CLARIFYING SOME ASPECTS OF DIAGNOSTIC-ACCURACY RESEARCH

Evidence-based medicine is an approach to improved patient care that integrates clinical experience with basic science and clinical research in diagnostic accuracy, prognostic indicators, efficacy, and safety of treatments. Both clinical experience and methodical research assessments are essential components in this type of medical practice and underscore the importance of providing residents the opportunity to gain clinical experience as well as training them in how to perform, apply, and interpret clinical research in diagnostic imaging. The challenge for researchers is to design a study so that the data are valid and may be generalized to clinical situations where the test will be used. When assisting residents in the design of a research project for accuracy assessment of an imaging test, we consistently have observed three problem areas that if uncorrected would preclude the study results from being generalized to clinical situations where the test will be used: (1) understanding what is being measured, (2) appropriate selection of the sample population, and (3) the impact of the variability of the decision criterion. In this paper, we review these issues and suggest some solutions.     

RT09Bayesian approaches in dosage selection

There are several means whereby dosage schedules for clinical use may be set, some more appropriate and scientific than others! The challenge of the 21st century must be for colleagues in the pharmaceutical industry, those serving registration bodies and academic colleagues to pool their expertise with the objective of designing dosage schedules for clinical use, which are based on the application of sound scientific principles appropriate for each drug class. In this Roundtable Session colleagues of international standing will review (a) pharmacological and other sources of variability in the responses to drugs; (b) the advantages and limitations of pre‐clinical studies for dose selection; (c) the roles of population PK and population PK/PD together with Monte Carlo simulations in dosage regimen selection; (d) Bayesian approaches to dosage selection and (e) regulatory guidelines on the type and extent of studies required for selecting dosages. There is no unanimity amongst stakeholders on either the principles or the methods underlying dosage schedule design. Dose titration studies have long been the principal means of fixing doses but PK‐PD and population PK‐PD studies are now challenging more traditional approaches. The papers and discussion in this Roundtable Session will provide a critical basis for future advances in this crucial area of therapeutic drug usage. Getting the doses right means that the patient will receive maximum benefit, in terms of optimal efficacy with minimal toxicity, and hence correct dosing will contribute enormously to animal welfare.     

Controlled but pragmatic investigations of interventions for behavioural disturbances in dogs and cats

Veterinarians are often directly involved in clinical studies or requested for information to help interpret their results. Therefore, it is reasonable to examine the reservoir of study methods. This article transfers methodological considerations from clinical research into veterinary medicine. The study question determines the appropriate study method. Recently a ten-step procedure was suggested for selection of appropriate study designs in humans. Based on this approach, a pragmatic study design was adapted to the conditions prevailing in interventional studies in dogs and cats with disturbed behaviour. The different concepts for clinical studies are introduced. Whether or not the design and the evaluation of pragmatic studies in dogs and cats with disturbed behaviour has been maintained and the prerequisites have thereby been fulfilled so that the obtained results are suitable to be applied under everyday conditions can be tested in eight steps. Using the pragmatic design the superiority of complex interventions can be investigated. The results of pragmatic studies help to substantiate a value judgement, i. e., the recommendation or rejection of a specific therapeutic intervention for a defined disease entity in a specific therapeutic setting. The goal of pragmatic studies is to obtain results appropriate for use in everyday situations. In conclusion, the suggested procedure is useful for the selection of the appropriate study designs for specific questions. This procedure is also suitable to test whether the conclusions of published study results coincide with the chosen methods.     

Designing and running clinical trials on farms.

This article covers the key concepts in design and implementation of clinical trials for valid, interpretable data. Well done field trials should include a clearly defined research question and assessment of a clinically relevant outcome, an appropriate sample size for the question and study design, an appropriate trial design that includes random assignment of animals to treatment and control group, blinded assessment of clinical outcome, and appropriate statistical analysis.     

Interpreting culture and susceptibility data in critical care: perks and pitfalls

Problem – The need for immediate, effective antimicrobial therapy in the critical care patient must be tempered by approaches which simultaneously minimize emergence of antimicrobial resistance. Ideally, therapy will successfully resolve clinical signs of infection, while eradicating infecting pathogens such that the risk of resistance is avoided. Increasing limitations associated with empirical antimicrobial choices direct the need for culture and susceptibility data as a basis of therapy. Even so, such in vitro data should be utilized within its limitations. Objectives – To demonstrate the attributes and limitations of patient and population culture and susceptibility (pharmacodynamic) data in the selection of antimicrobial drugs and to demonstrate the design of individualized dosing regimens based on integration of pharmacodynamic (PD) and pharmacokinetic (PK) data. Diagnosis – Limitations in culture and susceptibility testing begin with sample collection and continue through drug selection and dose design. Among the challenges in interpretation is discrimination between pathogens and commensals. Properly collected samples are critical for generation of data relevant to the patient's infection. Data are presented as minimum inhibitory concentrations (MICs). The MIC facilitate selection of the most appropriate drug, particularly when considered in the context of antimicrobial concentrations achieved in the patient at a chosen dose. Integration of MIC data with key PK data yields the C_max:MIC important to efficacy of concentration‐dependent drugs and T>MIC, which guides use of time‐dependent drugs. These indices are then used to design dosing regimens that are more likely to kill all infecting pathogens. In the absence of patient MIC data, population data (eg, MIC₉₀) may serve as a reasonable surrogate. Conclusions – Properly collected, performed, and interpreted culture and susceptibility data are increasingly important in the selection of and design of dosing regimens for antimicrobial drugs. Integration of PK and PD data as modified by host and microbial factors supports a hit hard, exit fast approach to therapy that will facilitate efficacy while minimizing resistance.     

Fine mapping quantitative trait loci under selective phenotyping strategies based on linkage and linkage disequilibrium criteria

In fine mapping of a large‐scale experimental population where collection of phenotypes are very expensive, difficult to record or time‐demanding, selective phenotyping could be used to phenotype the most informative individuals. Linkage analyses based sampling criteria (LAC) and linkage disequilibrium‐based sampling criteria (LDC) for selecting individuals to phenotype are compared to random phenotyping in a quantitative trait loci (QTL) verification experiment using stochastic simulation. Several strategies based on LAC and LDC for selecting the most informative 30%, 40% or 50% of individuals for phenotyping to extract maximum power and precision in a QTL fine mapping experiment were developed and assessed. Linkage analyses for the mapping was performed for individuals sampled on LAC within families and combined linkage disequilibrium and linkage analyses was performed for individuals sampled across the whole population based on LDC. The results showed that selecting individuals with similar haplotypes to the paternal haplotypes (minimum recombination criterion) using LAC compared to random phenotyping gave at least the same power to detect a QTL but decreased the accuracy of the QTL position. However, in order to estimate unbiased QTL parameters based on LAC in a large half‐sib family, prior information on QTL position was required. The LDC improved the accuracy to estimate the QTL position but not significantly compared to random phenotyping with the same sample size. When applying LDC (all phenotyping levels), the estimated QTL effect were closer to the true value in comparison to LAC. The results showed that the LDC were better than the LAC to select individuals for phenotyping and contributed to detection of the QTL.     

Demonstrating bioequivalence using clinical endpoint studies

For drug products not amenable to blood level studies, clinical endpoint studies have been used as an indirect measure of formulation difference in bioavailability between test and reference products. However, clinical endpoint studies are not as sensitive in detecting formulation differences as blood level studies and offer numerous challenges to both regulatory authorities and sponsors. The objective of this article is not to suggest new regulatory policies, but to explore new methodologies and alternative solutions to clinical endpoint bioequivalence (BE) studies, which are used when a blood level study is not considered to be appropriate. To achieve this objective, this article identifies situations where a clinical endpoint study might be appropriate, lists the advantages and disadvantages of this type of study design, and discusses possible alternative solutions. It is concluded that future evidence-based research is needed to explore new methodologies such as clinical trial simulations of various study designs, new statistical methods, and new in vitro methods to demonstrate BE.     

Study design synopsis: Designing and performing pharmacokinetic studies for systemically administered drugs in horses

The goal of this editorial is to discuss best practice design, execution and reporting of a pharmacokinetic (PK) study in horses. Our target readers are clinicians who plan to perform this type of research, in a field, clinic or research setting but we also hope that this article might help readers of such work to appraise the articles and understand the quality of the studies. Our emphasis will be on appropriate study design and analytical method, drug and drug formulation choice and route of administration, animal choice, sample collection, storage and shipping, and reporting, rather than the PK data analysis itself.     

A Systematic Review of Studies Performing the Hypo‐Osmotic Swelling Test to Evaluate the Quality of Canine Spermatozoa

The hypo‐osmotic swelling test (HOS test) is a simple and inexpensive test to evaluate the functional integrity of sperm cell membranes. According to the existing literature, its simple applicability has turned it into a valuable additional parameter to standard canine semen analysis. In the recent years, much research has been conducted in this field. The aim of this systematic review was to evaluate the quality of published literature in canine reproduction concerning the HOS test. Using two distinguished databases, 38 articles were detected and analysed subsequently according to various aspects, for example study design, population, semen sampling and implementation concerning the HOS test. Although there are numerous articles available, the diagnostic value of the HOS test remains ambiguous. Until now, neither a recognized test protocol nor reliable reference values have been defined. Most of the trials evaluated show serious methodological flaws and therefore do not permit drawing reliable conclusions. According to our results, approximately half of the studies (n = 20) included a sample size of five or less animals. None of the studies examined the inter‐ or intraobserver agreement for the HOS test. Further research is warranted including appropriate statistical methods and a sufficient number of animals to establish a standardized test protocol as well as reliable reference values. Most importantly, it is required to clarify a correlation between the HOS test and the fertilizing capacity to determine the diagnostic value of the HOS test.     

Dairy cow mortality. A review

Summary

We reviewed the literature to give an overview over the mortality among dairy cows in countries with a relatively intensive dairy production. A total of 19 studies focussing on dairy cow mortality were identified. Information about objectives, measures of mortality, sample sizes, study designs, causes of death and risk factors from these studies is presented and discussed. Additionally, recommendations for future recordings of mortality that will enable better possibilities for comparison of study results, generalization of results from a study population to a larger population and meta‐analysis are given.     

Evidence‐Based Medicine: The Design and Interpretation of Noninferiority Clinical Trials in Veterinary Medicine

Noninferiority trials are clinical studies designed to demonstrate that an investigational drug is at least as effective as an established treatment within a predetermined margin. They are conducted, in part, because of ethical concerns of administering a placebo to veterinary patients when an established effective treatment exists. The use of noninferiority trial designs has become more common in veterinary medicine with the increasing number of established veterinary therapeutics and the desire to eliminate potential pain or distress in a placebo‐controlled study. Selecting the appropriate active control and an a priori noninferiority margin between the investigational and active control drug are unique and critical design factors for noninferiority studies. Without reliable historical knowledge of the disease response in the absence of treatment and of the response to the selected active control drug, proper design and interpretation of a noninferiority trial is not possible. Despite the appeal of conducting noninferiority trials to eliminate ethical concerns of placebo‐controlled studies, there are real limitations and possible ethical conundrums associated with noninferiority trials. The consequences of incorrect study conclusions because of poor noninferiority trial design need careful attention. Alternative trial designs to typical noninferiority studies exist, but these too have limitations and must also be carefully considered.     

Examining heterogeneity in the diagnostic accuracy of culture and PCR for Salmonella spp. in swine: a systematic review/meta-regression approach

The accuracy of bacterial culture and PCR for Salmonella in swine was examined through systematic review of existing primary research in this field. A replicable search was conducted in 10 electronic databases. All steps of the review were conducted by two reviewers: to identify relevant publications, to assess their methodological soundness and reporting, and to extract raw data or reported test accuracy estimates. Meta-analyses and meta-regression were performed: to evaluate pooled estimates of test sensitivity (Se) and specificity (Sp), to identify variables explaining the variation in reported test estimates, and to evaluate the association between these variables and reported test Se and Sp. Twenty-nine studies were included in the review. Unique test evaluations reported in these 29 studies were categorized according to the type of test comparison: culture versus culture (n = 134 test evaluations) and PCR versus culture (n = 21). We identified significant heterogeneity among evaluations for each test category. For culture, more heterogeneity was caused by differences in individual test protocols (52%) than overall differences between studies (16%). Enrichment temperature, study population, agar and enrichment type were significantly associated with variation in culture Se. Furthermore, interaction between enrichment temperature and enrichment type was detected. For PCR, most of the heterogeneity was caused by overall differences between studies (65-70%); sample type and study size were associated with variation in reported PCR Se and Sp. The overall methodological soundness and/or reporting of primary studies included in this review were poor, with variable use of reference standards, and consistent lack of the use or reporting of blinding, randomization and subject (sample) selection criteria. Consequently, the food safety and veterinary public health research community should formally consider ways for standardizing the conduct and reporting of this type of research.     

Optimal endpoints of resuscitation and early goal-directed therapy

Objective: To review the available endpoints of shock resuscitation, including traditional perfusion parameters, oxygen‐transport variables, lactate, base deficit (BD), venous oxygen saturation, and gastric mucosal pH, and to discuss the currently accepted methods of assessing successful reversal of oxygen (O₂) debt in shock patients. Human‐based studies: Early goal‐directed therapy has unequivocally been shown to positively affect outcome in human patients experiencing cardiovascular shock. However, specific endpoints of resuscitation to target in critically ill patients remain controversial. Reliance on traditional endpoints of resuscitation (heart rate [HR], blood pressure [BP]) appears insufficient in detection of ongoing tissue hypoxia in shock states. A multitude of publications exist suggesting that indirect indices of global (lactate, base deficit, mixed/central venous oxygen saturation), regional (gastric intramucosal pH [pH_i]) and cellular (transcutaneous oxygen) oxygenation are more successful in outcome prediction and in assessing adequacy of resuscitative efforts in this patient population. Veterinary‐based studies: While there are several large studies evaluating endpoints of resuscitation in experimental canine shock models, this author was unable to find similar research pertaining to small animal veterinary patients. The few articles in which blood lactate is evaluated for prognostic purposes in canine patients are included in this review. Data sources: Veterinary and human literature review. Conclusions: Optimization of early resuscitative efforts has proven to have a survival benefit in human shock patients, and major strides have been made in determining which endpoints of resuscitation to target in this patient population. Similar clinical trials designed to evaluate indices of ongoing global and regional tissue hypoxia in small animal veterinary shock patients are warranted.     

Reference intervals for biochemical and haematological parameters in mature domestic donkeys (Equus asinus) in the UK

Reference intervals (RIs) for haematology and serum biochemistry for donkeys in a temperate climate have been previously published using blood sample results from the resident population of a large donkey shelter in the UK. Periodic review of reference intervals is recommended to ensure their applicability to the patient population and changes in laboratory methods and technologies. The current study aimed to revise the previously published haematology and serum biochemistry values for the adult domestic donkey (Equus asinus) in the UK in the light of a change in analytical equipment at the Donkey Sanctuary laboratory, but also to refine the demography of the sample population with respect to age, physiology and clinical history. Clinical pathology results from 138 clinically healthy mature (4–24 years inclusive) female and castrated male donkeys selected from the resident population of the Donkey Sanctuary, were analysed retrospectively. The animals were blood sampled during the period February 2008 to June 2011 as part of a routine health screen prior to rehoming. Results for a total of 38 biochemical and haematological parameters were analysed including 3 previously unreferenced parameters in addition to those assessed in the previous study. The new reference intervals and median values show very poor transferability with recently derived reference intervals for non‐Thoroughbred horses and only limited transferability with reference intervals previously published for donkeys in the UK. Of particular note is a marked reduction in the upper reference limit for triglycerides of 2.8 mmol/l (from 4.3 mmol/l) since this parameter is used to decide when donkeys are at risk of developing hyperlipaemia. This study demonstrates the value of intermittent review of reference intervals and refinement of study populations. Notwithstanding the caution with which reference interval data from different laboratories should be compared, the lack of transferability of results between donkeys and horses highlights the importance of use of species‐appropriate reference intervals for clinical decision‐making.     

Systematic Review of Nonsteroidal Anti‐Inflammatory Drug‐Induced Adverse Effects in Dogs

The aim of this systematic review was to identify, assess, and critically evaluate the quality of evidence of nonsteroidal anti‐inflammatory drug (NSAID)‐induced adverse effects in dogs. Original prospective studies published in peer‐reviewed journals in English (1990–2012) that reported data on the safety of NSAIDs administration in dogs were searched. For each study, design type (I, II, III, or IV) and assessment of quality (+, Ø, ?) were rated. For each drug, quantity and consistency rating (***, **, *) and strength of evidence (high, moderate, low, or extremely low) were identified and evaluated. The strength of evidence was defined in terms of how applicable and relevant the conclusions were to the target population. Sixty‐four studies met the inclusion criteria. Thirty‐five (55%) research studies and 29 (45%) clinical trials were identified. A high strength of evidence existed for carprofen, firocoxib, and meloxicam; moderate for deracoxib, ketoprofen, and robenacoxib; and low for etodolac. Quality and consistency rating were as follows: carprofen (***/***), deracoxib (**/***), etodolac (*/unable to rate), firocoxib (***/**), ketoprofen (**/***), meloxicam (***/***), and robenacoxib (**/**), respectively. Adverse effects were detected in 35 studies (55%) and commonly included vomiting, diarrhea, and anorexia. Three studies (5%) reported a power analysis related to adverse effects of ≥80%. In randomized, placebo‐controlled, blinded studies (n = 25, 39%), the incidence of adverse effects was not statistically different between treated and control dogs. Finally, most studies were not appropriately designed to determine the safety of NSAIDs, and involved a healthy nongeriatric population of research dogs.     

Fluid therapy for the traumatized patient

Objective: To review the rationale behind and experiences with traditional and newly evolving concepts of fluid therapy in the traumatized patient, and to review conventional and novel fluid preparations for use in trauma resuscitation. Data sources: Human and veterinary clinical and research studies. Human data synthesis: Current treatment guidelines recommend aggressive fluid resuscitation with lactated ringers solution (LRS) or saline as optimum management of hemorrhagic shock in trauma, regardless of whether bleeding is controlled or not. The rationale behind this strategy is to restore intravascular volume as rapidly as possible to ensure adequate vital organ perfusion. Recently, this strategy has been challenged, especially in patients with uncontrolled hemorrhage, as neither laboratory evidence nor clinical trials support this practice. Current research indicates that vigorous fluid infusion may exacerbate bleeding and cause severe hemodilution, both impairing resuscitation outcome. As a result, a new line of thinking is emerging that balances the risks and benefits of intravenous volume infusion by offering the clinician alternative treatment strategies and emphasizes continuous endpoint‐oriented monitoring. ‘Hypotensive’ or ‘hypovolemic’ resuscitation techniques as well as initial volume replacement with fluids other than LRS or saline (e.g., hypertonic saline [HTS], HTS with dextran 70 [HTS‐D]) have been introduced in human medical practice as additional options for treatment of victims of trauma under certain circumstances. Clinical studies evaluating the use of hemoglobin‐based oxygen carriers (HBOCs) in the trauma setting are underway and may soon lead to an expansion of the fluid arsenal available to the clinician for treatment of trauma patients. Veterinary data synthesis: Based on available animal data, neither strict guidelines nor a clear fluid preference for resuscitation of traumatic shock have been defined. Although systematic clinical trials are missing, combinations of crystalloid and colloid (natural or artificial) appear to be as effective for resuscitation as crystalloid alone. Judicious use of an HBOC (e.g., Oxyglobin^®) as a substitute for blood/red blood cells may be recommended in situations where whole blood or pRBCs are not or not yet available. Conclusions: The search for optimal methods of fluid resuscitation in trauma is ongoing. At this point the best solution is a differentiated approach to fluid therapy, one that tailors type and volume of resuscitation solution(s) used to the type and severity of injury in an individual patient and uses monitoring of perfusion and oxygenation parameters to guide resuscitation. Crystalloid fluids are effective for resuscitation but may need to be combined with or replaced by colloidal fluids in certain clinical situations.     

Survey of academic veterinarians' clinical practice in cardiopulmonary–cerebral resuscitation

Objective: To document the clinical practice of cardiopulmonary–cerebral resuscitation (CPCR) among academic veterinarians. Design: Survey. Setting: Eight colleges of veterinary medicine in the United States. Subjects: Two hundred and one academic veterinarians. Interventions: The survey was distributed by hand by the authors into the mailboxes of small animal faculty, residents, and interns. Demographic variables, questions regarding number of cardiopulmonary arrests (CPA) supervised and number successful, do not attempt resuscitation discussions, and Likert‐style questions about client presence during CPCR, appropriateness of CPCR, and CPCR decision‐making were included. Multiple linear regression models were constructed to determine the effect of multiple questions on different target variables of interest. Measurements and main results: Numerous differences were noted based on institution, gender, specialty, and position. Most institutions did not have a standard resuscitation consent form. Most respondents believed the client, house officer, and senior clinician should determine whether to perform resuscitation or not. Quality of life was the most significant determinant of whether to resuscitate or not, followed by long‐term prognosis, then short‐term prognosis. Conclusions: Veterinarians differ in many aspects of their approach to CPA and resuscitation. Creating consensus within the veterinary profession would benefit client service and patient care.     

Evaluation of the clinical efficacy of prokinetic drugs in the management of post-operative ileus: can retrospective data help us?

The objectives of the study were to determine whether retrospective data can be used to answer questions about the efficacy of prokinetic agents when used to treat horses with post-operative ileus (POI). We describe prevalence and mortality of POI with reference to treatment with four prokinetic agents. By combining data from two Hospitals a study population of 55 horses with POI following pedunculated lipoma obstruction (PLO) was established. Univariable and multivariable associations were determined between short term survival and potential explanatory variables. With death as outcome in multivariable models, breed and hospital were significantly associated with outcome but the use of prokinetic agents was not (P=0.15). However, sample size estimates indicate the low power of this study to detect differences in outcome. It was not possible definitively to evaluate the efficacy of prokinetics as treatment for POI following PLO using retrospective data. The data were suggestive of limited efficacy of prokinetics as treatment for POI. It is postulated that the identified association between hospital and survival reflects differences in clinician decision making. The study highlights the need for further prospective studies using randomised clinical trials to evaluate accurately the efficacy of prokinetic agents. This report illustrates difficulties with performing retrospective analysis of clinical data to determine the efficacy of treatment regimes.     

Pulmonary thromboembolism

Objective – To review the pathophysiology, clinical signs, diagnosis, and treatment of pulmonary thromboembolism (PTE) in small animals. Data Sources – Human and veterinary clinical studies, reviews, texts, and recent research in canine and feline PTE diagnosis and thromboembolic therapeutics. Human Data Synthesis – In humans, clinical probability assessment and point‐of‐care D‐dimer‐based algorithms are widely used. Computed tomography pulmonary angiography is the gold standard for PTE diagnosis in humans. Echocardiography is increasingly used for bedside assessment of affected patients. In low‐risk human patients anticoagulants alone are recommended while patients with cardiogenic shock are treated with thrombolytics followed by anticoagulation. Veterinary Data Synthesis – PTE is associated with numerous predisposing conditions causing hypercoagulability, blood flow stasis, or endothelial injury. Identifying at‐risk patients is key to diagnosis in small animals. Thromboelastography provides a method for identifying hypercoagulable patients. Computed tomography pulmonary angiography may replace selective pulmonary angiography as the imaging technique of choice for PTE diagnosis. PTE therapy consists of supportive treatment combined with appropriate, individualized thromboembolic pharmacotherapy for acute treatment and chronic management. Thrombolytic therapy for PTE remains controversial but may be indicated in hemodynamically unstable acute PTE. Thromboprophylaxis in specific conditions is rational although evidence of efficacy is limited. Prognosis depends upon degree of cardiopulmonary compromise and patient response to therapy. Mortality rates in small animals are unknown. Conclusions – New diagnostic techniques and advances in therapy offer significant potential for improvements in the identification and treatment of PTE in small animals. Further study must be directed to validating new diagnostic modalities and evaluating therapeutic regimes.