary movements of the head, tongue, lips, hands and feet and can affect speech, posture and sometimes breathing (Birchwood & Jackson, 2001; Jones & Buckley, 2006; Mueser & Gingerich, 2006). Typical presentations of the conditions involve protruding tongue, facial grimaces, and slow rhythmical movements of the hands and feet, sometimes even without the person knowing it (McEvoy et al. The chances of developing tardive dyskinesia can reportedly be reduced by using the lowest possible effective dose of medication (McEvoy et al. Since the development of the new, atypical antipsychotic medications, indications for typical antipsychotic medications are shrinking. McGorry (1992) posits that typical antipsychotic medications, in low dosages, may still have a role amongst a small proportion of consumers, who demonstrated a positive response to typical schedules including remission and good tolerability. They have also been indicated in the acute management of aggression or violence in some patients in the past (McEvoy et al. Advantages of typical antispychotic medications over atypical antipsychotic medications include greater medication familiarity for some consumers and clinicians and they are less expensive (Weiden et al. The development of atypical antipsychotic medications has also increased the probability of finding a suitable drug for individuals with schizophrenia, as there are now more options available to consumers and practitioners (Janssen et al. The wider choice offered by the advent of atypical medications, in addition to their increased tolerability, have been associated with more sustained adherence to prescriptions (Liberman & Kopelowicz, 2005). Clozapine, the first atypical antipsychotic medication, manufactured in 1959, was first tested in the 1970s and was discontinued due to serious blood reactions (Weiden et al. It was reintroduced for use in 1989 in the United States, followed by the introduction of the other atypical antipsyhotic medications in the 1990s or after 2000 (Weiden et al. The atypical antipsychotic medications currently available are: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, sertindole, zotepine and amisulpiride. With the exception of clozapine, these atypical antipsychotic medications were developed following years of scientific research aimed at understanding how typical antipsychotic medications work and trying to make more effective medications with fewer serious side effects (Mueser & Gingerich, 2006). Several studies have historically supported, and continue to support, the efficacy of atypical antipsychotic medications for treating positive symptoms of schizophrenia amongst treatment-responsive, recurrent- episode consumers, when compared with placebo (eg; Buchanan et al. A recent systematic review revealed some evidence that olanzapine, 22 ziprasidone and zotepine were more effective at reducing relapse rates over 12 months than placebo (Smith et al. A vast number of double-blind studies comparing the acute treatment effects of atypical antipsychotic medications with typical antipsychotic medications have been conducted. Many studies have claimed advantages of atypical medications over typical medications in terms of effectiveness. For example, it is often stated that atypical antipsychotics are more effective at treating negative symptoms and cognitive impairment and frequently lead to a better quality of life for consumers (Meltzer, 1999; Mueser & Gingerich, 2006). Furthermore, many experienced clinicians reportedly believe that the atypical medications are even better for negative symptoms than controlled trials have shown, as they have an antidepressant effect (Weiden et al. They have also been associated with cognitive-enhancing effects (Lewis & Lieberman, 2008). Research additionally indicates that atypical antipsychotics are highly tolerable, particularly for individuals with affective disorders and substance abuse problems, the young and elderly consumers (Conley, 2000). However, it is difficult to interpret the true advantages of atypical medications over typical medications in terms of efficacy, despite a significant body of research that indicates so. Furthermore, they have been reported to be up to ten times 23 less likely to induce tardive dyskinesia than typical antipsychotic medications (Jones & Buckley, 2006). Of note, clozapine is associated with virtually no risk of tardive dyskinesia, and has even been shown to reduce symptoms of the condition (Jones & Buckley, 2006; Weiden et al. Although anticholinergic side effects can still occur with some atypical antipsychotic medications, they are reportedly usually less severe than those associated with typical antipsychotic medications (Mueser & Gingerich, 2006). Atypical antipsychotic medications are associated with other serious side effects, however. In particular, they are more likely to cause metabolic effects, including the propensity to cause more weight gain and glucose elevation when compared with typical medications. Metabolic effects additionally increase consumers’ risk of developing diabetes, lipid abnormalities and coronary artery disease (Conley, 2000; Mueser & Gingerich, 2006). Like the typical antipsychotic medications, there is a considerable amount of intra-group variation of side effects amongst the atypical group of medications. In addition to research focused on effectiveness in treating symptoms and side effects, the schizophrenia literature also compares atypical antipsychotic medications with typical antipsychotic medications in terms of adherence rates, relapse likelihood, economic impact and amongst different populations of consumers. For example, research suggests that individuals who switch from typical antipsychotic medications to atypical antipsychotic medications are more adherent than those who continue taking typical antipsychotic medications (Janssen et al. Studies have also frequently associated atypical antipsychotic medications with reduced relapse rates compared to typical medications and report lower rehospitalisation rates with atypical medications compared to typical antipsychotic 24 medications (Conley, 2000; Weiden et al. In their systematic review and meta-analysis of studies assessing the potential of atypical medications to decrease relapse rates in schizophrenia, Leucht et al. Pharmaco-economic studies indicate that atypical antipsychotic medications are more economical than the typical antipsychotic medications, despite their disproportionately higher prescription costs, which is attributed to lower hospitalisation rates associated with atypical antipsychotic medications (Jones & Buckley, 2006). Atypical antipsychotic medication, clozapine, has been demonstrated to be effective in treating treatment-resistant schizophrenia (Buchanan et al; 2010; McGorry, 1992).
Then the total probability of the occurrence of the selected characteristics purchase piroxicam 20 mg overnight delivery, P(I) is calculated by formula 3 buy piroxicam 20mg on line. Obviously piroxicam 20 mg visa, some dependencies will exist purchase 20 mg piroxicam with amex, for example singly charged precursor ions always result in product ions al lower m/z. Therefore no exact quantitation of P(I) is obtained in this work, but rather a very good estimate. The result should therefore not be considered as a quantitative measure, but as a ranking tool for selectivity, e. The calculated value of P(I) in relation to the ranking of selectivity depends on fitness for purpose  and other factors affecting method selectivity like the preceding sample preparation procedure. In this work the applied sample preparation procedure is not taken into account in calculating P(I). Furthermore, if a derivatization procedure is used in the sample preparation procedure, e. Note that in this approach the relative ion abundances are not taken into account, whereas this would usually result in additional certainty on the identity of the compound. Therefore, the method presented here is on the safe side and gives an overestimation of the true P(I). It is observed that, in database A, an m/z of 387 is most common having a probability of 0. Consequently, interfering signals are more likely for compounds in the mass range around m/z 400 compared to the lower and higher mass range. Therefore, the detection of compounds with Mpr around m/z 400 is considered less powerful than detection of compounds with an Mpr of e. The obtained probability distribution is in good agreement with the distribution reported by Little et al. Kind and Fiehn, who used the Pubchem database  as a reference, found the highest probability at a slightly higher mass and reported a longer tail at the high mass range . This might be a result of the presence of complexes and compounds containing metal atoms present in the Pubchem database, which have been removed from database A. This is likely a result of the content of the eMolecules database, rather than a true lower relative occurrence of compounds at this specific mass. Probability distribution of the mass over charge ratio of the protonated molecules included in database A (n > 5,000,000). For application of the method without access to the original database, the probability distribution was modeled assuming binomial distributed data and using a logit link function. By doing so, P(Mpr) can be calculated by formula 4, in which Mpr is the m/z of a precursor ion. Some product ions show an exceptional high or an exceptionally low probability compared to this model (high residual) and for these cases the probabilities are presented individually in appendix 3. In the low mass range (Mpr = 100-200) the probability of the occurrence of a product ion around m/z 100 is the highest, in the mass range 200-300 this is m/z 140 and at the higher mass range (Mpr > 300) this is m/z 170. Overall a product ion at m/z 91 has the highest probability and is therefore the least selective, followed by 105, 121, 109, 100 and 72. The relation between the product ion probability distribution and the precursor ion mass was briefly studied. A clear decrease of the probability of the product ion at m/z 91 is observed with increasing precursor ion mass. One explanation for this observation is that for large precursor ion masses, sometimes only a limited product ion mass range has been acquired, missing certain low mass product ions. Therefore, the probability of product ions at m/z < 100 originating from large precursor ions can be 94 Chapter 3 somewhat underestimated. However, this effect is not apparent for the continuous distribution of product ions observed for high mass precursor ions and thus it is concluded that this effect is relatively small. The second explanation is that in large molecules, more sites are available to dissipate the dissociation energy and thus the number of fragment stabilization options increase with the molecular mass. As a result, the probability of producing s specific low weight product ions decreases. Modeling product ion probability for the selected precursor ion mass ranges yielded large differences in models compared to the overall product ion probability model. The differentiation in the selected precursor ion mass ranges was found to be effective in coping with the obvious dependency between product and precursor ion mass probabilities. Probability distribution of product ion masses for precursor ions of m/z (a) 100 - 200, (b) 200 - 300, (c) 300 - 400 and (d) > 400. Product ions showing a high residual from the constructed model are indicated with a cross. Although for neutral losses it is less obvious, a clear dependency between the neutral loss and the precursor ion mass was observed. Therefore, also for the neutral losses four product ion mass categories were established. Probability distribution of neutral losses for precursor ions of m/z (a) 100 - 200, (b) 200 - 300, (c) 300 - 400 and (d) > 400. Again, some neutral losses show an exceptional high or an exceptionally low probability 96 Chapter 3 compared to this model (high residual) and for these cases the individual neutral loss probability is presented in appendix 3. Overall a neutral loss of 18 Da has the highest probability and is therefore the least selective (as was reported previously ), followed by 46, 17, 45, 60, 73 and 59. From experience, it was expected that the loss of water (18 Da), ammonia (17 Da), formic acid (46 Da) and acetic acid (60 Da), and for larger molecules glycoside (162 Da), have a high probability and are thus non-selective. However, other observations are not considered general knowledge, like the low selectivity of the neutral loss 59 and 73 Da. The neutral losses of 22 – 25 Da have an exceptionally low probability (Pnl=0) compared to the empirical model. This can be explained because neural losses at these masses are chemically impossible; no molecular structure can be drawn that is in agreement with these neutral loss masses. In a previous version of database B the high probability of neutral loss 162, 176, 194 and 308 Da were quite dominant. These neutral losses are all to some extend related to the loss of glycoside, galactoside and glucuronide moieties. Especially the high probability of 176 Da was caused by the inclusion of the data obtained from Wissenbach et al. After removal of these data from database B, the probability of 176 Da dropped from 0. This demonstrates that the construction of the product ion spectra database is crucial for correct interpretation of the selectivity. To further improve this procedure the database should be extended to equally represent compounds from different groups. The relation between the neutral loss probability distribution and the precursor ion mass was studied. This might be explained by the increasing number of dissociation reactions possible with increasing molecular mass, e. As expected, the probability of multiple dissociation reactions in a high mass molecule increases, together resulting in higher neutral loss values. However, they divided the compounds in eight groups that were modeled individually, each group containing compounds with similar properties. From this model, the prediction error was calculated, which is the combination of the residual standard error of the model and the standard error of the regression line parameters. Because the residual standard deviation of the model is significantly larger than the standard deviation of the regression line parameters, the prediction error is 0. The largest probability of co-elution is observed for extremely hydrophilic compounds that do not show retention on the chromatographic system. Application of the procedure As an illustration of the proposed procedure given in figure 3. P(Mpr) is empirically determined from the probability distribution presented in figure 3. P(Mpd) and P(Mnl) of both mass transitions are empirically determined respectively from the probability distributions presented in figure 3. It is observed that the proposed procedure supports the legal requirement of monitoring at least two product ions : P(I) strongly increases when using two products ions, as expected. Cumulative distribution function of the fraction of the compounds (n=200) versus P(I) using (dotted line) one product ion and (solid line) two product ions. To be able to answer this question a calculated value P(I) should be ranked in terms of method selectivity, e.
New developments in advanced drug delivery always result purchase piroxicam with paypal, at first safe 20 mg piroxicam, in high-priced products which are more affordable in developed economies generic piroxicam 20mg without prescription. This will apply particularly to gene therapy delivery systems and targeted anticancer therapies order discount piroxicam on-line, because these are expected to command very high prices. At the same time, delivery systems which were revolutionary and high-priced on their first introduction (e. The increasing use of advanced drug delivery technology by generic companies is bringing it more into the realm of everyday medicine. Antihypertensive drugs form the largest product category within this market, accounting for sales of some $20 billion. Some antihypertensives are also used for long-term maintenance in angina, while there is a separate group of drugs used for short-term angina relief. Annual sales of antihypertensive and anti-anginal products using advanced drug delivery technology are estimated to be around $5 billion worldwide at 1995 levels, representing one-sixth or more of all cardiovascular sales. This share will increase in the near term, as sales of older drugs in conventional dosage forms decline. Anti-inflammatory drugs The market for prescription drugs used in the treatment of major inflammatory diseases, including arthritis and rheumatism, is currently valued at $7 billion worldwide. In fact Voltarol is the leading product in this market, with sales around $1 billion, largely contributed by the long-acting version. Most usage is still in the area of cytotoxic drugs, with hormonal therapy growing dramatically in recent years due to the increasing use of drugs such as tamoxifen. Because of their high price, these new products represent an unusually large share of the market; most cytotoxic and hormonal products are mature and relatively low-priced. The main opportunity for advanced drug delivery systems in this market is in the area of targeted drug delivery. Current research is focused on the development of carriers such as liposomes and on the use of monoclonal antibodies as targeting agents (see Sections 5. The eventual market opportunity is considerable—cancer is still one of the commonest fatal diseases, and some of the most deadly forms are resistant to available therapies. The potential market for effective targeting delivery systems may eventually exceed $5 billion. Whether, and how soon, it achieves this figure will depend on the speed with which successful products come to market. Anti-asthma therapies The asthma market is thought to be worth some $6 billion worldwide, and consists mainly of inhaled products—bronchodilators and corticosteroids. It is a growing market because the incidence of asthma is increasing, especially in developed countries. It has been postulated that this increase is partly related to overuse of inhaled bronchodilators, which can mask progression of the underlying inflammatory disease process. The asthma market will almost certainly continue to grow, with increasing use of inhaled therapy, favoring stronger growth of steroids over bronchodilators in the current climate of opinion. However, inhalation products now available go a considerable way towards compensating for the drawbacks of early metered-dose aerosols. The major suppliers (including AstraZeneca, 3M and GlaxoSmithKline) have developed improved delivery devices, as well as dry powder formulations and control of medication particle size to optimize penetration into the lung (see Chapter 10). However, it seems likely that the main factor driving this market upwards in the near term will be the rising prevalence of asthma, fuelling annual market growth in the region of 8–10%. Diabetes Insulin is the only currently effective treatment for the millions of diabetics who suffer from Type I diabetes (also known as insulin-dependent and juvenile onset diabetes). Insulin is a peptide, and if given orally it is broken down by enzymes in the gut (see Section 1. Although manufacturers have introduced user-friendly devices such as insulin pens, an effective, less invasive alternative would be instantly popular. This is an area in which active research is under way, including a project at Inhale Therapeutic systems to develop an inhalation dosage form (see Chapter 10). It is estimated that if an effective pulmonary formulation is developed and receives approval, there would be a 20% switch from the injectable products within a year. Assuming an initial high price (perhaps 30% above that of injectable insulin), this represents potential sales of $400 million for the new product a year after launch. There is a continuing demand for oral delivery systems, not only to preserve the commercial viability of major drug products as they come off-patent but also to solve specific problems such as delivery of large molecular weight drugs including calcitonin and insulin. Thus, although this sector of the market may have a smaller share of the total in 5–10 years time, it will continue to be a major opportunity for growth. Significant improvements in inhaler technology have already been made, and increasing use of these more sophisticated devices is already driving market growth; so will advances in absorption efficiency being sought by companies such as Inhale Therapeutic Systems. Separately, there is active research into the possibility of delivering, by the inhalation route, drugs which previously had to be given by injection. Although this condition is rare, and therefore does not represent a large market opportunity, the successful treatment of cystic fibrosis by means of inhaled gene therapy would encourage research into other therapeutic possibilities using the lung as an absorption site. Transdermal The transdermal market experienced a period of dramatic growth in the early 1990s, led by the popularity of nicotine patches as an aid to smoking cessation, and the growing use of hormone replacement therapy by this route. Growth has since slowed down, as some of the enthusiasm for nicotine patches waned. Another potent market driver in the transdermal sector is the growing numbers of elderly in the populations of developed countries. This will lead to increasing use of hormone replacement therapy, not only as a short-term treatment for menopausal symptoms but for the long-term prophylaxis of osteoporosis. Thus the transdermal market sector is expected to rise from its present value around $3 billion towards $5 billion or more in the next five years. Mucosal Mucosal absorption has been a rather neglected opportunity in the advanced drug delivery market; the mucous surfaces of the body—including the mouth, nose, rectum and vagina—offer less of a barrier than the skin to the systemic absorption of drugs, so it is surprising that more attention has not been paid to mucosal delivery systems. Practical difficulties include the fact that rectal dosage forms have never been widely acceptable in some countries, and the mouth and nose are not suitable for dosage forms which must remain in place for a prolonged period. However, they are ideal for rapid absorption of drugs when prompt effect is important, for example anti-anginals. Products formulated for mucosal delivery are now thought to contribute less than 5% of the total advanced drug delivery market, but wider utilisation of the mucosal route, now being researched by companies such as Theratech, 3M and Nomen, may eventually create a market worth over $300 billion. Parenteral The parenteral category includes such areas of major potential as the development of novel long-acting (implant) dosage forms (see Section 4. Thus, although parenteral advanced drug delivery systems now account for a very small share of the total advanced drug delivery market, they are likely to make a more significant impact when current research yields marketable products. Because much of this research is at an early stage, the parenteral sector may not achieve its full potential until well into the 21st century, with sales projected to rise to $2. This sector soon attracted the attention of pharmaceutical entrepreneurs who saw opportunities for specialist formulation companies. By the late 1970s there were a number of such companies in operation, including Alza, Elan, Eurand and Pharmatec International. Typically, there would be a development fee for such work, paid in stages as the project reached successive goals; finally, the client would either pay the developer royalties on the sales of the successful formulation, or subcontract production of the finished product to the advanced drug delivery company. These types of arrangements are still the basis for most development work in the advanced drug delivery sector carried out on behalf of pharmaceutical clients by specialist companies. Some of the early entrants into this field have expanded their activities into delivery routes other than their original core technology, so that they can offer solutions in the transdermal, inhalation and other fields as well as oral formulations. This is true of Alza, Elan and 3M, the latter being something of a hybrid since it is also a pharmaceutical company in the conventional sense. By contrast, some companies in this field are linked to specific routes of administration; Inhale Therapeutic systems, as its name implies, focuses on inhalation technology, while Pharmatec International, one of the oldest-established advanced drug delivery concerns, remains committed to the oral route. Drug delivery technology demands continual innovation in order to meet increasingly complex clinical demands and accommodate the needs of sophisticated new drugs. This places a heavy burden on existing specialist companies in terms of R&D commitment; it has led to the birth of a considerable number of small, research-driven concerns, often built around pharmaceutical specialists and teams from academia or the formulation departments of major pharmaceutical companies. Like companies in the biotechnology sector, these new ventures are set up to develop and exploit specific technologies, but their path to financial self- sufficiency is often shorter than that of a typical new biotech venture, because the regulatory hurdles are fewer when a new chemical entity is not involved. Here, the underlying technology is so new that it cannot even be described as “pharmaceutical” in any conventional sense.
D The bias is defined as the difference between the Chemistry/Evaluate laboratory data to assess the means of the two methods and is calculated using validity/Accuracy of procedures/Statistics/3 the formula: bias = y – × cheap piroxicam 20 mg free shipping. The student’s t test is used to determine by running 40 paired patient samples in duplicate if bias is statistically significant 20 mg piroxicam for sale. Te following results are is the ratio of bias to the standard error of the obtained: mean difference buy 20mg piroxicam with amex. B Proportional error (slope or percent error) results Method x (reference 235 mg/dL 3 buy piroxicam 20 mg without prescription. For example, if both level 1 and Assuming the samples are collected and stored level 2 controls for laboratory A average 5 mg/dL in the same way and the analysis done by a below the cumulative mean reported by all technologist who is familiar with both methods, other laboratories using the same method, then what is the bias of method y? When the magnitude of error increases with increasing sample concentration, it is called: A. Bias Chemistry/Evaluate laboratory data to assess validity/ Accuracy of procedures/Statistics/2 5. D A bias plot compares the bias (candidate method minus reference method) to the result of the 5 reference method. When the majority of points is below the zero line, 0 the candidate method is negatively biased (lower than the reference). A The linear regression analysis is the most useful statistic to compare paired patient results because -15 it estimates the magnitude of specific errors. Two methods that measure the same margin analyte will have a high correlation coefficient, C. Te new method is lower than the reference provided the concentrations are measured over a method by 5 mg/dL wide range, and this statistic should not be used D. Te new method is lower than the reference and to judge the acceptability of the new method. Each sample was assayed by both methods within 30 minutes of collection by a technologist familiar with both methods. Linear regression analysis was performed by the least-squares method, and results are as follows: Linear Correlation Standard Error of Regression Coefficient (r) Estimate (sy/x) ŷ=2. Tere is no disagreement between the methods because the correlation coeﬃcient approaches 1. Tere is no systematic error, but the random error of the new method is unacceptable Chemistry/Evaluate laboratory data to assess the validity/Accuracy of procedures/Statistics/2 234 Chapter 5 | Clinical Chemistry 44. False positives Chemistry/Calculation/Speciﬁcity/2 80 Answers to Questions 44–46 60 44. B The scatterplot shows that each sample produces a coordinate (x corresponds to the reference result 40 and y to the candidate method result) that is very close to the regression line. This means that the variance of regression is low and there is a high 20 degree of certainty that the predicted value of y will be close to its measured value. Te methods agree very well but show a high equation for this scatterplot is y = –0. Tere will be a signiﬁcant degree of uncertainty which is equal to (ŷ – xc) where xc is the expected in the regression equation concentration, and ŷ is the value predicted by the D. The probability of false positives is calculated from the speciﬁcity as: % speciﬁcity 1–( ) 100 5. A new tumor marker for ovarian cancer is Answers to Questions 47–50 evaluated for sensitivity by testing serum samples from patients who have been diagnosed by staging 47. C Sensitivity is deﬁned as the percentage of persons biopsy as having malignant or benign lesions. A new test for prostate cancer is found to have a 100, then dividing by the sum of true positives and sensitivity of 80. B Since the concentration of an analyte may not be by the regional population of adults age 18 and normally distributed in a population, the reference older. Te analyte concentration is known to be range should not be determined from the standard independent of race and gender. A minimum of 120 samples is the analyte from 40 healthy adults and calculate needed for statistical significance. Measure the analyte in 120 healthy adults and lowest value and the 118th is the highest value in calculate the central 95th percentile the reference range. Measure the analyte in 60 healthy adults and range, it can be considered valid for the patient 60 adults with conditions that aﬀect the analyte population. When comparing the laboratory’s monthly mean Answers to Questions 51–53 to its peer group to determine if bias is present, what statistic is most appropriate? Standard deviation index mean, and allows performance comparisons for any analyte. Which of the following methods is most useful distribution to a t test and a value greater than 2. Signiﬁcant change limit intervention is likely needed to prevent injury or Chemistry/Apply knowledge to identify sources of death. The significant change limit is the difference error/Statistics/2 in test results that is medically significant, or that 53. Which of the following total quality management which cannot be attributed to the sum of normal tools can be used to calculate the analytical error physiological and analytical variation. Laboratory information system patient’s status, other causes are sample misidentification, contamination, and random Chemistry/Apply principles of laboratory operations/ error. Delta limits are expressed in percent and Quality management/2 vary depending on analyte stability. At the six-sigma level, the analytical process has such small variance that an error of six times the standard deviation would still be within acceptable limits for total allowable error. For example, a six-sigma process for an analyte produces a signiﬁcant error in test result only 3. Conversely, a method performing at the three-sigma level would give 66,807 errors per million. The sigma of a method is calculated by subtracting its bias from the total method error and dividing by its standard deviation. In which circumstances is a validation study Answers to Questions 54–55 (versus performing routine quality control) required? Source lamp or ion selective electrode change two levels of control material following the C. Change in calibrator lot alter the test system more dramatically, especially when the reagent was subjected to storage and Chemistry/Apply principles of laboratory operations/ shipping conditions that alter its performance. Deamination of dibasic amino acids 2% daily from the oxidation of creatine mainly in D. Creatine can be converted to Chemistry/Apply knowledge of fundamental biological creatinine by addition of strong acid or alkali or by characteristics/Biochemical/1 the enzyme creatine hydroxylase. B Creatinine concentration is dependent upon muscle measure endogenous renal clearance because: mass, but varies by less than 15% per day. Te rate of formation per day is independent of is not metabolized by the liver, or dependent on diet, body size and is 100% ﬁltered by the glomeruli. It is completely ﬁltered by the glomeruli reabsorbed signiﬁcantly but is secreted slightly, C. Chemistry/Apply knowledge of fundamental biological characteristics/Biochemical/1 3. B Serum creatinine is a specific but not a sensitive measure of glomerular function. Serum levels are elevated in early renal disease serum creatinine becomes elevated. High serum levels result from reduced creatinine diminishes as serum creatinine increases glomerular ﬁltration in renal disease, the creatinine clearance is more C. Serum creatine has the same diagnostic utility as sensitive than serum creatinine in detecting serum creatinine glomerular disease. Serum creatinine is a more sensitive measure of 60 mL/min indicates loss of about 50% functional renal function than creatinine clearance nephron capacity and is classified as moderate Chemistry/Calculate laboratory data with physiological (stage 3) chronic kidney disease. Which of the following formulas is the correct same quantity of substance that is excreted in the expression for creatinine clearance? Separate reference ranges are needed for males, females, and children because each has a diﬀerent percentage of lean muscle mass. Which of the following conditions is most likely to Answers to Questions 5–8 cause a falsely high creatinine clearance result? D Urine in the bladder should be eliminated and not when collecting his or her urine saved at the start of the test because it represents B.