Chapter 9: Options for Summarizing Medical Test Performance in the Absence of a “Gold Standard”

The classical paradigm for evaluating test performance compares the results of an index test with a reference test. When the reference test does not mirror the “truth” adequately well (e.g. is an “imperfect” reference standard), the typical (“naïve”) estimates of sensitivity and specificity are biased. One has at least four options when performing a systematic review of test performance when the reference standard is “imperfect”: (a) to forgo the classical paradigm and assess the index test’s ability to predict patient relevant outcomes instead of test accuracy (i.e., treat the index test as a predictive instrument); (b) to assess whether the results of the two tests (index and reference) agree or disagree (i.e., treat them as two alternative measurement methods); (c) to calculate “naïve” estimates of the index test’s sensitivity and specificity from each study included in the review and discuss in which direction they are biased; (d) mathematically adjust the “naïve” estimates of sensitivity and specificity of the index test to account for the imperfect reference standard. We discuss these options and illustrate some of them through examples

Evidence for models of diagnostic service provision in the community: literature mapping exercise and focused rapid reviews

Background Current NHS policy favours the expansion of diagnostic testing services in community and primary care settings. Objectives Our objectives were to identify current models of community diagnostic services in the UK and internationally and to assess the evidence for quality, safety and clinical effectiveness of such services. We were also interested in whether or not there is any evidence to support a broader range of diagnostic tests being provided in the community. Review methods We performed an initial broad literature mapping exercise to assess the quantity and nature of the published research evidence. The results were used to inform selection of three areas for investigation in more detail. We chose to perform focused reviews on logistics of diagnostic modalities in primary care (because the relevant issues differ widely between different types of test); diagnostic ultrasound (a key diagnostic technology affected by developments in equipment); and a diagnostic pathway (assessment of breathlessness) typically delivered wholly or partly in primary care/community settings. Databases and other sources searched, and search dates, were decided individually for each review. Quantitative and qualitative systematic reviews and primary studies of any design were eligible for inclusion. Results We identified seven main models of service that are delivered in primary care/community settings and in most cases with the possible involvement of community/primary care staff. Not all of these models are relevant to all types of diagnostic test. Overall, the evidence base for community- and primary care-based diagnostic services was limited, with very few controlled studies comparing different models of service. We found evidence from different settings that these services can reduce referrals to secondary care and allow more patients to be managed in primary care, but the quality of the research was generally poor. Evidence on the quality (including diagnostic accuracy and appropriateness of test ordering) and safety of such services was mixed. Conclusions In the absence of clear evidence of superior clinical effectiveness and cost-effectiveness, the expansion of community-based services appears to be driven by other factors. These include policies to encourage moving services out of hospitals; the promise of reduced waiting times for diagnosis; the availability of a wider range of suitable tests and/or cheaper, more user-friendly equipment; and the ability of commercial providers to bid for NHS contracts. However, service development also faces a number of barriers, including issues related to staffing, training, governance and quality control. Limitations We have not attempted to cover all types of diagnostic technology in equal depth. Time and staff resources constrained our ability to carry out review processes in duplicate. Research in this field is limited by the difficulty of obtaining, from publicly available sources, up-to-date information about what models of service are commissioned, where and from which providers. Future work There is a need for research to compare the outcomes of different service models using robust study designs. Comparisons of ‘true’ community-based services with secondary care-based open-access services and rapid access clinics would be particularly valuable. There are specific needs for economic evaluations and for studies that incorporate effects on the wider health system. There appears to be no easy way of identifying what services are being commissioned from whom and keeping up with local evaluations of new services, suggesting a need to improve the availability of information in this area. Funding The National Institute for Health Research Health Services and Delivery Research programme

Breed differences in natriuretic peptides in healthy dogs

Background: Measurement of plasma concentration of natriuretic peptides (NPs) is suggested to be of value in diagnosis of cardiac disease in dogs, but many factors other than cardiac status may influence their concentrations. Dog breed potentially is 1 such factor. Objective: To investigate breed variation in plasma concentrations of pro-atrial natriuretic peptide 31-67 (proANP 31-67) and N-terminal B-type natriuretic peptide (NT-proBNP) in healthy dogs. Animals: 535 healthy, privately owned dogs of 9 breeds were examined at 5 centers as part of the European Union (EU) LUPA project. Methods: Absence of cardiovascular disease or other clinically relevant organ-related or systemic disease was ensured by thorough clinical investigation. Plasma concentrations of proANP 31-67 and NT-proBNP were measured by commercially available ELISA assays. Results: Overall significant breed differences were found in proANP 31-67 (P?<?0001) and NT-proBNP (P?<?0001) concentrations. Pair-wise comparisons between breeds differed in approximately 50% of comparisons for proANP 31-67 as well as NT-proBNP concentrations, both when including all centers and within each center. Interquartile range was large for many breeds, especially for NT-proBNP. Among included breeds, Labrador Retrievers and Newfoundlands had highest median NT-proBNP concentrations with concentrations 3 times as high as those of Dachshunds. German Shepherds and Cavalier King Charles Spaniels had the highest median proANP 31-67 concentrations, twice the median concentration in Doberman Pinschers. Conclusions and Clinical Importance: Considerable interbreed variation in plasma NP concentrations was found in healthy dogs. Intrabreed variation was large in several breeds, especially for NT-proBNP. Additional studies are needed to establish breed-specific reference ranges. 2014 by the American College of Veterinary Internal Medicine.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Immunotherapeutic targeting of aging-associated isoDGR motif in chronic lung inflammation

\ua9 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley &amp; Sons Ltd.Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable, with typical therapeutic strategies targeting genes or enzymes being ineffective in this domain. In this report, we demonstrate that an antibody targeting the isoDGR damage motif in lung tissue can guide immune clearance of harmful damaged proteins in vivo, effectively reducing age-linked lung inflammation. We observed age-dependent accumulation of the isoDGR motif in human lung tissues, as well as an 8-fold increase in isoDGR-damaged proteins in lung fibrotic tissues compared with healthy tissue. This increase was accompanied by marked infiltration of CD68+/CD11b + macrophages, consistent with a role for isoDGR in promoting chronic inflammation. We therefore assessed isoDGR function in mice that were either naturally aged or lacked the isoDGR repair enzyme. IsoDGR-protein accumulation in mouse lung tissue was strongly correlated with chronic inflammation, pulmonary edema, and hypoxemia. This accumulation also induced mitochondrial and ribosomal dysfunction, in addition to features of cellular senescence, thereby contributing to progressive lung damage over time. Importantly, treatment with anti-isoDGR antibody was able to reduce these molecular features of disease and significantly reduced lung pathology in vivo

Brain type carnosinase in dementia: a pilot study

Research articl

Screening for hypoglycemia at the bedside in the neonatal intensive care unit (NICU) with the Abbott PCx glucose meter

BACKGROUND: Point of care (POC) glucose meters are routinely used as a screening tool for hypoglycemia in a neonatal setting. Glucose meters however, lack the same accuracy as laboratory instruments for glucose measurement. In this study we investigated potential reasons for this inaccuracy and established a cut off value for confirmatory testing. METHODS: In this prospective study, all patients in the neonatal intensive care unit who had a plasma glucose test ordered were eligible to participate. Demographic information, sample collection information (nine variables) and a recent hematocrit value were recorded for each sample. Glucose measurements were taken at the bedside on the glucose meter (RN PCx) as well as in the laboratory on both the glucose meter (LAB PCx) and the laboratory analyzer (PG). Data were analyzed by simple and mixed-effects regression analysis and by analysis of a receiver operator characteristics (ROC) curve. RESULTS: There were 475 samples analyzed from 132 patients. RN PCx values were higher than PG values (mean = 4.9%), while LAB PCx results were lower (mean = -5.2%) than PG values. Only 31% of the difference between RN PCx – PG and 46% of the difference for LAB PCx – PG could be accounted for by the variables tested. The largest proportion of variance between PCx and PG measurements was explained by hematocrit (about 30%) with a greater effect seen at glucose concentrations ≤4.0 mmol/L (≤72 mg/dL)(48% and 40% for RN PCx and LAB PCx, respectively). The ROC analysis showed that for detection of all cases of hypoglycemia (PG < 2.6 mmol/L)(PG < 47 mg/dL) the PCx screening cut off value would need to be set at 3.8 mmol/L (68 mg/dL) requiring 20% of all samples to have confirmatory analysis by the laboratory method. CONCLUSION: The large difference between glucose results obtained by PCx glucose meter compared to the laboratory analyzer can be explained in part by hematocrit and low glucose concentration. These results emphasize that the glucose meter is useful only as a screening device for neonatal hypoglycemia and that a screening cut off value must be established

Diagnosing gestational diabetes

The newly proposed criteria for diagnosing gestational diabetes will result in a gestational diabetes prevalence of 17.8%, doubling the numbers of pregnant women currently diagnosed. These new diagnostic criteria are based primarily on the levels of glucose associated with a 1.75-fold increased risk of giving birth to large-for-gestational age infants (LGA) in the Hyperglycemia Adverse Pregnancy Outcome (HAPO) study; they use a single OGTT. Thus, of 23,316 pregnancies, gestational diabetes would be diagnosed in 4,150 women rather than in 2,448 women if a twofold increased risk of LGA were used. It should be recognised that the majority of women with LGA have normal glucose levels during pregnancy by these proposed criteria and that maternal obesity is a stronger predictor of LGA. The expected benefit of a diagnosis of gestational diabetes in these 1,702 additional women would be the prevention of 140 cases of LGA, 21 cases of shoulder dystocia and 16 cases of birth injury. The reproducibility of an OGTT for diagnosing mild hyperglycaemia is poor. Given that (1) glucose is a weak predictor of LGA, (2) treating these extra numbers has a modest outcome benefit and (3) the diagnosis may be based on a single raised OGTT value, further debate should occur before resources are allocated to implementing this change