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Editorial Note: See https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD014461.pub2/full for a more recent review that covers this topic and has superseded this review., Background: Low-back pain (LBP) is a common condition seen in primary care. A principal aim during a clinical examination is to identify patients with a higher likelihood of underlying serious pathology, such as vertebral fracture, who may require additional investigation and specific treatment. All 'evidence-based' clinical practice guidelines recommend the use of red flags to screen for serious causes of back pain. However, it remains unclear if the diagnostic accuracy of red flags is sufficient to support this recommendation., Objectives: To assess the diagnostic accuracy of red flags obtained in a clinical history or physical examination to screen for vertebral fracture in patients presenting with LBP., Search Methods: Electronic databases were searched for primary studies between the earliest date and 7 March 2012. Forward and backward citation searching of eligible studies was also conducted., Selection Criteria: Studies were considered if they compared the results of any aspect of the history or test conducted in the physical examination of patients presenting for LBP or examination of the lumbar spine, with a reference standard (diagnostic imaging). The selection criteria were independently applied by two review authors., Data Collection and Analysis: Three review authors independently conducted 'Risk of bias' assessment and data extraction. Risk of bias was assessed using the 11-item QUADAS tool. Characteristics of studies, patients, index tests and reference standards were extracted. Where available, raw data were used to calculate sensitivity and specificity with 95% confidence intervals (CI). Due to the heterogeneity of studies and tests, statistical pooling was not appropriate and the analysis for the review was descriptive only. Likelihood ratios for each test were calculated and used as an indication of clinical usefulness., Main Results: Eight studies set in primary (four), secondary (one) and tertiary care (accident and emergency = three) were included in the review. Overall, the risk of bias of studies was moderate with high risk of selection and verification bias the predominant flaws. Reporting of index and reference tests was poor. The prevalence of vertebral fracture in accident and emergency settings ranged from 6.5% to 11% and in primary care from 0.7% to 4.5%. There were 29 groups of index tests investigated however, only two featured in more than two studies. Descriptive analyses revealed that three red flags in primary care were potentially useful with meaningful positive likelihood ratios (LR+) but mostly imprecise estimates (significant trauma, older age, corticosteroid use; LR+ point estimate ranging 3.42 to 12.85, 3.69 to 9.39, 3.97 to 48.50 respectively). One red flag in tertiary care appeared informative (contusion/abrasion; LR+ 31.09, 95% CI 18.25 to 52.96). The results of combined tests appeared more informative than individual red flags with LR+ estimates generally greater in magnitude and precision., Authors' Conclusions: The available evidence does not support the use of many red flags to specifically screen for vertebral fracture in patients presenting for LBP. Based on evidence from single studies, few individual red flags appear informative as most have poor diagnostic accuracy as indicated by imprecise estimates of likelihood ratios. When combinations of red flags were used the performance appeared to improve. From the limited evidence, the findings give rise to a weak recommendation that a combination of a small subset of red flags may be useful to screen for vertebral fracture. It should also be noted that many red flags have high false positive rates; and if acted upon uncritically there would be consequences for the cost of management and outcomes of patients with LBP. Further research should focus on appropriate sets of red flags and adequate reporting of both index and reference tests., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Outcomes in a clinical trial can be affected by any underlying preferences that its participants have for the treatments under comparison and by whether they actually receive their preferred treatment. These effects cannot be evaluated in standard trial designs but are estimable in the alternative two-stage randomised trial design, in which some patients can choose their treatment, while the rest are randomly assigned. We have previously shown that, when all two-stage trial participants have a preferred treatment, the preference effects can be evaluated, in addition to the usual direct effect of treatment. We also determined criteria by which to optimise how many participants should be given a choice of treatment vs being randomised. More recently, we extended our methodology to allow for participants who are unable or unwilling to express a treatment preference if they are assigned to the choice group. In this paper, we show how to optimise the two-stage design when some participants are undecided about their treatment. We demonstrate that the undecided group should be regarded as distinct in the analysis, to obtain valid estimates of the preference effects. We derive the optimal proportion of participants who should be offered a choice of treatment, which in many cases will be close to 50%. More generally, the optima depend on the preference rates for treatments and the proportion of undecided participants, and the parameters of primary interest. We discuss some advantages and disadvantages of the two-stage trial design in this situation and describe a practical example., (© 2019 John Wiley & Sons, Ltd.)

Background: The prognosis of acute low back pain (LBP) is typically good; however, there is substantial variation in individual patient's outcomes. We recently developed a prediction model that was able to predict the likelihood of pain recovery in patients with acute LBP who continue to have pain approximately 1 week after initially seeking care. The aims of the current study were to (a) re-categorize the variables in the developmental dataset to be able to validate the model in the validation dataset; (b) refit the existing model in the developmental dataset; and (c) validate the model in the validation dataset., Methods: The validation study sample comprised 737 patients with acute LBP, with a pain score of ≥2/10, 1 week after initially seeking care and with duration of current episode of ≤4 weeks. The primary outcome measure was days to pain recovery. Some of the variables from the development dataset were re-categorized prior to refitting the existing model in the developmental dataset using Cox regression. The performance (calibration and discrimination) of the prediction model was then tested in the validation dataset., Results: Three variables of the development dataset were re-categorized. The performance of the prediction model with re-categorized variables in the development dataset was good (C-statistic = 0.76, 95% CI 0.70-0.82). The discrimination of the model using the validation dataset resulted in a C-statistic of 0.71 (95% CI 0.63-0.78). The calibration for the validation sample was acceptable at 1 month. However, at 1 week the predicted proportions within quintiles tended to overestimate the observed recovery proportions, and at 3 months, the predicted proportions tended to underestimate the observed recovery proportions., Conclusions: The updated prediction model demonstrated reasonably good external validity and may be useful in practice, but further validation and impact studies in relevant populations should be conducted., Significance: A clinical prediction model based on five easily collected variables demonstrated reasonable external validity. The prediction model has the potential to inform patients and clinicians of the likely prognosis of individuals with acute LBP but requires impact studies to assess its clinical usefulness., (© 2018 European Pain Federation - EFIC®.)

Background: The identification of serious pathologies, such as spinal malignancy, is one of the primary purposes of the clinical assessment of patients with low-back pain (LBP). Clinical guidelines recommend awareness of "red flag" features from the patient's clinical history and physical examination to achieve this. However, there are limited empirical data on the diagnostic accuracy of these features and there remains very little information on how best to use them in clinical practice., Objectives: To assess the diagnostic performance of clinical characteristics identified by taking a clinical history and conducting a physical examination ("red flags") to screen for spinal malignancy in patients presenting with LBP., Search Methods: We searched electronic databases for primary studies (MEDLINE, EMBASE, and CINAHL) and systematic reviews (PubMed and Medion) from the earliest date until 1 April 2012. Forward and backward citation searching of eligible articles was also performed., Selection Criteria: We considered studies if they compared the results of history taking and physical examination on patients with LBP with those of diagnostic imaging (magnetic resonance imaging, computed tomography, myelography)., Data Collection and Analysis: Two review authors independently assessed the quality of each included study with the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) tool and extracted details on patient characteristics, study design, index tests, and reference standard. Diagnostic accuracy data were presented as sensitivities and specificities with 95% confidence intervals for all index tests., Main Results: We included eight cohort studies of which six were performed in primary care (total number of patients; n = 6622), one study was from an accident and emergency setting (n = 482), and one study was from a secondary care setting (n = 257). In the six primary care studies, the prevalence of spinal malignancy ranged from 0% to 0.66%. Overall, data from 20 index tests were extracted and presented, however only seven of these were evaluated by more than one study. Because of the limited number of studies and clinical heterogeneity, statistical pooling of diagnostic accuracy data was not performed.There was some evidence from individual studies that having a previous history of cancer meaningfully increases the probability of malignancy. Most "red flags" such as insidious onset, age > 50, and failure to improve after one month have high false positive rates.All of the tests were evaluated in isolation and no study presented data on a combination of positive tests to identify spinal malignancy., Authors' Conclusions: For most "red flags," there is insufficient evidence to provide recommendations regarding their diagnostic accuracy or usefulness for detecting spinal malignancy. The available evidence indicates that in patients with LBP, an indication of spinal malignancy should not be based on the results of one single "red flag" question. Further research to evaluate the performance of different combinations of tests is recommended.

Background: Low-back pain (LBP) is a common condition seen in primary care. A principal aim during a clinical examination is to identify patients with a higher likelihood of underlying serious pathology, such as vertebral fracture, who may require additional investigation and specific treatment. All 'evidence-based' clinical practice guidelines recommend the use of red flags to screen for serious causes of back pain. However, it remains unclear if the diagnostic accuracy of red flags is sufficient to support this recommendation., Objectives: To assess the diagnostic accuracy of red flags obtained in a clinical history or physical examination to screen for vertebral fracture in patients presenting with LBP., Search Methods: Electronic databases were searched for primary studies between the earliest date and 7 March 2012. Forward and backward citation searching of eligible studies was also conducted., Selection Criteria: Studies were considered if they compared the results of any aspect of the history or test conducted in the physical examination of patients presenting for LBP or examination of the lumbar spine, with a reference standard (diagnostic imaging). The selection criteria were independently applied by two review authors., Data Collection and Analysis: Three review authors independently conducted 'Risk of bias' assessment and data extraction. Risk of bias was assessed using the 11-item QUADAS tool. Characteristics of studies, patients, index tests and reference standards were extracted. Where available, raw data were used to calculate sensitivity and specificity with 95% confidence intervals (CI). Due to the heterogeneity of studies and tests, statistical pooling was not appropriate and the analysis for the review was descriptive only. Likelihood ratios for each test were calculated and used as an indication of clinical usefulness., Main Results: Eight studies set in primary (four), secondary (one) and tertiary care (accident and emergency = three) were included in the review. Overall, the risk of bias of studies was moderate with high risk of selection and verification bias the predominant flaws. Reporting of index and reference tests was poor. The prevalence of vertebral fracture in accident and emergency settings ranged from 6.5% to 11% and in primary care from 0.7% to 4.5%. There were 29 groups of index tests investigated however, only two featured in more than two studies. Descriptive analyses revealed that three red flags in primary care were potentially useful with meaningful positive likelihood ratios (LR+) but mostly imprecise estimates (significant trauma, older age, corticosteroid use; LR+ point estimate ranging 3.42 to 12.85, 3.69 to 9.39, 3.97 to 48.50 respectively). One red flag in tertiary care appeared informative (contusion/abrasion; LR+ 31.09, 95% CI 18.25 to 52.96). The results of combined tests appeared more informative than individual red flags with LR+ estimates generally greater in magnitude and precision., Authors' Conclusions: The available evidence does not support the use of many red flags to specifically screen for vertebral fracture in patients presenting for LBP. Based on evidence from single studies, few individual red flags appear informative as most have poor diagnostic accuracy as indicated by imprecise estimates of likelihood ratios. When combinations of red flags were used the performance appeared to improve. From the limited evidence, the findings give rise to a weak recommendation that a combination of a small subset of red flags may be useful to screen for vertebral fracture. It should also be noted that many red flags have high false positive rates; and if acted upon uncritically there would be consequences for the cost of management and outcomes of patients with LBP. Further research should focus on appropriate sets of red flags and adequate reporting of both index and reference tests.

Response rules are increasingly used by the Pharmaceuticals Benefits Scheme (PBS) in Australia and the National Institute of Clinical Excellence (NICE) in the U.K. to limit continued subsidy of very expensive drugs to patients who demonstrate an 'adequate' response. By targeting therapy to patients who appear to benefit most, policy makers aim to increase the cost-effectiveness of therapy. However, the value of response rules in fulfilling this aim is unproven. We present a four-item checklist that may be used to help decision makers identify when a response rule is appropriate. As an example, we apply our checklist to the response rules used for tumour necrosis factor (TNF) inhibitors in rheumatoid arthritis. On the basis of the checklist we find that the response rules in both countries are inadequate and may cause therapy to be inappropriately ceased in some and continued in others. Careful assessment is needed before decision makers adopt a response rule as a way of increasing the cost effectiveness of therapy.

Background: Vitamin D compounds are used to suppress elevated serum parathyroid hormone (PTH) in people with chronic kidney disease (CKD)., Objectives: To assess the efficacy of vitamin D therapy on biochemical, bone, cardiovascular, and mortality outcomes in people with CKD and not requiring dialysis., Search Strategy: We searched The Cochrane Renal Group's specialised register, Cochrane's Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of retrieved articles., Selection Criteria: Randomised controlled trials (RCTs) comparing different forms, schedules, or routes of administration of vitamin D compounds for people with CKD not requiring dialysis were included. Vitamin D compounds were defined as established (calcitriol, alfacalcidol, 24,25(OH)(2)vitamin D(3)) or newer (doxercalciferol, maxacalcitol, paricalcitol, falecalcitriol) vitamin D compounds., Data Collection and Analysis: Data were extracted by two authors. Statistical analyses were performed using the random effects model. Results were summarized as risk ratio (RR) for dichotomous outcomes or mean differences (MD) for continuous outcomes with 95% confidence intervals (CI)., Main Results: Sixteen studies (894 patients) were included. No formulation, route, or schedule of vitamin D compound was found to alter the mortality risk or need for dialysis. Vitamin D compounds significantly lowered serum PTH (4 studies, 153 patients: MD -49.34 pg/mL, 95% CI -85.70 to -12.97 (-5.6 pmol/L, 95% CI -9.77 to -1.48)) and were more likely to reduce serum PTH > 30% from baseline value (264 patients: RR 7.87, 95% CI 4.87 to 12.73). Vitamin D treatment was associated with increased end of treatment serum phosphorus (3 studies, 140 patients: MD 0.37 mg/dL, 95% CI 0.09, 0.66 (0.12 mmol/L, 95% CI 0.03, 0.21)) and serum calcium (5 studies, 184 patients: MD 0.20 mg/dL, 95% CI 0.17 to 0.23 (0.05 mmol/L, 95% CI 0.04 to 0.06)). Few data were available comparing intermittent with daily vitamin D administration, or other schedules of dosing., Authors' Conclusions: There are not sufficient data to determine the effect of vitamin D compounds on mortality and cardiovascular outcomes in people with CKD not requiring dialysis. While vitamin D compounds reduce serum PTH (49.3 pg/mL (5.6 pmol/L)) compared with placebo, the relative clinical benefits of PTH lowering versus treatment-related increases in serum phosphorus and calcium remain to be understood.

Background: Clinical guidelines recommend vitamin D compounds to suppress serum parathyroid hormone (PTH) in chronic kidney disease (CKD), however treatment may be associated with increased serum phosphorus and calcium, which are associated with increased mortality in observational studies. Observational data also indicate vitamin D therapy may be independently associated with reduced mortality in CKD., Objectives: We assessed the effects of vitamin D compounds on clinical, biochemical, and bone outcomes in people with CKD and receiving dialysis., Search Strategy: We searched The Cochrane Renal Group's specialised register, Cochrane's Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of retrieved articles., Selection Criteria: Randomised controlled trials (RCTs) in subjects with CKD and requiring dialysis that assessed treatment with vitamin D compounds., Data Collection and Analysis: Data was extracted by two authors. Results are summarised as risk ratios (RR) for dichotomous outcomes or mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI)., Main Results: Sixty studies (2773 patients) were included. No formulation, route, or schedule of administration was associated with altered risks of death, bone pain, or parathyroidectomy. Marked heterogeneity in reporting of outcomes resulted in few data available for formal meta-analysis. Compared with placebo, vitamin D compounds lowered serum PTH at the expense of increasing serum phosphorus. Trends toward increased hypercalcaemia and serum calcium did not reach statistical significance but may be clinically relevant. Newer vitamin D compounds (paricalcitol, maxacalcitol, doxercalciferol) lowered PTH compared with placebo, with increased risks of hypercalcaemia, although inadequate data were available for serum phosphorus. Intravenous vitamin D may lower PTH compared with oral treatment, and be associated with lower serum phosphorus and calcium levels, although limitations in the available studies precludes a conclusive statement of treatment efficacy. Few studies were available for intermittent versus daily and intraperitoneal versus oral administration or directly comparative studies of newer versus established vitamin D compounds., Authors' Conclusions: We confirm that vitamin D compounds suppress PTH in people with CKD and requiring dialysis although treatment is associated with clinical elevations in serum phosphorus and calcium. All studies were inadequately powered to assess the effect of vitamin D on clinical outcomes and until such studies are conducted the relative importance of changes in serum PTH, phosphorus and calcium resulting from vitamin D therapy remain unknown. Observational data showing vitamin D compounds may be associated with improved survival in CKD need to be confirmed or refuted in specifically designed RCTs.

Combining dichotomous (or dichotomized) results of two diagnostic tests will result in a trade-off in sensitivity and specificity of the combined test relative to the component tests. Because of this inherent trade-off, likelihood ratios provide a clinically relevant means of comparing the combined test with one of its components. The likelihood ratios depend on both sensitivity and specificity and hence take into account the trade-off between them. A graphical approach is used to assess whether the combined test is superior to a component test, or vice versa. Asymptotic standard errors are derived for comparing likelihood ratios when a paired study design is used. The trade-off in the expected number of additional true positive and false positive results (or true negative and false negative results) is used as the basis for deciding whether to use tests in combination when neither the combined nor a component test shows superior test performance based on their likelihood ratios. These methods are illustrated with an example that considers the combined use of Pap and HPV testing., (Copyright 2002 John Wiley & Sons, Ltd.)

Two dichotomous screening tests may be compared by applying both tests to all members of a sampled population. For individuals with a positive result on either test the disease status may be verified by a reference standard, but for individuals negative on both tests the disease status may be unverified because the probability of disease is so low that further investigation is costly, unacceptable and perhaps unethical. If the tests have been applied to samples from two populations which have different disease prevalences then unbiased estimates of the true positive and false positive rates of each test, the prevalences in the two populations, and two parameters representing dependence between the two tests can be estimated using maximum likelihood methods. The methods are based on the assumption that the sensitivities and specificities of the two tests, and the dependencies between the tests, are independent of prevalence. A test of goodness of fit provides a test of this., (Copyright 2002 John Wiley & Sons, Ltd.)

Meta-analyses are subject to bias for many of reasons, including publication bias. Asymmetry in a funnel plot of study size against treatment effect is often used to identify such bias. We compare the performance of three simple methods of testing for bias: the rank correlation method; a simple linear regression of the standardized estimate of treatment effect on the precision of the estimate; and a regression of the treatment effect on sample size. The tests are applied to simulated meta-analyses in the presence and absence of publication bias. Both one-sided and two-sided censoring of studies based on statistical significance was used. The results indicate that none of the tests performs consistently well. Test performance varied with the magnitude of the true treatment effect, distribution of study size and whether a one- or two-tailed significance test was employed. Overall, the power of the tests was low when the number of studies per meta-analysis was close to that often observed in practice. Tests that showed the highest power also had type I error rates higher than the nominal level. Based on the empirical type I error rates, a regression of treatment effect on sample size, weighted by the inverse of the variance of the logit of the pooled proportion (using the marginal total) is the preferred method., (Copyright 2001 John Wiley & Sons, Ltd.)