Part 2 book Veterinary clinical epidemiology From patient to population includes content: Design and evaluation of clinical trials, statistical significance, medical ecology and outbreak investigation, measuring and expressing occurrence, establishing cause, source and transmission of disease agents, the cost of disease. Đề tài Hoàn thiện công tác quản trị nhân sự tại Công ty TNHH Mộc Khải Tuyên được nghiên cứu nhằm giúp công ty TNHH Mộc Khải Tuyên làm rõ được thực trạng công tác quản trị nhân sự trong công ty như thế nào từ đó đề ra các giải pháp giúp công ty hoàn thiện công tác quản trị nhân sự tốt hơn trong thời gian tới.
VetBooks.ir Design and Evaluation of Clinical Trials 8.1 INTRODUCTION Throughout this text, a distinction has been made between epidemiologic studies of naturally occurring disease and laboratory studies of experimentally induced disease Within the field of clinical epidemiology, the evaluation of treatment effects (the clinical trial) comes as close to a laboratory experiment as any activity that we have discussed In evaluating clinical trials, the practitioner must consider not only whether the data support the author(s)’ conclusions, but also whether the study design was appropriate for the question being asked In this chapter, we first examine factors that can influence the outcome of clinical trials and then apply these criteria to selected case studies Treatments should be adopted not because they ought to work, but because they work Therapeutic hypotheses may come from an understanding of the mechanisms of disease, clinical observations, or epidemiologic studies of populations Regardless of their source, new treatment regimens must be tested In other words, treatments should be adopted not because they ought to work, but because they work (Fletcher et al., 1982) 8.2 EFFICACY, EFFECTIVENESS, AND COMPLIANCE Efficacy is a measure of how well a treatment works among those who receive it Effectiveness, on the other hand, is a measure of how well a treatment works among those to whom it is offered Compliance is a measure of the proportion of patients (or their owners) that adhere to a prescribed treatment regimen Thus, an efficacious treatment could be ineffective due to poor compliance This relationship can be summarized as Effectiveness ≈ Efficacy × Compliance Intention-to-treat (ITT) analysis considers the outcome for all subjects entered into a trial, regardless of whether they received the treatment they were actually supposed to receive, e.g., analysis according to treatment assigned rather than treatment received It is a measure of treatment effectiveness It addresses the question actually faced by clinicians: Which treatment choice is best at the time the decision must be made? Per-protocol analysis only considers the outcome for subjects that actually received an intervention, regardless of the group to which they were originally assigned (Fletcher et al., 2014) ITT analyses may prevent overestimation of treatment efficacy in case of substantial withdrawal of study subjects, as in response to adverse drug effects (Olivry and Mueller, 2003) 8.3 CLINICAL TRIALS: STRUCTURE AND EVALUATION Practitioners initiate an observational study of treatment effects every time they treat a patient However, because of the many potential sources of bias during routine patient care, a more formal approach to evaluating treatment outcomes is usually required The clinical trial is a cohort study 133 134 Veterinary Clinical Epidemiology VetBooks.ir (2, 3) Control (1, 3) Patients (4) Allocation (5) Intervention (6, 7) Outcome (2, 3) Treatment FIGURE 8.1 Design and potential sources of bias (see Table 8.1) in clinical trials (From Fletcher RH et al Clinical Epidemiology—The Essentials Baltimore: Williams and Wilkins; 1982 With permission.) specifically designed to facilitate the detection and measurement of treatment effects, free of extraneous variables Because of the experimental nature of clinical trials, they are sometimes referred to as intervention or experimental studies The design and potential sources of bias in a clinical trial are depicted in Figure 8.1 and summarized in Table 8.1 They are discussed in greater detail in Sections 8.3.1–8.3.8 below When designing a clinical trial, the first step should be a determination of the minimum number of subjects required to achieve the desired level of statistical power Too few subjects and random variation in outcome may obscure the effects of a beneficial treatment Study subjects are allocated to either treatment or control groups Both are treated identically with the exception that the treatment group receives an intervention that is believed to be beneficial The control group usually receives a placebo, an intervention designed to simulate the act of treatment but lacking its beneficial component(s) Any differences that emerge between the two groups over time are attributed to the treatment Virtually any parameter can be used to measure and express the outcome of a clinical trial In veterinary medicine, the outcome may be expressed in terms of the health benefit to the patient, or as productivity or economic benefits The clinical trial is a cohort study specifically designed to facilitate the measurement of treatment effects, free of extraneous variables There are two measures of validity for clinical trials: internal and external Internal validity refers is the extent to which conclusions drawn from a study are correct for the sample of patients being studied External validity (generalizability) is the degree to which results of a study can be generalized to the population at large from which the sample was drawn, e.g., the target population The first requirement for external validity is internal validity, e.g., invalid conclusions from a clinical trial will also be invalid when applied to the broader population of patients However, a study may produce valid results but still lack external validity because study subjects are not representative of the general patient population Examples might be clinical trials whose patient composition does not accurately reflect the gender, age distribution, or clinical severity of patients at large External TABLE 8.1 Factors That May Influence the Outcome and Relevance of Clinical Trials Is the case definition explicit, exclusive, and uniform? Is a comparison group explicitly identified? Are both treated and control patients selected from the same time and place? Are patients allocated to treatment and control groups without bias? Is the intended intervention, and only that intervention, experienced by all of the patients in the treated group and not in the control group? Is the outcome assessed without regard to treatment status? Is the method used to determine the significance of the observed results defined explicitly? Can we be certain that the observed results could not have occurred by chance alone? VetBooks.ir Design and Evaluation of Clinical Trials 135 validity can be maximized by selecting study subjects that are as similar as possible to the patient population to which the results are to be generalized Many factors (biases) can affect the internal validity of cohort studies of risk, prognosis, and treatment (Sackett, 1979) These generally originate from one of the following sources (Fletcher et al., 2014): Selection bias: Selection (or assembly) bias occurs when the criteria for inclusion of patients in a study not ensure uniformity of individuals Patients may differ in ways that are not under study and that can affect the outcome Measurement bias: Measurement bias occurs when uniform standards for measurement of clinical events cannot be maintained over time Confounding: Confounding occurs when two factors are associated with each other, or “travel together,” and the effect of one is confused with or distorted by the effect of the other The effect of confounding is usually dealt with during data analysis, after the study is over The criteria outlined in Table 8.1 have proven useful for reducing bias in cohort studies The points at which they influence the outcome of a clinical trial are indicated in Figure 8.1 and discussed in greater detail below Many factors can affect the outcome of cohort studies of risk, prognosis, and treatment These generally originate from assembly, migration, measurement, or confounding bias 8.3.1 Case Definition The first step in a clinical trial is selection of patients who meet the case definition This is not as easy as it might first appear It may be difficult to define a set of disease signs that will include all true cases of a disease and exclude similar, but unrelated, conditions Few cases will show the complete range of disease signs and symptoms; thus, minimal criteria for a diagnosis often have to be established As the number of signs and symptoms required to meet the case definition increases, the definition becomes more and more restrictive and includes a progressively smaller number of cases Furthermore, the criteria used for the case definition should be uniformly applied when multiple clinics are involved Misclassification bias (a form of information bias) occurs when the assignment of subjects to groups (such as cases or controls, or exposure status) are erroneous This may result, for example, from limited sensitivity and/or specificity of a diagnostic test, or from inadequacy of information derived from medical or other records (Gordis, 2014) 8.3.2 Uncontrolled Clinical Trials In uncontrolled clinical trials, the effects of treatment are assessed by comparing patients’ clinical courses before and after treatment, without reference to an untreated comparison group, to see whether an intervention changes the established course of disease in individual patients The difficulty in interpreting the results of an uncontrolled trial relates to the predictability of the course of disease For some conditions, the prognosis without treatment is so predictable that an untreated control group is either unnecessary or unethical In most cases, however, the clinical course is not so predictable Some diseases normally improve after an initial attack If a treatment is given at this time, it may be mistakenly credited with the favorable outcome Clients tend to seek care for their animals when signs are at their worst Patients sometimes begin to recover after seeing the veterinarian because of the natural course of events (natural history of the disease), regardless of what was done Severe diseases that normally are not self-limiting may nonetheless undergo spontaneous remission In these cases, improvement in the patient’s condition would mistakenly be attributed to the treatment if it had been initiated when signs were most evident VetBooks.ir 136 Veterinary Clinical Epidemiology EXAMPLE 8.1: WHAT IS THE CLINICAL COURSE OF EQUINE SARCOID IN YOUNG HORSES? Background: Equine sarcoids (ES) are the most common skin neoplasia in equids, accounting for up to 90% of all cutaneous tumors Sarcoids invade dermal and/or subcutaneous tissues locally, but true metastatic dissemination does not occur Two common forms of ES are occult (roughly circular hairless areas of skin) and verrucous (wart-like) Although the disease is rarely fatal, tumors may become ulcerated or infected, and recurrence is frequently observed after tumor removal Accordingly, welfare and economic aspects must be considered when treating this disease The progression of ES is notoriously unpredictable Making a choice for the appropriate treatment is challenging when dealing with milder manifestations of ES Objectives: Berruex et al (2016) investigated the clinical course of ES in young horses with and without therapeutic interventions Study Design: Non-randomized controlled clinical trial Methods: A cohort of 61 ES-affected 3-year-old Franches-Montagnes horses and a breed-, age-, and geographically matched control group of 75 ES-free peers were examined twice over a period of 5–7 years Owners and caretakers were queried using a standardized questionnaire Results: More than half (38/61 = 62%) of the horses that were ES-affected at the age of had become ES free at the time of follow-up (age 8–11) In 29 of 38 horses, representing 48% of the entire ES study population, lesions had spontaneously disappeared without therapy At the time of follow-up examination, (8%) of the 75 horses of the control group had acquired ES lesions Of 12 horses that received specific treatment for ES disease, therapy was successful in eliminating the ES lesions in half of them When differentiating the clinical types of ES lesions, occult ES underwent complete spontaneous regression in 65% (11/17), while verrucous lesions regressed spontaneously in 32% (9/28) None of the evaluated intrinsic or environmental factors showed a significant effect on the risk for development, regression, or exacerbation of ES disease Conclusions and Significance: The results document a surprisingly high rate of spontaneous ES regression for young horses affected with milder manifestations of ES disease These findings justify a “wait-and-see” approach in selected cases of occult and verrucous ES, provided that all lesions are closely monitored Furthermore, results of this study should also be considered when critically assessing treatment effects of therapies directed against ES, especially in the context of uncontrolled studies The results suggest that any therapeutic regimen may yield positive results regardless of efficacy FOLLOW-UP QUESTION 8.1 What study design is most vulnerable to misinterpretation of results based on the clinical course of equine sarcoid reported in this study? See Answer 8.2 at the end of this chapter 8.3.3 Comparisons across Time and Place Diagnosis and treatment strategies change over time Similarly, the nature of patients, clinical expertise, and medical procedures differ among clinical settings Thus, the time and place in which conditions are diagnosed and treated can affect the expected prognosis Clinical trials in which treatment and comparison groups are selected at the same time (concurrent controls) and place are less likely to be biased However, a historical comparison group (historical controls) may be the only alternative when it is ethically inappropriate to withhold a promising new treatment from client-owned animals 137 VetBooks.ir Design and Evaluation of Clinical Trials EXAMPLE 8.2: HOW DO NEW TREATMENT MODALITIES FOR RELIEVING URETERAL OBSTRUCTION IN CATS, SUCH AS URETERAL STENTING, COMPARE WITH TRADITIONAL SURGERY? Background: Ureteral obstruction in cats is uncommon but can lead to life-threatening acidbase and electrolyte disturbances Affected cats are often examined for nonspecific clinical signs such as vomiting, lethargy, and anorexia, and frequently develop azotemia (abnormally high levels of urea or creatinine in the blood) Objectives: Culp et al (2016) compared the outcome for cats with benign ureteral obstructions treated by means of ureteral stenting with that of a historical cohort of cats treated by means of the more traditional ureterotomy (surgical removal of the ureterolith) only Study Design: Non-randomized controlled clinical trial Methods: Data were recorded prospectively on 26 cats treated with ureteral stenting between 2010 and 2014 and compared with medical records data from 36 cats previously treated with ureterotomy at the same veterinary teaching hospital between 2003 and 2009 Procedural complications included the need for at least ureterotomy in of the 26 (19%) ureteral stenting cats to allow for guidewire passage when the guidewire would not pass a ureterolith Results: Cats treated with ureteral stents had significantly greater decreases (p