The Adrenal Vein Sampling Outcomes Study (AVOS): success rates following adrenalectomy for unilateral primary aldosteronism.

The objective was to determine the clinical and biochemical success rates and assess the nature of follow-up after adrenalectomy in patients with unilateral primary aldosteronism (PA), subtyped by adrenal vein sampling (AVS) in West Australia (WA) using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Clinical and biochemical outcomes were retrospectively evaluated in patients with unilateral PA who underwent adrenalectomy according to AVS between September 2017 and September 2020. Pre- and post-surgical data were collected using a standardised questionnaire, review of clinic letters and examination of private and public pathology results and radiological reports. Follow-up data were available for 47 patients post-adrenalectomy; biochemical outcome data were available for 37 patients, clinical outcome data for 40 patients, with 30 patients having both outcomes available. Final assessment was performed between 0 to 3 months in 23/37 (62.2%) patients with biochemical outcomes, 15/40 (37.5%) with clinical outcomes, and 17/30 (56.7%) with both clinical and biochemical outcomes. Complete biochemical success was achieved in 83.8% (31/37) of patients, with 26.7% (8/30) obtaining both complete clinical and biochemical success. Complete clinical success was achieved in 35.0% (14/40) of patients, with 47.5% (19/40) obtaining partial clinical success. Overall, 93.6% (44/47) of patients derived benefit from adrenalectomy. The outcomes of adrenalectomy for unilateral PA in Western Australian using standardised PASO criteria demonstrate highly comparable clinical and biochemical success rates to international data. However, further standardisation of post-operative follow-up care needs to be implemented to ensure the recommended repeat follow-up assessment criteria are collected.

Functional Reference Limits: Describing Physiological Relationships and Determination of Physiological Limits for Enhanced Interpretation of Laboratory Results.

Functional reference limits describe key changes in the physiological relationship between a pair of physiologically related components. Statistically, this can be represented by a significant change in the curvature of a mathematical function or curve (e.g., an observed plateau). The point at which the statistical relationship changes significantly is the point of curvature inflection and can be mathematically modeled from the relationship between the interrelated biomarkers. Conceptually, they reside between reference intervals, which describe the statistical boundaries of a single biomarker within the reference population, and clinical decision limits that are often linked to the risk of morbidity or mortality and set as thresholds. Functional reference limits provide important physiological and pathophysiological insights that can aid laboratory result interpretation. Laboratory professionals are in a unique position to harness data from laboratory information systems to derive clinically relevant values. Increasing research on and reporting of functional reference limits in the literature will enhance their contribution to laboratory medicine and widen the evidence base used in clinical decision limits, which are currently almost exclusively contributed to by clinical trials. Their inclusion in laboratory reports will enhance the intellectual value of laboratory professionals in clinical care beyond the statistical boundaries of a healthy reference population and pave the way to them being considered in shaping clinical decision limits. This review provides an overview of the concepts related to functional reference limits, clinical examples of their use, and the impetus to include them in laboratory reports.

Analytical performance specifications for the measurement uncertainty of 24,25-dihydroxyvitamin D examinations.

OBJECTIVES: The exploration of the metabolites in the degradation pathways of vitamin D (VTD) has gained importance in recent years and simultaneous quantitation of twenty-five-hydroxy vitamin D (25(OH)D) mass concentration together with 24,25-dihydroxyvitamin D (24,25(OH)2D) has been proposed as a newer approach to define VTD deficiency. Yet, no data are available on 24,25(OH)2D biological variation (BV). In this study, we evaluated 24,25(OH)2D's BV on the European Biological Variation Study (EuBIVAS) cohort samples to determine if analytical performance specifications (APS) for 24,25(OH)2D could be generated. METHODS: Six European laboratories recruited 91 healthy participants. 25(OH)D and 24,25(OH)2D concentrations in K3-EDTA plasma were examined weekly for up to 10 weeks in duplicate with a validated LC-MS/MS method. The Vitamin D Metabolite Ratio (24,25(OH)2D divided by 25(OH)D × 100) was also calculated at each time point. RESULTS: Linear regression of the mean 24,25(OH)2D concentrations at each blood collection showed participants were not in steady state. Variations of 24,25(OH)2D over time were significantly positively associated with the slopes of 25(OH)D concentrations over time and the concentration of 25(OH)D of the participant at inclusion, and negatively associated with body mass index (BMI), but not with age, gender, or location of the participant. The variation of the 24,25(OH)2D concentration in participants over a 10 weeks period was 34.6%. Methods that would detect a significant change linked to the natural production of 24,25(OH)2D over this period at p<0.05 would need a relative measurement uncertainty (u%)<14.9% while at p<0.01, relative measurement uncertainty should be <10.5%. CONCLUSIONS: We have defined for the first time APS for 24,25(OH)2D examinations. According to the growing interest in this metabolite, several laboratories and manufacturers might aim to develop specific methods for its determination. The results presented in this paper are thus necessary prerequisites for the validation of such methods.

Practical Considerations for the Clinical Application of Bone Turnover Markers in Osteoporosis.

Bone turnover markers (BTMs) are released during the bone remodelling cycle and are measurable in blood or urine, reflecting bone remodelling rate. They have been useful in elucidating the pharmacodynamics and effectiveness of osteoporosis medication in clinical trials and are increasingly used in routine clinical management of osteoporosis, especially for monitoring therapy, in addition to their use in other metabolic bone disease such as Paget's disease of bone and osteomalacia. Serum ß isomerised C-terminal telopeptide of type I collagen and pro-collagen I N-terminal propeptide have been designated as reference BTMs for use in osteoporosis. In addition, bone-specific isoenzyme of alkaline phosphatase (B-ALP) secreted by osteoblasts and tartrate-resistant acid phosphatase 5b (TRACP-5b) secreted by osteoclasts are also found to be specific markers of bone formation and resorption, respectively. The concentrations of the latter enzymes in blood measured by immunoassay provide reliable measures of bone turnover even in the presence of renal failure. B-ALP is recommended for use in the assessment of renal bone disease of chronic kidney disease, and TRACP-5b shows promise as a marker of bone resorption in that condition. BTMs in blood do not suffer from biological variation to the same extent as the older BTMs that were measured in urine. Appropriate patient preparation and sample handling are important in obtaining accurate measures of BTMs for clinical use. Reference change values and treatment targets have been determined for the reference BTMs for their use in monitoring osteoporosis treatment. Further ongoing studies will enhance their clinical applications.

Current use of bone turnover markers in the management of osteoporosis.

The adult bone is continuously being remodelled to repair microdamage, preserve bone strength and mechanical competence as well as maintain calcium homeostasis. Bone turnover markers are products of osteoblasts (bone formation markers) and osteoclasts (bone resorption markers) providing a dynamic assessment of remodelling (turnover). Resorption-specific bone turnover markers are typically degradation products of bone collagen molecules (N- [NTX] and C-telopeptide cross-linked type 1 collagen [CTX]), which are released into the circulation and excreted in urine; or enzymatic activities reflecting osteoclastic resorption, tartrate-resistant acid phosphatase [TRACP]. Formation-specific bone turnover markers embrace different osteoblastic activities: type 1 collagen synthesis (Procollagen type I N- propeptide [PINP]), osteoblast enzymes (bone-specific alkaline phosphatase [BALP]), or bone matrix proteins [osteocalcin]. Among individuals not receiving osteoporosis treatment, resorption and formation markers are tightly linked and highly correlated (r = 0.6-0.8). Significant biological variability was reported in the past, but these issues have been greatly improved with automated assays and attention to pre-analytical and analytical factors that are known to influence bone turnover marker levels. Bone turnover markers are not useful in the diagnosis of osteoporosis, the individual prediction of bone loss, fracture, or rare complications, or in the selection of pharmacological treatment. Despite remaining issues with reference intervals and assays harmonization, bone turnover markers have proven to be useful in elucidating the pharmacodynamics and effectiveness of osteoporosis medications in clinical trials. As an alternative to BMD testing, BTMs may be useful to monitor osteoporosis therapies.

Comparison of two (data mining) indirect approaches for between-subject biological variation determination.

BACKGROUND: Between-subject biological variation (CVg) is an important parameter in several aspects of laboratory practice, including setting of analytical performance specification, delta checks and calculation of index of individuality. Using simulations, we compare the performance of two indirect (data mining) approaches for deriving CVg. METHODS: The expected mean squares (EMS) method was compared against that proposed by Harris and Fraser. Using numerical simulations, d the percentage difference in the mean between the non-pathological and pathological populations, CVi the within-subject coefficient of variation of the non-pathological distribution, f the fraction of pathological values, and e the relative increase in CVi of the pathological distribution were varied for a total of 320 conditions to examine the impact on the relative fractional of error of the recovered CVg compared to the true value. RESULTS: Comparing the two methods, the EMS and Harris and Fraser's approaches yielded similar performance of 158 conditions and 157 conditions within ± 0.20 fractional error of the true underlying CVg, for the normal and lognormal distributions, respectively. It is observed that both EMS and Harris and Fraser's method performed better using the calculated CVi rather than the actual ('presumptive') CVi. The number of conditions within 0.20 fractional error of the true underlying CVg did not differ significantly between the normal and lognormal distributions. The estimation of CVg improved with decreasing values of f, d and CViCVg. DISCUSSIONS: The two statistical approaches included in this study showed reliable performance under the simulation conditions examined.

Comparison of four indirect (data mining) approaches to derive within-subject biological variation.

OBJECTIVES: Within-subject biological variation (CVi ) is a fundamental aspect of laboratory medicine, from interpretation of serial results, partitioning of reference intervals and setting analytical performance specifications. Four indirect (data mining) approaches in determination of CVi were directly compared. METHODS: Paired serial laboratory results for 5,000 patients was simulated using four parameters, d the percentage difference in the means between the pathological and non-pathological populations, CVi the within-subject coefficient of variation for non-pathological values, f the fraction of pathological values, and e the relative increase in CVi of the pathological distribution. These parameters resulted in a total of 128 permutations. Performance of the Expected Mean Squares method (EMS), the median method, a result ratio method with Tukey's outlier exclusion method and a modified result ratio method with Tukey's outlier exclusion were compared. RESULTS: Within the 128 permutations examined in this study, the EMS method performed the best with 101/128 permutations falling within ±0.20 fractional error of the 'true' simulated CVi , followed by the result ratio method with Tukey's exclusion method for 78/128 permutations. The median method grossly under-estimated the CVi . The modified result ratio with Tukey's rule performed best overall with 114/128 permutations within allowable error. CONCLUSIONS: This simulation study demonstrates that with careful selection of the statistical approach the influence of outliers from pathological populations can be minimised, and it is possible to recover CVi values close to the 'true' underlying non-pathological population. This finding provides further evidence for use of routine laboratory databases in derivation of biological variation components.

Comparison of 8 methods for univariate statistical exclusion of pathological subpopulations for indirect reference intervals and biological variation studies.

BACKGROUND: Indirect reference intervals and biological variation studies heavily rely on statistical methods to separate pathological and non-pathological subpopulations within the same dataset. In recognition of this, we compare the performance of eight univariate statistical methods for identification and exclusion of values originating from pathological subpopulations. METHODS: The eight approaches examined were: Tukey's rule with and without Box-Cox transformation; median absolute deviation; double median absolute deviation; Gaussian mixture models; van der Loo (Vdl) methods 1 and 2; and the Kosmic approach. Using four scenarios including lognormal distributions and varying the conditions through the number of pathological populations, central location, spread and proportion for a total of 256 simulated mixed populations. A performance criterion of ± 0.05 fractional error from the true underlying lower and upper reference interval was chosen. RESULTS: Overall, the Kosmic method was a standout with the highest number of scenarios lying within the acceptable error, followed by Vdl method 1 and Tukey's rule. Kosmic and Vdl method 1 appears to discriminate better the non-pathological reference population in the case of log-normal distributed data. When the proportion and spread of pathological subpopulations is high, the performance of statistical exclusion deteriorated considerably. DISCUSSIONS: It is important that laboratories use a priori defined clinical criteria to minimise the proportion of pathological subpopulation in a dataset prior to analysis. The curated dataset should then be carefully examined so that the appropriate statistical method can be applied.

The Role of PINP in Diagnosis and Management of Metabolic Bone Disease.

Serum procollagen type I N-propeptide (PINP) is designated the reference marker of bone formation in osteoporosis; the reference marker for resorption is C-terminal telopeptide of type I collagen (CTX). PINP has very low circadian and biological variation, is not affected by food intake, and is very stable in serum after venepuncture. The two automated commercial assays for PINP provide similar results in subjects with normal renal function, allowing reference intervals to be used interchangeably. Bone turnover markers (BTM) are currently not recommended for fracture risk assessment and therefore not included in fracture risk calculators. In the management of osteoporosis, the main utility of BTM including PINP is for monitoring therapy, both antiresorptive as well as anabolic agents; monitoring is thought to help improve adherence. PINP as well as CTX may also be used in assessing offset of drug action following a pause in bisphosphonate therapy, to help decide when to re-instate therapy, or following cessation of denosumab therapy to assess efficacy of follow-on bisphosphonate therapy. PINP may also be used in the diagnosis of Paget's disease of bone as well as in monitoring response to therapy and for recurrence. Although BTM other than bone alkaline phosphatase are currently not recommended for use in metabolic bone disease of chronic kidney disease, PINP measured by assays specific to the intact molecule has potential in this condition. Further studies are needed to examine this area, as well as in malignant bone disease.

Interpretative commenting in clinical chemistry with worked examples for thyroid function test reports.

Correct interpretation of pathology results is a requirement for accurate diagnosis and appropriate patient management. Clinical Pathologists and Scientists are increasingly focusing on providing quality interpretative comments on their reports and these comments are appreciated by clinicians who receive them. Interpretative comments may improve patient outcomes by helping reduce errors in application of the results in patient management. Thyroid function test (TFT) results are one of the areas in clinical chemistry where interpretative commenting is practised by clinical laboratories. We have provided a series of TFT reports together with possible interpretative comments and a brief explanation of the comments. It is felt that this would be of help in setting up an interpretative service for TFTs and also assist in training and continuing education in their provision.

Recommendations on the measurement and the clinical use of vitamin D metabolites and vitamin D binding protein - A position paper from the IFCC Committee on bone metabolism.

Vitamin D, an important hormone with a central role in calcium and phosphate homeostasis, is required for bone and muscle development as well as preservation of musculoskeletal function. The most abundant vitamin D metabolite is 25-hydroxyvitamin D [25(OH)D], which is currently considered the best marker to evaluate overall vitamin D status. 25(OH)D is therefore the most commonly measured metabolite in clinical practice. However, several other metabolites, although not broadly measured, are useful in certain clinical situations. Vitamin D and all its metabolites are circulating in blood bound to vitamin D binding protein, (VDBP). This highly polymorphic protein is not only the major transport protein which, along with albumin, binds over 99% of the circulating vitamin D metabolites, but also participates in the transport of the 25(OH)D into the cell via a megalin/cubilin complex. The accurate measurement of 25(OH)D has proved a difficult task. Although a reference method and standardization program are available for 25(OH)D, the other vitamin D metabolites still lack this. Interpretation of results, creation of clinical supplementation, and generation of therapeutic guidelines require not only accurate measurements of vitamin D metabolites, but also the accurate measurements of several other "molecules" related with bone metabolism. IFCC understood this priority and a committee has been established with the task to support and continue the standardization processes of vitamin D metabolites along with other bone-related biomarkers. In this review, we present the position of this IFCC Committee on Bone Metabolism on the latest developments concerning the measurement and standardization of vitamin D metabolites and its binding protein, as well as clinical indications for their measurement and interpretation of the results.

Analytical Performance Specifications for 25-Hydroxyvitamin D Examinations.

Currently the 25-hydroxy vitamin D (25(OH)D) concentration is thought to be the best estimate of the vitamin D status of an individual. Unfortunately, its measurement remains complex, despite recent technological advances. We evaluated the biological variation (BV) of 25(OH)D in order to set analytical performance specifications (APS) for measurement uncertainty (MU). Six European laboratories recruited 91 healthy participants. The 25(OH)D concentrations in K3-EDTA plasma were examined weekly for up to 10 weeks in duplicate on a Lumipulse G1200 (Fujirebio, Tokyo, Japan). The linear regression of the mean 25(OH)D concentrations at each blood collection showed that participants were not in a steady state. The dissection of the 10-sample collection into two subsets, namely collections 1-5 and 6-10, did not allow for correction of the lack of homogeneity: estimates of the within-subject BV ranged from 5.8% to 7.1% and the between-subject BV ranged from 25.0% to 39.2%. Methods that would differentiate a difference induced by 25(OH)D supplementation at p < 0.05 should have MU < 13.6%, while at p < 0.01, the MU should be <9.6%. The development of APS using BV assumes a steady state of patients. The findings in this study suggest that patients are not in steady state. Therefore, APS that are based on MU appear to be more appropriate.

The path to the standardization of PTH: Is this a realistic possibility? a position paper of the IFCC C-BM.

Parathyroid hormone (PTH) determination is of greatest importance for patients suffering from parathyroid gland disorders and for the follow-up of bone turnover in patients suffering from chronic kidney disease (CKD). Two generations of PTH assays are simultaneously present on the market for PTH quantification. As these assays are not yet standardized, this results in a significant level of confusion in the care of CKD patients. One key objective of the IFCC Committee for Bone Metabolism is to improve this situation. In this position paper, we will highlight the current state of PTH testing and propose a pathway to ultimately overcome issues resulting from PTH assay variability.

Analytical considerations and plans to standardize or harmonize assays for the reference bone turnover markers PINP and ß-CTX in blood.

Procollagen type I N-propeptide (PINP) and the C-terminal telopeptide of type I collagen (ß-CTX) in blood have been designated as reference bone turnover markers in osteoporosis by the International Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). The IFCC Committee on Bone Metabolism (C-BM) has examined current commercial assays and performed a multicentre study to examine the agreement between assays for PINP and ß-CTX in serum and plasma. The results of these studies will inform our work towards the harmonization of PINP assays and the standardization of ß-CTX assays in blood, with the development of common calibrators and reference measurement procedures in collaboration with the reagent manufacturing industry. Successful achievement of these goals will help develop universally acceptable practice guidelines for the management of osteoporosis with the inclusion of common reference intervals and treatment targets for PINP and ß-CTX.

Trends in Laboratory Testing Practice for Diabetes Mellitus.

BACKGROUND: India, with diabetes mellitus (DM) prevalence of nearly 7%, contributes 20% of the DM population in the world. The diagnosis and management of DM is largely dependant on laboratory parameters. We aimed to survey the laboratory testing practices for DM in this country. METHODS: A survey of 890 practising Laboratorians in India was conducted through Survey Monkey. RESULTS: A total of 310 (35%) complete responses were received. The majority of respondents worked in academic institutions, public hospital laboratories and private hospital laboratories. HbA1c was approved for diagnosis in 75% of laboratories. The HbA1c method was NGSP (National Glycohaemoglobin Standardisation Programme) certified in 70% of laboratories only. Oral glucose tolerance testing (OGTT) was recommended for diagnosis of gestational diabetes (GDM) in 56% of respondents. Fifty-nine percent respondents recommended an early morning urine sample for microalbuminuria testing whilst 39% and 2% opted for 24 hour urine and timed overnight sample respectively. Sixty-six percent participated in proficiency testing (PT) for both glucose and HbA1c. Twelve percent and 4% respondents respectively participated in PT for glucose only and HbA1c only, and 9% participated in PT for neither. CONCLUSIONS: Based on the above survey we recommend that Scientific bodies and Professional Associations in India should educate Laboratorians to adopt NGSP certified methods for HbA1c testing and morning spot sample for microalbuminuria testing. DIPSI (Diabetes in Pregnancy Study Group in India) guidelines for diagnosis of Gestational diabetes since it is a simple, single step procedure, non-fasting, cost effective, feasible method should be implemented.

Short- and long-term biological variation of cardiac troponin I in healthy individuals, and patients with end-stage renal failure requiring haemodialysis or cardiomyopathy.

Objectives High-sensitivity (hs) cardiac troponin (cTn) assays can quantitate small fluctuations in cTn concentration. Determining biological variation allows calculation of reference change values (RCV), to define significant changes. We assessed the short- and long-term biological variation of cardiac troponin I (cTnI) in healthy individuals and patients with renal failure requiring haemodialysis or cardiomyopathy. Methods Plasma samples were collected hourly for 4 h and weekly for seven further weeks from 20 healthy individuals, 9 renal failure patients and 20 cardiomyopathy patients. Pre- and post-haemodialysis samples were collected weekly for 7 weeks. Samples were analysed using a hs-cTnI assay (Abbott Alinity ci-series). Within-subject biological variation (CVI), analytical variation (CVA) and between-subject biological variation (CVG) was used to calculate RCVs and index of individuality (II). Results For healthy individuals, CVI, CVA, CVG, RCV and II values were 8.8, 14.0, 43.1, 45.8% and 0.38 respectively for short-term, and 41.4, 14.0, 25.8, 121.0% and 1.69 for long-term. For renal failure patients, these were 2.6, 5.8, 50.5, 17.6% and 0.30 respectively for short-term, and 19.1, 5.8, 11.2, 55.2% and 1.78 for long-term. For cardiomyopathy patients, these were 4.2, 10.0, 65.9, 30.0% and 0.16 respectively for short-term, and 17.5, 10.0, 63.1, 55.8% and 0.32 for long-term. Mean cTnI concentration was lower post-haemodialysis (15.2 vs. 17.8 ng/L, p < 0.0001), with a 16.9% mean relative change. Conclusions The biological variation of cTnI is similar between end-stage renal failure and cardiomyopathy patients, but proportionately greater in well-selected healthy individuals with very low baseline cTnI concentrations.

A multicenter study to evaluate harmonization of assays for N-terminal propeptide of type I procollagen (PINP): a report from the IFCC-IOF Joint Committee for Bone Metabolism.

Background Biochemical bone turnover markers (BTM) are useful tools to assess bone remodeling at the cellular level. N-terminal propeptide of type I procollagen (PINP) has been recommended as a reference marker for bone formation in research studies. Methods We describe the results of a multicenter study for routine clinical laboratory assays for PINP in serum and plasma. Four centers (Athens, Greece [GR], Copenhagen, Denmark [DK], Liege, Belgium [BE] and Sheffield, United Kingdom [UK]) collected serum and plasma (EDTA) samples from 796 patients presenting to osteoporosis clinics. Specimens were analyzed in duplicate with each of the available routine clinical laboratory methods according to the manufacturers' instructions. Passing-Bablok regressions, Bland-Altman plots, V-shape evaluation method and the concordance correlation coefficient for PINP values between serum and plasma specimens and between methods were used to determine the agreement between results. A generalized linear model was employed to identify possible variables that affected the relationship between the methods. Results We showed that both EDTA plasma and serum were suitable for PINP determination. We observed a significant proportional bias between Orion radioimmunoassay and the automated methods for PINP (Roche Cobas and IDS iSYS), which both gave very similar results. The multivariate model did not improve the excellent correlation that was observed between the methods. Conclusions Harmonization of PINP assays is possible by applying a correction factor or correctly assigning the values of the calibrators. This work will benefit from further collaboration between assays manufacturers and clinical laboratory professionals.

High-Sensitivity Cardiac Troponin I Improves Cardiovascular Risk Prediction in Older Men: HIMS (The Health in Men Study).

Background The Framingham Risk Score estimates the 10-year risk of cardiovascular events. However, it performs poorly in older adults. We evaluated the incremental benefit of adding high-sensitivity cardiac troponin I (hs-cTnI) to the Framingham Risk Score. Methods and Results The HIMS (Health in Men Study) is a cohort study of community-dwelling men aged 70 to 89 years in Western Australia. Participants were identified from the electoral roll, with a subset undergoing plasma analysis. Hs- cTnI (Abbott Architect i2000 SR ) was measured in 1151 men without prior cardiovascular disease. The Western Australia Data Linkage System was used to identify incident cardiovascular events. After 10 years of follow-up, 252 men (22%) had a cardiovascular event ( CVE +) and 899 did not (CVE-). The Framingham Risk Score placed 148 (59%) CVE + and 415 (46%) CVE- in the high-risk category. In CVE - men, adding hs- cTnI affected the risk categories of 244 (27.2%) men, with 64.8% appropriately reclassified to a lower and 35.2% to a higher category, which decreased the number of high-risk men in the CVE- to 39%. In CVE + men, adding hs- cTnI affected the risk categories of 61 (24.2%), with 50.8% appropriately reclassified to a higher and 49.2% to a lower category and 82.5% remaining above the 15% risk treatment threshold. The net reclassification index was 0.305 ( P<0.001). Adding hs- cTnI increased the C-statistic modestly from 0.588 (95% CI , 0.552-0.624) to 0.624 (95% CI , 0.589-0.659) and improved model fit (likelihood ratio test, P<0.001). Conclusions Adding hs- cTnI to the Framingham Risk Score provided incremental prognostic benefit in older men, especially aiding reclassification of individuals into a lower risk category.

The challenge of improving the diagnostic yield from metanephrine testing in suspected phaeochromocytoma and paraganglioma.

Background Plasma-free metanephrines (PFM) or urinary fractionated metanephrines (UFM) are the preferred biochemical tests for the diagnosis of phaeochromocytoma and paraganglioma (PPGL). Borderline increased results should be followed up to either exclude or confirm diagnosis. Methods We extracted all PFM and UFM results reported by our laboratory over a six-month period from the laboratory information system. We categorized patients with borderline increased results according to whether follow-up testing had been performed as suggested in the initial laboratory report. Questionnaires were then sent to all requesting doctors and medical notes reviewed where available. Results Two hundred and four patients with borderline increased PFM or UFM were identified. Sixty-five (38.5%) of 169 patients with borderline increased PFM had a repeat test out of which 36 were normal and 29 did not normalize. Of 35 patients with borderline increased UFM, 17 (48.6%) had subsequent PFM measurement, out of which 15 were normal. Questionnaires were returned to 106 (52%) patients. Of these, the most frequent indication for testing was hypertension ( n = 50); 15 patients had an incidental adrenal mass and two of these patients were diagnosed with a phaeochromocytoma. Conclusion Only 38% of patients with borderline increased PFM had a repeat PFM measurement. This was not significantly higher when compared with the 28% in a previous audit that we reported in 2010 ( P = 0.10). Forty-nine per cent of patients with a borderline increased UFM had a repeat UFM or PFM measurement. There remains a substantial possibility of missed detection of PPGL.