Self-monitoring of blood glucose in patients with diabetes who do not use insulin--are guidelines evidence-based?

AIMS: To evaluate if clinical practice guideline recommendations regarding self-monitoring of blood glucose in patients with diabetes not using insulin follow the principles of evidence-based medicine. METHODS: After a search from 1999 to 2011, 18 clinical practice guidelines were included. Recommendations regarding self-monitoring of blood glucose were graded on a scale from one (strongly against self-monitoring) to four (strongly in favour of self-monitoring) and compared with the similarly graded conclusions of systematic reviews that were cited by the clinical practice guidelines. We also investigated how clinical practice guideline characteristics, for example funding sources, and quality of references cited could be related to the guideline recommendations. RESULTS: The clinical practice guidelines cited in total 15 systematic reviews, 14 randomized controlled trials, 33 non-randomized controlled trials papers and 18 clinical practice guidelines or position statements. The clinical practice guideline recommendations had an average grade of 3.4 (range 2.0-4.0). Higher grades were seen for clinical practice guidelines that acknowledged industry funding (mean value 4.0) or were issued by organizations depending on private funding (mean value 3.6 vs. 3.0 for governmental funding). The conclusions of the 15 systematic reviews had a mean grade of 2.2 (range 1.0-3.8). Systematic reviews with low grades were less cited. In total, 21 randomized controlled trials were included in the systematic reviews. Approximately half of these evaluated an educational intervention where the effect of self-monitoring of blood glucose could not be clearly isolated. CONCLUSIONS: Clinical practice guidelines were more in favour of self-monitoring use than the systematic reviews that were cited. The citation practice was non-systematic and industry funding seemingly led to a more positive attitude towards use of self-monitoring of blood glucose.

[Prospective comparison of the flow chart for laboratory investigations for anaemia from the Dutch College of General Practitioners' guideline 'Anaemia' with a self-developed, substantive and logistical alternative flow chart]. / Prospectieve vergelijking van het stroomschema voor laboratoriumonderzoek van anemie uit de NHG-standaard 'Anemie' met een eigen, inhoudelijk en logistiek alternatief stroomschema.

OBJECTIVE: To compare the flow diagram for the diagnosis of anaemia from the guideline 'Anaemia' from the Dutch College of General Practitioners (NHG) with a substantive and logistical alternative protocol. DESIGN: Prospective. METHOD: For evaluation of anaemia, 124 patients from primary care reported to the laboratories of the St. Elisabeth Hospital in Tilburg (n = 94) and the Scheper Hospital in Emmen (n = 30), the Netherlands. Two flow charts were used: the NHG's flow chart and a self-developed chart in which not mean corpuscular volume, but ferritin concentration occupies the central position. All the laboratory tests mentioned in both flow charts were carried out in every patient with, for practical reasons, the exception of Hgb electrophoresis and bone marrow investigations. General practitioners were approached and patient dossiers were consulted to obtain further clinical data. RESULTS: According to the NHG protocol, on the grounds of the laboratory investigations, 64 (52%) of patients could not be put in a specific category. The majority were patients with normocytary anaemia who did not fulfil the criteria for iron deficiency anaemia or the anaemia of chronic disease. According to the alternative chart, in 36 (29%) patients no diagnosis was made. These were patients in whom no abnormal laboratory findings were observed, other than low haemoglobin values. The majority of the patients had normocytary anaemia, in some cases this was interpreted as the anaemia of chronic disease, but more often the anaemia could not be assigned to a particular category. A large number ofpatients had a raised creatinine value. This value did not appear in the NHG protocol. In 15% of patients, more than one cause for anaemia was found. The NHG protocol did not enable these multiple diagnoses to be made. Accordingly, the NHG protocol was difficult to implement in the laboratory. CONCLUSION: Using the NHG flow diagram a large percentage of patients could not be assigned to a particular category. Using the alternative flow diagram, which procedure is easier to carry out in the laboratory, it was possible to make multiple diagnoses.

How Useful are Laboratory Practice Guidelines?

Clinical practice guidelines (CPGs) relating to laboratory diagnostic testing are increasingly produced with the aim of standardizing practice and improving patient care based on the best available evidence. However, the production of a CPG is merely the first step in the process of getting evidence into practice, to be undertaken by laboratories and other stakeholders. This process should evaluate the information provided in the guidelines on laboratory tests, devise a strategy for implementing the CPG or the laboratory aspects of the CPG and finally, once implemented, assess the impact of the CPG on clinical practice, patient outcomes and costs of care. The purpose of CPG evaluation by the laboratory is to determine whether sufficient information is provided on the particular test recommended. CPGs may not always be written with the involvement of a laboratory specialist and this underlies the paucity of relevant information in some national guidelines. When laboratory specialists are involved, CPGs can provide practical information which supports local laboratories as well as clinicians in the implementation and appropriate use of recommendations. Implementation of CPGs is an often neglected area that needs attention and thought. There are many barriers to successful implementation, which may vary at local level. These need to be identified early if CPGs are to be successfully adhered to. The effectiveness of CPGs also needs to be audited using process and health outcome indicators. Clinical audit is an effective tool for assessing adherence to recommendations and for measuring the impact and success of the CPG.

Evaluation of the incremental diagnostic value and impact on patient treatment of thallium scintigraphy.

The incremental diagnostic yield of exercise 201Tl scintigraphy with visual and quantitative analysis was determined in 191 patients with known or suspected coronary artery disease (CAD). The coronary arteriogram was used as the gold standard. After pre-test clinical and exercise electrocardiographic data were taken into consideration, scintigraphy was found to have additional diagnostic value both in the diagnosis of CAD and of multivessel disease, with quantitative analysis being superior to visual analysis. The impact of 201Tl scintigraphy on the patient's treatment--conservative treatment versus revascularization--was also evaluated. The impact was relatively low, as the decision for revascularization was based primarily on the angiographic result and the severity of the anginal pain. This result reflects only the decision making process used in our clinic and permits no conclusion to be made concerning the possible value of 201Tl scintigraphy in this type of medical decision making process.

Clinical value of TPS, CEA and CA 15-3 in breast cancer patients.

Serum TPS, CA 15-3 and CEA levels were measured in 121 women with breast cancer. The combination of TPS (which measures tumour activity) and CA 15-3 (which measures tumour mass) had a sensitivity of 72% to detecting metastatic disease (n = 71). All 3 markers could significantly discriminate local versus distant metastatic relapsed breast cancer and TPS was more often elevated in the case of bone metastases. In a total of 46 relapsed patients and 49 situations which required therapeutic changes because of progressive disease, the response to treatment (hormonal or chemotherapy) was recorded together with tumour marker changes (25% +/-). After 3 months of therapy TPS (68%) responded earlier and faster than CEA (38%) or CA 15-3 (49%) with no progression (SD+PR+CR). The correlation with clinical deterioration after 6 months of therapy was 44% for TPS 33% for CEA and 28% for CA 15-3. In patients with bone metastases, TPS in addition to CA 15-3 could be used to monitor therapy.

Reference values: Bhattacharya or the method proposed by the IFCC?

The Bhattacharya method was used to calculate reference values from unselected patient data. These values were compared with reference values obtained from data from a blood donor population group following the recommendations of the IFCC. Differences between the results could be attributed in part to different statistical methods, and in part to differences between populations. With some limitations, the Bhattacharya method can be of help in the determination of reference values and quality control.

Bhattacharya: a new application for quality control.

The Bhattacharya method and the 'average of normals' method for internal quality control were compared. Both are based on unselected patient test results. The Bhattacharya method is mostly used in clinical chemistry for calculation of reference intervals but could be modified for quality control procedures. Using the data of a coagulation test and stimulating systematic errors, it was concluded that the Bhattacharya method is more sensitive to expected shifts and is more flexible than the 'average of normals' method.

Exercise 201Tl scintigraphy: evaluation of the additional diagnostic value.

The additional diagnostic yield of exercise 201Tl scintigraphy using both visual and quantitative analysis was determined in 221 patients with known or suspected coronary artery disease (CAD). The coronary arteriogram was adopted as the gold standard. After pretest clinical and exercise electrocardiographic data were taken into consideration, scintigraphy added diagnostic accuracy both in the diagnosis of CAD and of multivessel disease. The diagnostic yield of the scintigraphy in terms of sensitivity and specificity was, however, not significant. In 79% (121/153) of the patients, the diagnosis of the presence, or exclusion, of CAD was highly probable (P > 0.80 or P < 0.20) when considering clinical and exercise data. The diagnosis was, however, not significantly improved by the scintigraphic result. Twenty-seven per cent (20/73) returned a negative scintigraphic results with a high (P > 0.80) prescintigraphic probability for CAD and a positive arteriogram. It was concluded that 201Tl scintigraphy has additional diagnostic value after clinical and exercise parameters were taken into consideration in the diagnosis of coronary artery and multiple vessel disease. It is not recommended to refer patients with either a low or high probability of CAD for screening and diagnosis as in a high proportion of patients the diagnosis of CAD could have been made using clinical or exercise data alone.

A patient with a variant form of hairy cell leukaemia.

A 57-year-old woman was admitted because of weakness, fatigue, abdominal discomfort, easy bruising and splenomegaly. A highly elevated leukocyte count with hairy-cell-like cells was found, the cells being positive for the monoclonal antibodies CD19, FMC7, CD11c and B-ly-7 and negative for CD24 and CD25. Blood and bone marrow were investigated not only in our own laboratory but also in several other laboratories resulting in a variety of possible diagnoses. Only after combining all data could a definitive diagnosis of variant hairy cell leukaemia be made. The patient was treated initially with a splenectomy and later on with interferon-alpha-2b, resulting in a steady decrease in the leukocyte count. After a follow-up of 2 years a nearly complete remission was obtained with a good quality of life. The differential diagnosis of this rare disorder is discussed with emphasis on the relative contribution of different diagnostic procedures.

The value of the Thomas-plot in the diagnostic work up of anemic patients referred by general practitioners.

In patients with inflammatory conditions, diagnosing classic iron deficiency or anemia of chronic disease is challenging. In this study, we assessed the diagnostic value of the so-called Thomas'-plot [soluble transferrin receptor (sTfR)/log ferritin (sTfr/log Ferr) and the reticulocyte hemoglobin equivalent (Ret-HE)] in the anemia work up of patients referred by general practitioners. During July 2008-March 2009, 337 consecutive patients were included because of lowered Hb values. The laboratory results of the first 133 consecutive patients were used to determine the cut-off values for the diagnostic plot. The laboratory results of these patients were assessed and interpreted independently by two investigators, blinded from sTfR/log Ferr and Ret-HE values. The following 204 patients were used to test the plot in practice. In 32% of the first 133 patients, no indication of the cause of anemia could be found. However, when using the diagnostic plot in the following 204 patients, this fraction decreased to 14%. The 'Thomas'-plot is of diagnostic value for distinguishing functional iron deficiency from classic iron deficiency in a patient population referred by general practitioners.

Evaluation of LabRespond, a new automated validation system for clinical laboratory test results.

BACKGROUND: Manual validation of laboratory test results is time-consuming, creating a demand for expert systems to automate this process. We have started to set up the program "LabRespond", which covers five validation levels: administrative, technical, sample, patient, and clinical validation. We present the evaluation of a prototype of an automated patient validation system based on statistical methods, in contrast to the commercially available program "VALAB", a rule-based automated validation system. METHODS: In the present study, 163 willfully altered, erroneous test results out of 5421 were submitted for validation to LabRespond, VALAB, and to a group of clinical chemists (n = 9) who validated these test results manually. The test results rejected by three or more clinical chemists (n = 281) served as a secondary reference standard. RESULTS: The error recovery rates of clinical chemists ranged from 23.9% to 71.2%. The recovery rates of LabRespond and VALAB were 77.9% and 71.8%, respectively (difference not significant). The false-positive rates were 82.7% for LabRespond, 83.6% for VALAB, and 27.8-86.7% for clinical chemists. Using the consensus of three or more clinical chemists as the secondary reference standard, we found error recovery rates of 64.8% for LabRespond and 72.2% for VALAB (P = 0.06). Compared with VALAB, LabRespond detected more (P = 0.003) erroneous test results of the type that were changed from abnormal to normal. CONCLUSIONS: The statistical plausibility check used by LabRespond offers a promising automated validation method with a higher error recovery rate than the clinical chemists participating in this study, and a performance comparable to VALAB.

The science of systematic reviewing studies of diagnostic tests.

BACKGROUND: Systematic reviews have gradually replaced single studies as the highest level of documented effectiveness of health care interventions. Systematic reviewing is a new scientific method, concerned with the development and application of methods for identifying relevant literature, analysing the material while increasing validity and precision, and presenting and discussing the results in a way that does justice to the research question and to the available evidence. The objective of this study was to review the systematic reviews in laboratory medicine, to evaluate the methods applied in these reviews and the applicability of guidelines of the Cochrane Methods Working Group on Screening and Diagnostic Tests, and identify areas for future research. METHODS: All the systematic reviews in the field of clinical chemistry and laboratory haematology that could be identified in Medline, EMBASE and other literature databases up to December 1998, were evaluated. RESULTS: We studied 23 reviews of diagnostic trials. Although all reviews share the same basic methodology, there was a wide variation in the methods applied. There was no consensus on the quality criteria for inclusion of primary studies. The results of the primary studies were heterogeneous in most cases. This was partly due to design flaws in the primary studies, but was also inherent in the diverse study designs in diagnostic trials. We observed differences in the analysis of the factors that cause heterogeneity of the results, and in the summary statistics used to pool the data from the primary studies. The additional diagnostic value of a test, after other test results are taken into consideration, was only addressed in one study. CONCLUSION: This overview of 23 reviews of diagnostic trials identifies areas in the methods of systematic reviewing where consensus is lacking, such as quality rating of primary studies, analysis of heterogeneity between primary studies and pooling of data. Guidelines need to be improved on these points.

Diagnostic value of the mean corpuscular volume in the detection of vitamin B12 deficiency.

In clinical practice, the finding of an elevated mean corpuscular volume (MCV), macrocytic anaemia or specific neurological symptoms is often the reason to test for vitamin B12 (B12) deficiency. Use of the MCV as a test for the detection or exclusion of B12 deficiency is only justified if the diagnostic accuracy is sufficiently high. However, the sensitivity and specificity are not well known. We performed a systematic review of the diagnostic value of an elevated MCV for B12 deficiency in both anaemic and non-anaemic patients. Of approximately 3500 titles and/or abstracts that were screened, 37 original papers contained usable data. The population under study proved to be the characteristic of major influence on the study outcome. Pooling of data from different studies was performed in subsets of the data corresponding to the different populations studied. The cut-off levels of both MCV and serum B12 had a significant influence on the study outcomes. The data, however, were pooled without taking these cut-off levels into account. The pooled estimates should be interpreted with this limitation in mind. The reference standards were (1) a low serum B12 concentration and (2) a B12 deficiency confirmed by low serum B12 combined with additional diagnostic investigations. In the population that was randomly screened for low serum B12, the sensitivity of the MCV for B12 deficiency was 17%, whereas the sensitivity was 30% for B12 deficiency in patients with anaemia. When measurement of serum B12 was ordered to exclude B12 deficiency as part of the patients' treatment, the sensitivity was 30% for low serum B12 concentration, 58% for B12 deficiency and 75% for B12 deficiency in patients with anaemia. In the population with pernicious anaemia, the sensitivity was far from perfect (77%). In the five studies that reported data on the positive predictive value of the MCV for B12 deficiency, this ranged from 0% (0/6) to 55% (11/20). This systematic review shows that a considerable number of B12-deficient patients will remain unnoticed when the MCV is used to rule in patients for further evaluation. Depending on the population studied, up to 84% of cases will than be missed. The MCV can be used to make the diagnosis of B12 deficiency more--or less--probable. An elevated MCV justifies the measurement of serum B12. The MCV should not be used as the only parameter ruling out the diagnosis of B12 deficiency.

Perinatal development of the lung in rat and spiny mouse: its relation to altricial and precocial timing of birth.

Rat and spiny mouse (Acomys cahirinus) are closely related murinoid species that represent altricial (rat) and precocial (spiny mouse) modes of development. The late intrauterine developmental stages of the spiny mouse therefore seem comparable to the early extrauterine developmental stages of the rat. To elucidate the question to what extent the development of the lung is related to the developmental timing of birth, we have studied some enzymes involved in the de novo synthesis of phosphatidylcholine. Of the enzymes studied, cholinephosphate cytidylyltransferase shows peaks in activity in the perinatal period (rat and spiny mouse) and at the beginning of the 3rd postnatal week (rat only). This enzyme fulfills the requirements for a developmental parameter best as changes in activity of this enzyme can be correlated with phases of cell proliferation and surface expansion in the lung of the rat. The single peak of cholinephosphate cytidylyltransferase activity in the spiny mouse as well as microscopical examination of the lung support the hypothesis that the processes of proliferation and surface expansion, which occur consecutively in the rat, develop concurrently in the spiny mouse.

Reflex sympathetic dystrophy: is the immune system involved?

OBJECTIVE: Evaluation of immune system function in patients with reflex sympathetic dystrophy (RSD). DESIGN: Survey on blood samples obtained from RSD patients and from a randomly selected control group. The lymphocyte populations (T, B, NK cells), and the activated T cells (CD25, and HLA-Dr-positive CD4 and CD8 cells) were analyzed by flow cytometry with dual-color direct immunofluorescence after whole-blood lysis. Clinical chemistry parameters were analyzed in additional serum samples. SETTING: Tertiary care center (outpatient rehabilitation clinic). SUBJECTS: Thirteen patients (nine women) with RSD and a control group of 21 healthy individuals. MAIN OUTCOME MEASURES: The results of the flow cytometry analysis of RSD patients were related to those of the control subjects. Means were analyzed, and confidence intervals for differences of the means were calculated. The means of the clinical chemical analysis were related to local reference values. RESULTS: The flow cytometry analysis did not differ between RSD patients and healthy controls. Although in some patients an individual parameter of clinical chemical analysis differed from its reference value, all of the mean values were within reference limits. Stratification on medications with immunomodulatory effects and on probability of a definite diagnosis of RSD had no influence on the results. CONCLUSION: No association between immunologic indices and RSD was found. This finding is relevant, because recent theories stress that it is not the sympathetic nervous system but a local inflammatory reaction that is fundamental in the pathogenesis of RSD. The results of this study do not support this theory.

Multivariate statistical modeling: alternative approach to test evaluation, applied to counting reticulocytes by flow cytometry.

We present a statistical path analysis model for the evaluation of two tests in the absence of a "gold standard" method. This model is applied to the evaluation of flow-cytometric and visual reticulocyte counting by using as the comparison method a combination of three hematological measurements: hemoglobin concentration (HGB), mean cellular volume (MCV), and erythrocyte density width (EDW). We assumed that, in general, a higher reticulocyte count is associated with a lower HGB value and with greater values for MCV and EDW. Applying this assumption and the statistical model, we demonstrated that flow cytometry was superior to visual reticulocyte counting in the low-value range studied. The path analysis model is potentially applicable in other cases where two tests are to be compared, and when no gold standard is available.