Identifying Diagnostic Studies in MEDLINE: Reducing the Number Needed to Read

Objectives. The search filters in PubMed have become a cornerstone in information retrieval in evidence-based practice. However, the filter for diagnostic studies is not fully satisfactory, because sensitive searches have low precision. The objective of this study was to construct and validate better search strategies to identify diagnostic articles recorded on MEDLINE with special emphasis on precision.Design. A comparative, retrospective analysis was conducted. Four medical journals were hand-searched for diagnostic studies published in 1989 and 1994. Four other journals were hand-searched for 1999. The three sets of studies identified were used as gold standards. A new search strategy was constructed and tested using the 1989-subset of studies and validated in both the 1994 and 1999 subsets. We identified candidate text words for search strategies using a word frequency analysis of the abstracts. According to the frequency of identified terms, searches were run for each term independently. The sensitivity, precision, and number needed to read (1/precision) of every candidate term were calculated. Terms with the highest sensitivity × precision product were used as free text terms in combination with the MeSH term “SENSITIVITY AND SPECIFICITY” using the Boolean operator OR. In the 1994 and 1999 subsets, we performed head-to-head comparisons of the currently available PubMed filter with the one we developed.Measurements. The sensitivity, precision and the number needed to read (1/precision) were measured for different search filters.Results. The most frequently occurring three truncated terms (diagnos*; predict* and accura*) in combination with the MeSH term “SENSITIVITY AND SPECIFICITY” produced a sensitivity of 98.1 percent (95% confidence interval: 89.9–99.9%) and a number needed to read of 8.3 (95% confidence interval: 6.7–11.3%). In direct comparisons of the new filter with the currently available one in PubMed using the 1994 and 1999 subsets, the new filter achieved better precision (12.0% versus 8.2% in 1994 and 5.0% versus 4.3% in 1999. The 95% confidence intervals for the differences range from 0.05% to 7.5% (p = 0.041) and –1.0% to 2.3% (p = 0.45), respectively). The new filter achieved slightly better sensitivities than the currently available one in both subsets, namely 98.1 and 96.1% (p = 0.32) versus 95.1 and 88.8% (p = 0.125).Conclusions. The quoted performance of the currently available filter for diagnostic studies in PubMed may be overstated. It appears that even single external validation may lead to over optimistic views of a filter’s performance. Precision appears to be more unstable than sensitivity. In terms of sensitivity, our filter for diagnostic studies performed slightly better than the currently available one and it performed better with regards to precision in the 1994 subset. Additional research is required to determine whether these improvements are beneficial to searches in practice.Biomedical databases are important sources of evidence in medical practice. However, information retrieval in such databases can become very time-consuming because searches that are likely to identify all relevant information also find many irrelevant articles.In recent years researchers have adopted various approaches in the development of search strategies to selectively retrieve different types of studies (therapy, prognosis, diagnosis and etiology) and different study designs.^1,2 Search strategies targeted at diagnostic studies have also been developed.^1,3–4 The most commonly used filter for diagnostic studies is almost certainly the one now publicly available in PubMed (Clinical Queries),⁵ which based on the work of Haynes and coworkers.¹ Their search filter with emphasis on sensitivity achieved a cross-validated mean sensitivity of approximately 87% combined with a (non–cross-validated) mean precision of approximately 8%.Compared with the filter for therapeutic studies, the diagnostic filter’s precision in particular is much lower. The main reason for this difference may be the inconsistent terminology used in diagnostic studies making them difficult to index and retrieve in electronic databases.In view of this high false-positive rate, we wondered if it would be possible to develop a more precise search strategy for selecting publications on diagnostic test evaluations without losing sensitivity. Our objective was to develop, test and validate a generic search strategy for the detection of diagnostic articles recorded on MEDLINE that can be applied in any diagnostic field in Medicine.     

Coughing in pre‐school children in general practice: When are RAST's for inhalation allergy indicated?

To identify patterns of clinical history associated with extreme (high or low) probabilities of allergic sensitization in coughing children so as to restrict allergy testing to those with an intermediate probability of sensitization. A total of 752 children, aged 1-4, visiting their GPs for coughing (>or=5 days), were tested for IgE-antibodies to house dust mite, cat and dog [RadioAllergoSorbent Test (RAST)]. Parents completed a questionnaire on family history of atopy, breastfeeding, smoking, pets, and floor covering. Data of 640 children could be analyzed, 83 (13%) were IgE-positive. In a logistic regression analysis, a scoring formula for the prediction of being IgE-positive was constructed using variables from the patient's history. Significant contributors for sensitization were: age (3-4 yr), infantile eczema, positive family history of mite-allergy, sibling(s) with pollen-allergy, and smoking by parents. If only one of these characteristics is present, the probability of sensitization is < 25%. In such cases watchful waiting may be preferred over allergy testing. In other cases, a negative RAST may help to exclude sensitization, whereas a positive RAST helps to establish the diagnosis. Thus, acting on clinical history alone may save approximately 80% of RAST's. Patient history-derived information contributes to distinguishing children who are at low risk for sensitization to house dust mite, cat, and dog. The scoring formula may help GPs to identify children with a low probability of being sensitized. This may form the basis for watchful waiting. In others, allergy testing may be useful to gain more diagnostic certainty.     

The Autonomic Nervous System and the Immune System in Juvenile Rheumatoid Arthritis

This study demonstrates that juvenile rheumatoid arthritis is associated with a dysregulation of the autonomic nervous system as well as with disturbances in the capacity of the immune system to respond to mediators of the autonomic nervous system. In patients with active disease heart rate at rest is higher than in healthy controls. In addition, 3-hydroxy-4-phenoxyphenylglycol levels in urine are higher in all patients than in the control group. Cardiovascular responses to an orthostatic stress test (tilt up) are reduced in patients with active and nonactive disease. Plasma norepinephrine responses to tilt up are reduced in subjects with active juvenile rheumatoid arthritis. In summary, our data show that patients with juvenile rheumatoid arthritis have an altered function of the autonomic nervous system associated with increased central noradrenergic outflow, presumably leading to increased vasoconstriction, resulting in a decreased response to an orthostatic stressor. The altered function of the autonomic nervous system is associated with changes in the response of leukocytes to mediators of the autonomic nervous system via β2-adrenergic receptors. Leukocytes of patients with active juvenile rheumatoid arthritis have a lower cAMP response to a β2-adrenergic agonist, presumably due to increased cAMP–phosphodiesterase activity in these cells.     

Crohn's disease patients homozygous for the 3020insC NOD2 mutation have a defective NOD2/TLR4 cross-tolerance to intestinal stimuli

Mutations in nucleotide-binding oligomerization domain-2 (NOD2), leading to defective recognition of bacterial peptidoglycans, are associated with Crohn's disease. The underlying mechanism that results in increased inflammation in the guts of the patients bearing NOD2 mutations is still unclear. We hypothesized that NOD2 engagement leads to cross-tolerance to stimulation of Toll-like receptors (TLR), and we investigated whether patients with Crohn's disease who bear NOD2 mutations display a disturbed NOD2/TLR cross-tolerance. Peripheral blood mononuclear cells preincubated with NOD2 ligands were specifically down-regulated for the production of tumour necrosis factor-alpha (TNF-alpha) induced by the TLR4 ligand lipopolysaccharide, as well as by intestinal microorganisms, whereas the production of anti-inflammatory cytokines was not modulated. While in cells isolated from patients with Crohn's disease with the wild-type NOD2 allele, the NOD2 engagement led to a similar cross-tolerance to TLR4-dependent stimulation of TNF-alpha, the cross-tolerance between NOD2 and TLR4 was absent in the cells of five patients homozygous for the 3020insC NOD2 mutation, leading to uninhibited release of TNF-alpha by TLR4 ligands and intestinal bacteria. In conclusion, we propose the absence of NOD2/TLR4 cross-tolerance as a central mechanism for the increased susceptibility to Crohn's disease in individuals with NOD2 mutations.     

Avidity of Antibodies against Infecting Pneumococcal Serotypes Increases with Age and Severity of Disease

The incidence of invasive pneumococcal disease (IPD) rises with age. Among adult IPD patients, the avidity of antipneumococcal polysaccharide antibodies against the infecting serotype increased with age and severity of disease, indicating that susceptibility to IPD in the elderly may rather be due to flaws in other aspects of opsonophagocytosis.     

FSAP‐mediated nucleosome release from late apoptotic cells is inhibited by autoantibodies present in SLE

Inefficient clearance of apoptotic cells and the subsequent exposure of the immune system to nuclear contents are crucially involved in the pathogenesis of systemic lupus erythematosus (SLE). Factor VII‐activating protease (FSAP) is activated in serum upon contact with dead cells, and releases nucleosomes from late apoptotic cells into the extracellular environment. We investigated whether FSAP‐mediated nucleosome release from late apoptotic cells is affected in SLE patients. Nucleosome release in sera of 27 SLE patients and 30 healthy controls was investigated by incubating late apoptotic Jurkat cells with serum and analyzing the remaining DNA content by flow cytometry. We found that nucleosome release in sera of SLE patients with high disease activity was significantly decreased when compared with that in SLE sera obtained during low disease activity or from healthy individuals. Upon removal of IgG/IgM antibodies from SLE sera, nucleosome release was restored. Similarly, monoclonal antinuclear antibodies inhibited nucleosome release in healthy donor serum or by plasma‐purified FSAP. This inhibition was lost when Fab fragments were used, suggesting that antigen cross‐linking is involved. In conclusion, FSAP‐mediated nucleosome release from late apoptotic cells is greatly impaired in SLE patient sera, possibly hampering the clearance of these cells and thereby propagating inflammation.     

The Wiskott-Aldrich syndrome: The actin cytoskeleton and immune cell function

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency characterised by immune dysregulation, microthrombocytopaenia, eczema and lymphoid malignancies. Mutations in the WAS gene can lead to distinct syndrome variations which largely, although not exclusively, depend upon the mutation. Premature termination and deletions abrogate Wiskott-Aldrich syndrome protein (WASp) expression and lead to severe disease (WAS). Missense mutations usually result in reduced protein expression and the phenotypically milder X-linked thrombocytopenia (XLT) or attenuated WAS [1-3]. More recently however novel activating mutations have been described that give rise to X-linked neutropenia (XLN), a third syndrome defined by neutropenia with variable myelodysplasia [4-6]. WASP is key in transducing signals from the cell surface to the actin cytoskeleton, and a lack of WASp results in cytoskeletal defects that compromise multiple aspects of normal cellular activity including proliferation, phagocytosis, immune synapse formation, adhesion and directed migration.     

The mediating role of sleep,physical activity,and diet in the association between shift work and respiratory infections

Objectives:Shift work may be associated with an increased incidence of respiratory infections. However, underlying mechanisms are unclear. Therefore, our aim was to examine the mediating role of sleep, physical activity, and diet in the association between shift work and respiratory infections.Methods:This prospective cohort study included 396 shift and non-shift workers employed in hospitals. At baseline, sleep duration and physical activity were measured using actigraphy and sleep/activity diaries, sleep quality was reported, and frequency of meal and snack consumption was measured using food diaries. In the following six months, participants used a smartphone application to report their influenza-like illness/acute respiratory infection (ILI/ARI) symptoms daily. Mediation analysis of sleep, physical activity, and diet as potential mediators of the effect of shift work on ILI/ARI incidence rate was performed using structural equation modeling with negative binomial and logistic regression.Results:Shift workers had a 23% [incidence rate ratio (IRR) 1.23, 95% CI 1.01–1.49] higher incidence rate of ILI/ARI than non-shift workers. After adding the potential mediators to the model, this reduced to 15% (IRR 1.15, 95% CI 0.94–1.40). The largest mediating (ie, indirect) effect was found for poor sleep quality, with shift workers having 29% more ILI/ARI episodes via the pathway of poorer sleep quality (IRR 1.29, 95% CI 1.02–1.95).Conclusions:Compared to non-shift workers, shift workers had a higher incidence rate of ILI/ARI that was partly mediated by poorer sleep quality. Therefore, it may be relevant for future research to focus on perceived sleep quality as an underlying mechanism in the relation between shift work and increased infection susceptibility.     

Epidemiology of frequent attenders: a 3-year historic cohort study comparing attendance, morbidity and prescriptions of one-year and persistent frequent attenders

Background  

General Practitioners spend a disproportionate amount of time on frequent attenders. So far, trials on the effect of interventions on frequent attenders have shown negative results. However, these trials were conducted in short-term frequent attenders. It would be more reasonable to target intervention at persistent frequent attenders. Typical characteristics of persistent frequent attenders, as opposed to 1-year frequent attenders and non-frequent attenders, may generate hypotheses regarding modifiable factors on which new randomized trials may be designed.