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Clin Biochem Rev [journal]
- Protein Biomarker Research in UK Hospital Clinical Biochemistry Laboratories: A Survey of Current Practice and Views. [Journal Article]
- Clin Biochem Rev 2014 May; 35(2):115-33.
With the increasing drive for more and better disease biomarkers to underpin the stratified or personalised medicine agenda, clinical biochemistry laboratories should be ideally placed to play a major role in their translation into clinical practice. However, little is known about the current extent of biomarker-related research activity in UK National Health Service clinical biochemistry departments.In December 2010, an online questionnaire was sent to active UK members of the Association for Clinical Biochemistry (ACB) to determine the extent of their current research activity and involvement in protein biomarker discovery and translation, including an assessment of the awareness of proteomics.A total of 198 eligible responses (19% response rate) was received from across the UK. Of a further 50 eligible people who responded to a follow-up for initial non-responders, most cited insufficient knowledge about the topic as the reason for non-response (24% total response rate). The results illustrate the highly skilled nature of the workforce with many having experience in a research environment (75%) with postgraduate qualifications. However, more than half spend <10% of their time undertaking research in their current role, and many (61%) would like to be more research active. Encouragingly, approximately a third were involved in biomarker discovery activities, even though for <10% of their time, with slightly more reporting involvement in biomarker translation.Although there are people with the necessary skills and desire to be involved in biomarker research in clinical biochemistry departments, their involvement is small, predominantly due to issues with capacity and resources. It is likely that the majority of biomarker programmes will therefore continue to be carried out by a small number of academic groups, hopefully with collaborative input from hospital laboratories.
- Laboratory medicine best practice guideline: vitamins a, e and the carotenoids in blood. [Journal Article]
- Clin Biochem Rev 2014 May; 35(2):81-113.
Despite apparent method similarities between laboratories there appear to be confounding factors inhibiting uniform reporting and standardisation of vitamin assays. The Australasian Association of Clinical Biochemists (AACB) Vitamins Working Party, in conjunction with The Royal College of Pathologists of Australasia Quality Assurance Programs, has formulated a guideline to improve performance, reproducibility and accuracy of fat-soluble vitamin results. The aim of the guideline is to identify critical pre-analytical, analytical and post-analytical components of the analysis of vitamins A, E and carotenoids in blood to promote best practice and harmonisation. This best practice guideline has been developed with reference to the Centers for Disease Control and Prevention (CDC) "Laboratory Medicine Best Practices: Developing an Evidence-Based Review and Evaluation Process". The CDC document cites an evaluation framework for generating best practice recommendations that are specific to laboratory medicine. These 50 recommendations proposed herein, were generated from a comprehensive literature search and the extensive combined experience of the AACB Vitamins Working Party members. They were formulated based on comparison between an impact assessment rating and strength of evidence and were classified as either: (1) strongly recommend, (2) recommend, (3) no recommendation for or against, or (4) recommend against. These best practice recommendations represent the consensus views, in association with peer reviewed evidence of the AACB Vitamins Working Party, towards best practice for the collection, analysis and interpretation of vitamins A, E and carotenoids in blood.
- Challenges to the measurement of oestradiol: comments on an endocrine society position statement. [Journal Article, Review]
- Clin Biochem Rev 2014 May; 35(2):75-9.
- Estimated Glomerular Filtration Rate versus Albuminuria in the Assessment of Kidney Function: What's More Important? [Journal Article, Review]
- Clin Biochem Rev 2014 May; 35(2):67-73.
Clinical practice guidelines state that any evaluation of kidney disease requires the assessment of (1) kidney function in the form of the estimated glomerular filtration rate (eGFR) and (2) kidney damage by a quantitative assessment of proteinuria, preferably by the determination of the urine albumin-to-creatinine ratio. This review discusses the relative merits of each measurement, focusing on the strengths of each measurement in relationship to all-cause and cardiovascular mortality risk prediction as well as the prediction of kidney disease progression with loss of kidney function over time and the progression to end-stage kidney disease treated by dialysis or kidney transplantation.
- Uncertainty in Measurement: A Review of Monte Carlo Simulation Using Microsoft Excel for the Calculation of Uncertainties Through Functional Relationships, Including Uncertainties in Empirically Derived Constants. [REVIEW]
- Clin Biochem Rev 2014 Feb; 35(1):37-61.
The Guide to the Expression of Uncertainty in Measurement (usually referred to as the GUM) provides the basic framework for evaluating uncertainty in measurement. The GUM however does not always provide clearly identifiable procedures suitable for medical laboratory applications, particularly when internal quality control (IQC) is used to derive most of the uncertainty estimates. The GUM modelling approach requires advanced mathematical skills for many of its procedures, but Monte Carlo simulation (MCS) can be used as an alternative for many medical laboratory applications. In particular, calculations for determining how uncertainties in the input quantities to a functional relationship propagate through to the output can be accomplished using a readily available spreadsheet such as Microsoft Excel. The MCS procedure uses algorithmically generated pseudo-random numbers which are then forced to follow a prescribed probability distribution. When IQC data provide the uncertainty estimates the normal (Gaussian) distribution is generally considered appropriate, but MCS is by no means restricted to this particular case. With input variations simulated by random numbers, the functional relationship then provides the corresponding variations in the output in a manner which also provides its probability distribution. The MCS procedure thus provides output uncertainty estimates without the need for the differential equations associated with GUM modelling. The aim of this article is to demonstrate the ease with which Microsoft Excel (or a similar spreadsheet) can be used to provide an uncertainty estimate for measurands derived through a functional relationship. In addition, we also consider the relatively common situation where an empirically derived formula includes one or more 'constants', each of which has an empirically derived numerical value. Such empirically derived 'constants' must also have associated uncertainties which propagate through the functional relationship and contribute to the combined standard uncertainty of the measurand.
- Genetic Insights into Cardiometabolic Risk Factors. [REVIEW]
- Clin Biochem Rev 2014 Feb; 35(1):15-36.
Many biochemical traits are recognised as risk factors, which contribute to or predict the development of disease. Only a few are in widespread use, usually to assist with treatment decisions and motivate behavioural change. The greatest effort has gone into evaluation of risk factors for cardiovascular disease and/or diabetes, with substantial overlap as 'cardiometabolic' risk. Over the past few years many genome-wide association studies (GWAS) have sought to account for variation in risk factors, with the expectation that identifying relevant polymorphisms would improve our understanding or prediction of disease; others have taken the direct approach of genomic case-control studies for the corresponding diseases. Large GWAS have been published for coronary heart disease and Type 2 diabetes, and also for associated biomarkers or risk factors including body mass index, lipids, C-reactive protein, urate, liver function tests, glucose and insulin. Results are not encouraging for personal risk prediction based on genotyping, mainly because known risk loci only account for a small proportion of risk. Overlap of allelic associations between disease and marker, as found for low density lipoprotein cholesterol and heart disease, supports a causal association, but in other cases genetic studies have cast doubt on accepted risk factors. Some loci show unexpected effects on multiple markers or diseases. An intriguing feature of risk factors is the blurring of categories shown by the correlation between them and the genetic overlap between diseases previously thought of as distinct. GWAS can provide insight into relationships between risk factors, biomarkers and diseases, with potential for new approaches to disease classification.
- Physiology and its Importance for Reference Intervals. [REVIEW]
- Clin Biochem Rev 2014 Feb; 35(1):3-14.
Reference intervals are ideally defined on apparently healthy individuals and should be distinguished from clinical decision limits that are derived from known diseased patients. Knowledge of physiological changes is a prerequisite for understanding and developing reference intervals. Reference intervals may differ for various subpopulations because of differences in their physiology, most obviously between men and women, but also in childhood, pregnancy and the elderly. Changes in laboratory measurements may be due to various physiological factors starting at birth including weaning, the active toddler, immunological learning, puberty, pregnancy, menopause and ageing. The need to partition reference intervals is required when there are significant physiological changes that need to be recognised. It is important that laboratorians are aware of these changes otherwise reference intervals that attempt to cover a widened inter-individual variability may lose their usefulness. It is virtually impossible for any laboratory to directly develop reference intervals for each of the physiological changes that are currently known, however indirect techniques can be used to develop or validate reference intervals in some difficult situations such as those for children. Physiology describes our life's journey, and it is only when we are familiar with that journey that we can appreciate a pathological departure.
- Erratum. [PUBLISHED ERRATUM]
- Clin Biochem Rev 2013 Nov; 34(3):145.
[This corrects the article on p. 96 in vol. 34.].
- In Search of Mechanisms Associated with Mesenchymal Stem Cell-Based Therapies for Acute Kidney Injury. [REVIEW]
- Clin Biochem Rev 2013 Nov; 34(3):131-144.
Acute kidney injury (AKI) is classically described as a rapid loss of kidney function. AKI affects more than 15% of all hospital admissions and is associated with elevated mortality rates. Although many advances have occurred, intermittent or continuous renal replacement therapies are still considered the best options for reversing mild and severe AKI syndrome. For this reason, it is essential that innovative and effective therapies, without side effects and complications, be developed to treat AKI and the end-stages of renal disease. Mesenchymal stem cell (MSC) based therapies have numerous advantages in helping to repair inflamed and damaged tissues and are being considered as a new alternative for treating kidney injuries. Numerous experimental models have shown that MSCs can act via differentiation-independent mechanisms to help renal recovery. Essentially, MSCs can secrete a pool of cytokines, growth factors and chemokines, express enzymes, interact via cell-to-cell contacts and release bioagents such as microvesicles to orchestrate renal protection. In this review, we propose seven distinct properties of MSCs which explain how renoprotection may be conferred: 1) anti-inflammatory; 2) pro-angiogenic; 3) stimulation of endogenous progenitor cells; 4) anti-apoptotic; 5) anti-fibrotic; 6) anti-oxidant; and 7) promotion of cellular reprogramming. In this context, these mechanisms, either individually or synergically, could induce renal protection and functional recovery. This review summarises the most important effects and benefits associated with MSC-based therapies in experimental renal disease models and attempts to clarify the mechanisms behind the MSC-related renoprotection. MSCs may prove to be an effective, innovative and affordable treatment for moderate and severe AKI. However, more studies need to be performed to provide a more comprehensive global understanding of MSC-related therapies and to ensure their safety for future clinical applications.
- The De Ritis Ratio: The Test of Time. [REVIEW]
- Clin Biochem Rev 2013 Nov; 34(3):117-130.
De Ritis described the ratio between the serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) almost 50 years ago. While initially described as a characteristic of acute viral hepatitis where ALT was usually higher than AST, other authors have subsequently found it useful in alcoholic hepatitis, where AST is usually higher than ALT. These interpretations are far too simplistic however as acute viral hepatitis can have AST greater than ALT, and this can be a sign of fulminant disease, while alcoholic hepatitis can have ALT greater than AST when several days have elapsed since alcohol exposure. The ratio therefore represents the time course and aggressiveness of disease that would be predicted from the relatively short half-life of AST (18 h) compared to ALT (36 h). In chronic viral illnesses such as chronic viral hepatitis and chronic alcoholism as well as non-alcoholic fatty liver disease, an elevated AST/ALT ratio is predictive of long terms complications including fibrosis and cirrhosis. There are methodological issues, particularly whether or not pyridoxal phosphate is used in the transaminase assays, and although this can have specific effects when patient samples are deficient in this vitamin, these method differences generally have mild effects on the usefulness of the assays or the ratio. Ideally laboratories should be using pyridoxal phosphate supplemented assays in alcoholic, elderly and cancer patients who may be pyridoxine deplete. Ideally all laboratories reporting abnormal ALT should also report AST and calculate the De Ritis ratio because it provides useful diagnostic and prognostic information.