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Since it is the third most common cancer developed and the fourth cause of cancer related death worldwide, CRC still presents a major health problem (1). However, if colorectal neoplasia is detected at an early stage, outcomes for individuals are much improved (2). Asymptomatic population-based screening programmes for colorectal neoplasia have been widely introduced since the criteria for successful screening are more than met.

The results of investigations in laboratory medicine are used for many purposes. Most are performed for monitoring individuals in acute situations and following the improvement or deterioration of chronic disease. In diagnosis, case-finding, and screening, conventional population-based reference intervals are relevant, and they are partitioned if necessary according to age, sex, or other important characteristics. In spite of the advantages of fixed decision limits, these intervals remain the mainstay of interpreting numerical results. Such tools are of very limited use, however, in evaluating serial results obtained for an individual. Within-individual biological variation is well known to be much smaller than between-individual variation for nearly all substances assayed in laboratory medicine (1). Each individual has a range of values that span only a part of the reference interval. In consequence, individuals can have important changes in results when they all lie within the reference interval. Such changes will usually be considered unremarkable by both laboratory professionals and clinicians, and thus ignored. In addition, results can change from inside to outside the interval (and vice versa) without having clinical importance. Laboratories conventionally flag results outside the reference limits, probably provoking some unnecessary follow-up activity, if only a repetition of the investigation (2). Katzmann and coworkers in the current issue of the Journal have tackled the difficult problem of establishing criteria for monitoring changes in monoclonal protein concentrations (3). For some laboratory investigations, expert groups have recommended numerical criteria for interpreting changes. For the abnormal proteins in serum and urine investigated by Katzmann and colleagues (3), the guidelines from such expert groups state that reductions in the monoclonal protein in serum of at least 25% and 50% are considered minimal and partial responses, respectively, and the corresponding responses for urine monoclonal protein require at least 50% and 90% decreases (4, 5 …

Few patients being assessed and treated in acute situations in hospitals have only one set of laboratory investigations undertaken. While the more esoteric and specialist investigations may be done less frequently, readily available tests in laboratory medicine such as urea and electrolytes, liver function tests, bone studies and full blood count are often requested on a daily basis, if not more often. Although this practice is often considered inappropriate and wasteful, it does give serial results on individuals: these should be used to add value in both laboratory and clinical management. Although fixed numerical decision limits based on risk, for example, have many advantages and are becoming more widely applied throughout medicine, laboratories fulfil accreditation and other requirements by reporting population-based reference intervals, sometimes partitioned according to age, gender or other important factors, with almost every test result. These remain the basis of interpretation of numerical results when no previous data are available on an individual, as in some diagnosis and screening settings. However, it is now well recognized that withinsubject biological variation (CVI) is much smaller than between-subject biological variation (CVG) for nearly all quantities assayed in laboratory medicine. As a result, traditional reference intervals have limited value in diagnosis and screening because many patients will have results that are highly unusual for them but that still lie within the reference intervals, irrespective of whether these are generated by the individual laboratory, transferred, validated or harmonized. Conventional reference intervals are of even more limited use in the assessment of serial results generated on an individual. Each individual has values that span only a part of the conventional reference interval. In consequence, individuals can have significant changes in results when these all lie within the reference interval. In addition, results can change from inside the interval to outside (and vice versa) without significance. Making better use of differences in serial laboratory results is required. In this issue, Garner et al. report an investigation on the detection of acute kidney injury (AKI) in hospital patients by comparing three of the proposed AKI definitions and a very simple delta check using serial serum creatinine results. Unsurprisingly, it was found that use of the different definitions proposed for AKI detected different populations of patients, although all definitions make use of rises in serum creatinine concentration in an individual. However, it was demonstrated that the laboratory delta check detected 98% of all the patients identified by Acute Kidney Injury Network (AKIN), Risk, Injury, Failure (RIFLE) and Waikar & Bonventre strategies combined and therefore suggested that the delta check could provide a practical way of detecting AKI patients. This work could be emulated for other quantities for which use of differences in serial results is of clinical importance. Delta check functionality is embedded in most laboratory information management systems (LIMS). Although there are a number of ways to select the delta check values, setting is usually done somewhat empirically with the aim of detecting major blunders, such as the submission for analysis of samples from different patients but which have been labelled with a single identifier, but not flagging too many cases for further time-consuming, but often inconsequential, investigation by professionals in laboratory medicine. Garner et al. selected the delta check value of an increase of 26 mmol/L in serum creatinine for the detection of AKI using the criteria set in the AKIN and Waikar & Bonventre strategies for diagnosis of Stage 1 AKI, and this simple approach did appear to be potentially clinically useful. Others have proposed similarly simple numerical criteria for interpretation of differences in serial results: recent examples include that reductions of at least 25% and 50% are considered minimal and partial responses to treatment for monoclonal proteins in serum and a change of 20% is significant for serum troponin. The question arises as to whether such criteria should be used as delta check values in the laboratory and then differences greater than the delta check values notified to users in some way so as to point out that these are of potential clinical interest. The question of communication of information on the patients identified by the delta check was not addressed by Garner et al. In addition, a perhaps more interesting question is whether there are better, more scientific, ways to set criteria for interpretation of differences in serial results and whether these criteria can then be applied as delta check values and for other purposes in laboratory medicine. Garner et al. discuss the use of reference change values (RCV) and consider that RCV could potentially provide a more efficient means of detecting AKI patients. Differences in serial results from an individual may be due to the

To the Editor: There is an increasing interest among professionals in laboratory medicine to achieve global harmonization, and that needs to go beyond the analytical phase and must include all steps within the total testing process, as well as terminology and units (1). The generation and application of data on biological variation (BV) have been studied for many years (2, 3). Unfortunately, the range of terms and variety of symbols used to define the components of BV has become ever larger with the increasing body of literature. This issue has been given little attention to date. We aimed to ( a ) assess the degree of heterogeneity in terms and symbols used to define the components of BV in the 13 highest ranked clinical chemistry journals in the Web of Science category Medical Laboratory Technology within the 2012 Thomson Reuters Journal Citation Reports and ( b ) propose terms and symbols to be used in the future. Journals included were Clinical Chemistry, …

The setting of analytical quality specifications in laboratory medicine has been a topic of discussion and debate for over 50 years: 15 years ago, as the subject matured and a profusion of recommendations appeared, many of them from expert groups, it was realised by a number of leading professionals that there was a need for a global consensus on the setting of such specifications. The Stockholm Conference held in 1999 on “Strategies to set global analytical quality specifications in laboratory medicine” achieved this and advocated the ubiquitous application of a hierarchical structure of approaches. The hierarchy has five levels, namely: 1) evaluation of the effect of analytical performance on clinical outcomes in specific clinical settings; 2) evaluation of the effect of analytical performance on clinical decisions in general using a) data based on components of biological variation, or b) analysis of clinicians’ opinions; 3) published professional recommendations from a) national and international expert bodies, or b) expert local groups or individuals; 4) performance goals set by a) regulatory bodies, or b) organisers of external quality assessment (EQA) schemes; and 5) goals based on the current state of the art as a) demonstrated by data from EQA or proficiency testing scheme, or b) found in current publications on methodology. This approach has been much used since its wide promulgation, but there have been ongoing criticisms and new developments. The time seems right for an objective reappraisal of recommended strategies to set analytical performance goals.

ObjectiveTo investigate the relationship between deprivation and faecal haemoglobin concentration (f-Hb).SettingScottish Bowel Screening Programme.MethodsA total of 66725 men and women, aged 50 to 74, were invited to provide a single sample for a faecal immunochemical test. Deprivation was estimated using the Scottish Index of Multiple Deprivation quintiles: f-Hb was measured (OC-Sensor, Eiken, Japan) on 38439 participants. The relationship between deprivation quintiles and f-Hb was examined.ResultsMedian age was 60 years, 53.6% women, with 14.1%, 19.7%, 17.7%, 25.9% and 22.6% in the lowest to the highest deprivation quintiles respectively. No detectable f-Hb was found in 51.9%, ranging from 45.5% in the most deprived up to 56.5% in the least deprived. As deprivation increased, f-Hb increased (p ConclusionsDeprivation and f-Hb are related. This has important implications for selection of cut-off f-Hb for screening programmes, and supports the inclusion of deprivation in risk-scoring systems.

Lack of reference materials and standard procedures, on faecal tests leads to major problems in harmonisation of methods and do not allow the comparison of outcome data. In particular the absence of standardisation of pre-analytical characteristic was noted for faecal test methods for haemoglobin since different manufacturers have developed different sampling procedures and report units. Moreover the physical characteristics of the faecal specimen and the designs of specimen collection devices do not allow analysis of samples on different systems in consequence, faecal tests cannot be compared using standard evaluation protocols. To improve the harmonization of results generated using different analytical systems and the overall performances of test on faecal materials we propose the introduction of standard procedures for sampling and pre-analytical phase and the adoption of specific procedures based on the use of artificial biological samples for comparison of methods. Harmonization of sampling devices with the use of a standard design for pickers and a standard ratio between analyte and buffer for different manufacturers represent a mandatory step in the roadmap for harmonization of clinical laboratory measurement on faecal materials and can allow a significant standardisation of results generated by different devices. The creation of specific protocols for the evaluation and comparison of analytical methods for analyse of faeces could lead to a significant improvement in the performance of methods and systems.

Colorectal cancer (CRC) screening continues to be a subject of considerable research interest. In 2013, the European Journal of Cancer Prevention published one review, nine research papers and one short paper on this topic. A number of these papers discussed aspects of faecal testing for CRC screeni

BACKGROUND Faecal immunochemical tests (FIT) are becoming widely used in colorectal cancer (CRC) screening. Availability of data on faecal haemoglobin concentrations (f-Hb) in three countries prompted an observational study on sex and age and the transferability of data across geography. METHODS Single estimates of f-Hb in large groups were made in Scotland, Taiwan and Italy using quantitative automated immunoturbidimetry on the Eiken OC-Sensor. Distributions were examined for men and women overall and in four different age groups. RESULTS The distributions of f-Hb were not Gaussian and had kurtosis and positive skewness. The distributions were different in the three countries: f-Hb varies with sex and age in all countries, being higher in men and the elderly, but the degree of variation is inconsistent across countries, f-Hb being higher in Scotland than in Taiwan than in Italy, possibly due to different lifestyles. At any cut-off concentration, more men are declared positive than women and more older people are declared positive than younger individuals. CONCLUSIONS Our analysis supports the view that setting and using a single f-Hb cut-off in any CRC screening programme is far from ideal. We suggest that individualisation is the optimum approach with f-Hb, alone or with other important factors such as sex and age, used to determine important personal issues such as need for colonoscopy, screening interval between tests and risk of future CRC. Whether there is merit in monitoring f-Hb in individuals over time remains an interesting research question for the future.

The prognostic abilities of the MDRD and Cockcroft–Gault methods for estimating renal function were compared in a cohort study of 1287 patients with acute stroke admitted to a Scottish tertiary care teaching hospital. Using Cox regression analysis corrected for other prognostic variables, both the MDRD and Cockcroft–Gault equations predicted mortality independently of other prognostic factors. A 1 ml/min reduction in GFR as calculated by MDRD was associated with a 1.0% (95% CI: 0.3–1.6) increase in risk of death. A 1 ml/min reduction in creatinine clearance from the Cockcroft–Gault equation was associated with a 1.7% (95% CI: 0.9–2.6) increase in risk of death. The Cockcroft–Gault equation weakly predicted length of stay ( r =0.066, p =0.02, Spearman's rank test). In conclusion, both methods independently predict early and late mortality in stroke patients, but the Cockcroft–Gault estimate has greater predictive power in this population.

A model for characterization of measurements on the ordinal scale is presented. It is based on transformation of the calculated fractions (fractiles) of positives from measurements on samples with known concentrations to a probit-natural log (probit-ln) scale. Such measurements could be made by other methods on ratio or difference scales but, for convenience (for example for speed or low cost), are measured on the ordinal scale by “simple” methods. The model is examined, and verified, using three examples from published data (haemoglobin, glucose, and leukocytes) and an external quality assessment survey on measurements of streptococcus. We show that it is possible to obtain reliable analytical quality specifications and to establish design of control systems for measurements on the ordinal scale. It is concluded that the presented probit-ln model for the ordinal scale is a tool which can improve and facilitate (i) characterizing methods with measurements on the ordinal scale, (ii) defining analytical quality specifications, (iii) designing external assessment as well as internal control schemes, (iv) validation of methods with measurements on the ordinal scale according to the analytical quality specifications, and further, (v) reduction of the number of samples required for method validation and the number of replicate measurements needed.

OBJECTIVES This study was designed to compare different proposed methods of assessing adherence with angiotensin-converting enzyme (ACE) inhibitor (ACEI) therapy in chronic heart failure. BACKGROUND The use of ACEIs in chronic heart failure gives us a unique opportunity to assess a patient’s adherence by measuring whether the expected biochemical effect of an ACEI is present in the patient’s bloodstream. In fact, there are several different ways of assessing ACE in vivo: these are serum ACE activity itself, plasma N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), urine AcSDKP, plasma angiotensin I (AI), plasma angiotensin II (AII), or the AII/AI ratio. METHODS Patients with chronic heart failure (n = 39) were randomized to regimens of ACEI nonadherence for one week, ACEI adherence for one week or two versions of partial adherence for one week, after which the above six tests were performed. RESULTS All six tests significantly distinguished between full nonadherence for one week and full or partial adherence. Only plasma AcSDKP produced a significantly different result between partial adherence and either full adherence or full nonadherence for one week. In terms of their ability to distinguish full nonadherence from full adherence, plasma AcSDKP was 89% sensitive and 100% specific with an area under its ROC of 0.95. Corresponding figures for urine AcSDKP were 92%, 97% and 0.95 and for serum ACE they were 86%, 95% and 0.90. CONCLUSIONS All six tests distinguished full nonadherence from all other forms of adherence. The rank order of performance was plasma AcSDKP, urine AcSDKP, serum ACE, AII/AI ratio and plasma AII followed by plasma AI.

OBJECTIVE—To assess whether serum angiotensin converting enzyme (ACE) activity during routine clinical practice accurately reflects patient adherence to ACE inhibitor treatment for chronic heart failure (CHF). DESIGN—Retrospective assessment of ACE inhibitor adherence and serum ACE activity measurements. SETTING—Teaching hospital outpatient department PATIENTS AND INTERVENTIONS—During 1994-95, serum ACE was measured in 73 CHF patients who were routinely attending the heart failure clinic at Ninewells Hospital. At the same time, the medicines monitoring unit collected data on whether and when prescriptions for ACE inhibitors were redeemed at community pharmacies, which enabled each patient's adherence over a prolonged period to be assessed. MAIN OUTCOME MEASURES—Routine collected serum ACE measurements were correlated with measured adherence with ACE inhibitor treatment. RESULTS—In total, 18% of CHF patients appeared to exhibit 12 u/l gave 91% positive predictive accuracy that the patient was 85% adherent with ACE inhibitor treatment. CONCLUSIONS—Non-adherence with ACE inhibitor treatment was found to be common in patients with CHF. The simple, inexpensive test of serum ACE activity can be used in CHF patients to identify many, although not all, non-adherent patients so that adherence enhancing strategies can be targeted towards them. Further work is clearly required to explore the precise clinical use of this promising test. Keywords: angiotensin converting enzyme inhibitors; heart failure; compliance

Every analytical method used in laboratory medicine can be fully described in terms of its performance characteristics. Ideally, quality specifications should be available for all of these, particularly precision and bias. Specifications for these can be set using a variety of strategies. Consideration of the clinical settings of monitoring individual patients and diagnosis using reference intervals shows that generally applicable quality specifications can be based on the components of biological variation, namely, within-subject [CVI] and between-subject [CVG] variation. Current consensus is that precision should be

The concept of the “index of individuality” was introduced by Eugene Harris in 1974. The index of individuality, calculated as (CVA 2 + CVI 2)1/2/CVG, where CvA, CvI, and CvG are analytical, within-subject, and between-subject coefficients of variation respectively, has been used by many to investigate the utility of conventional population-based reference values. For a high index of individuality, >1.4, it has been said that reference intervals will be more useful than for a low index, < 0.6. The validity of these concepts is investigated here and a number of our findings are at odds with the generally held opinion. The index of individuality has no impact on the fraction of individuals classified using population-based reference values, as long as the change in concentration from the usual state is of the same absolute magnitude and one sample is assayed to detect disease. However, when a measurement falling outside a reference limit is repeated in order to verify the finding, the index of individuality has considerable influence. For quantities with very low indices, the repeat test result, will be close to the first and give no new information, whereas for quantities with high indices, a repeat test will decrease the number of true positives and false positives.

Faecal occult blood tests, better described as tests for the presence of haemoglobin in faeces, are widely used in asymptomatic population-based screening programmes for colorectal cancer (CRC) as the best available non-invasive initial investigation. However, previously published authoritative guidelines did state that there was no role for these tests in assessment of patients presenting with lower abdominal symptoms in primary care. In consequence, the traditional widely used guaiac-based faecal occult blood test (gFOBT) was eliminated from the repertoires of many laboratories and its use in clinical settings other than screening very much discouraged. New significant controversy has been raised by the recently issued referral guidance for suspected CRC from the National Institute for Health and Care Excellence (NICE) which states that, in possible CRC, patients who do not meet criteria for suspected cancer referral should be offered testing for occult blood in faeces. These recommendations have been subject to significant criticism, in part because the evidence-base was largely founded on the use of gFOBT: these have many well-documented disadvantages throughout the pre-analytical, analytical and post-analytical phases of generation of a result. NICE did note that the recommendation to test for occult blood in faeces would necessitate a change in practice, because such tests are not currently available. It was also recognized by NICE that some evidence suggested that quantitative faecal immunochemical tests (FITs) for haemoglobin might have applicability in triaging symptomatic patients presenting to primary care. There is now significant evidence that FITs do have applicability in assessment of symptomatic patients presenting to primary care, including those who warrant urgent referral, as shown in recent peerreviewed publications, particularly from Scotland and Spain. Although much of the evidence was generated during and after the work on the NICE guidelines was done, it is vital that laboratories are not pressurized into again offering gFOBT to satisfy general practitioner requests made ‘to comply with the NICE guidelines’. Rather, the accumulated evidence is that FIT should be used, ideally using quantitative immunoturbidimetry to measure faecal haemoglobin concentration (f-Hb) with good performance characteristics. It has been shown that use of f-Hb measurements performs better than previous high-risk symptom-based strategies for fast-tracking suspected CRC referrals. Every one of the studies on use of f-Hb at low cut-off concentration in assessment of those presenting with lower abdominal symptoms has shown very high clinical sensitivity (often 100%) for CRC, so that a ‘positive’ test result should stimulate rapid referral for colonoscopy. Moreover and, most importantly, f-Hb in this context has very high negative predictive value (often well over 90%) for the detection of significant colorectal diseases well worthy of detection, namely, CRC, higher-risk adenoma, sometimes precursors of CRC, and inflammatory bowel disease (IBD). In consequence, a ‘negative’ test result provides considerable reassurance that colonoscopy is not required urgently or even at all. There is no doubt that f-Hb

The analytical, within-subject and between-subject components of variation were estimated for serum total creatine kinase (TCK) activity, CK-MB (creatine kinase-MB) activity, CK-MB mass, ratios of CK-MB activity and CK-MB mass to TCK activity and myoglobin concentration in a cohort of 16 apparently healthy subjects over 5 days. Analytical goals based on biological variation showed that, for all quantities except CK-MB mass, methodological improvement is warranted. All cardiac markers showed marked individuality which casts doubt on the utility of conventional population-based reference values as interpretative criteria. The critical differences required for significance of changes in serial results differ markedly from marker to marker and the data allow generation of objective criteria for monitoring individuals.

Quality specifications for analytical imprecision and bias based on ‘the state of the art’, ‘biology’ and ‘analysis of clinical situations’ have been proposed by several scientists. Most interesting is the assessment of ‘diagnostic misclassifications’ based on direct evaluation of the consequences of analytical bias on the percentage of false positives and false negatives from a clinical decision situation, or based on the percentage of healthy individuals outside each reference limit when common reference intervals are used. With use of graphical or computer simulations assuming increasing (positive or negative) analytical bias, the expected percentage of misclassifications can be estimated — and, for the error for which the outcome (the fraction of misclassifications) is considered unacceptable, the maximum allowable analytical bias can be defined. An overview is given of previous proposals for specification of allowable analytical bias, and new examples are presented: (i) for S-transferrin, an analytical bias of + 10% will increase the percentage of healthy individuals with measured concentration values above the upper reference limit from 2.5 to 10%; (ii) the percentage of healthy men with concentration values for S-cholesterol above 6.2 mmol/1 (240 mg/dl) will vary between 25 and 85% for analytical bias from − 1.0 to + 1.0 mmol/l (± 16%); (iii) for glycated haemoglobin, two examples are given which illustrate the effect of analytical bias on the risk of retinopathy and so-called ‘microalbuminuria’ for measured values identical to the target 7.5% and 10.1% glycated haemoglobin, respectively. It is concluded that analytical bias may have significant impact on diagnostic performance, better standardization is needed, and quality specifications for allowable analytical bias should be based on medical usefulness criteria or, if such data are not available, on biological criteria.

Apple et al. (1), on behalf of the Committee on Standardization of Markers of Cardiac Damage of the IFCC, recently reviewed and abstracted the scientific literature to provide recommendations pertaining to the quality specifications for B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) assays (together abbreviated here as NPs). They stated that a decision concerning what is acceptable imprecision is needed and concurred with the goals derived using the model proposed by Cotlove et al. (2) based on the concept that analytical imprecision (CVA) should not significantly affect clinical use. This model suggests that this desired negligible clinical impact can be obtained when CVA is lower than or equal to one-half the intraindividual biological variation (CVI). The mathematical explanation of this and the many other models available for the setting of quality specifications for analytical performance characteristics have been described in detail (3). The authors state that, because of high biological variation for NPs (CVI, 30%–50%), very low CVA may be unnecessary: however, for monitoring of therapy with serial BNP measurements in clinical cases, it may be desirable to minimize CVA (1). Furthermore, Apple et al. (1) state that a desirable CVA of

Fecal immunochemical tests for hemoglobin (FIT) are changing the manner in which colorectal cancer (CRC) is screened. Although these tests are being performed worldwide, why is this test different from its predecessors? What evidence supports its adoption? How can this evidence best be used? This review addresses these questions and provides an understanding of FIT theory and practices to expedite international efforts to implement the use of FIT in CRC screening.

Objectives To investigate the characteristics of participants screened for bowel cancer using a faecal immunochemical test for haemoglobin (FIT). Setting Scottish Bowel Screening Programme. Methods 65909 men and women in two NHS Boards, aged 50 to 74, were invited to participate in an evaluation of FIT as a first-line test. Uptake was calculated by sex, age in quintiles, and deprivation in quintiles, and compared with a group who had completed a guaiac faecal occult blood test (gFOBT) and for whom details of sex, age and deprivation were well documented. Results FIT kits from 38672 participants were tested. The overall uptake of 58.7% was significantly higher than the 53.9% for gFOBT (p < 0.0001). Uptakes in the two NHS Boards were 57.6% and 54.4% for men and 63.2% and 59.1% for women, higher than the 49.5% and 58.1% completing gFOBT. Uptake was higher for FIT than gFOBT in all age and deprivation quintiles for both men and women in both NHS Boards. The difference in uptake fell with age for men but rose for women; the increase in uptake was greater for men than women. Uptake fell as deprivation decreased for both sexes, and was similar in both NHS Boards. Conclusions Use of FIT increases uptake over gFOBT, and the greatest increases are seen in men, younger participants, and more deprived individuals, groups for which an increase in uptake is likely to be beneficial. The results support a move to FIT as a first-line screening test for those countries still using gFOBT.

Aim The patterns of response in faecal occult blood test (FOBT) screening were studied. Method A total of 251 578 people invited three times for faecal occult blood testing were categorized according to how they responded to the invitations, as follows: YNN, NYN, NNY, NYY, YNY, YYN, YYY or NNN (Y = response; N = no response). Results Overall, 163 038 (64.8%) responded at least once, and of those the biggest category was YYY (98 494, 60.4%). Of 1927 cancers diagnosed in the age group eligible for screening, there were 405 screendetected cancers, 529 interval cancers and 993 cancers arising in people who had not been screened for over 2 years (i.e. falling outside the interval cancer category). In the YYY group, 79 screen-detected cancers would have been missed had the members of this group responded YNN and 65 had they responded YYN. In the YYN group, 104 screening cancers would have been missed if they had followed the YNN pattern. In most cases, the screen-detected cancers were diagnosed at the last invitation accepted, indicating that, after a diagnosis of cancer, further screening invitations were rarely accepted. Accordingly, the numbers of screen-detected and interval cancers were adjusted for likely pattern of response according to the proportion of the whole population falling into each pattern. With this adjustment, 40.9% of the cancers in the YYY group were screen detected compared with 29.3% in the YYN group and 20.7% in the YNN group (P < 0.001). Among those who responded once, twice and three times, the stage distribution of screen-detected cancers was similar, indicating that the prognosis of screen-detected cancer is unlikely to be poorer if not detected at the first screen. Conclusion This study is the first to examine patterns of response to screening invitations and confirms the importance to individuals of continuing to accept repeated screening invitations.

Background: In guaiac-based faecal occult blood tests (FOBT), blue colours are considered positive. Blue-green colours should also be considered positive. Distinct green colours are said to be due to bile and it is stated that these should be interpreted as negative. The purpose of this study was to determine the clinical outcomes in individuals in whom the FOBT had difficult-to-interpret green colours that did not wash out on addition of developer. Methods: During the examination of 134 844 FOBT received in the Scottish laboratory in the first screening round of the UK Colorectal Cancer Screening Pilot, samples with green colour that did not wash out during development were identified. The clinical outcomes were determined from the comprehensive data set collected for each participant. Results: A small number (77) of FOBT were recorded as green-coloured on development. These were reported as positive and the usual investigation algorithm followed. Significant pathology was present in 31 of the 77 participants (40.3%). Negative outcomes encompassed 39 of the 77 participants (50.6%). The outcome could not be determined accurately for seven of the 77 participants (9.1%). Importantly, 17 of the participants (22.1%) had polyps. Conclusions: Any green colour that does not wash out to the periphery of the guaiac tape on development of FOBT should be reported as a positive result, and manufacturers should clarify their instructions on interpretation.

Guaiac-based faecal occult blood tests (gFOBT) are still used in asymptomatic population bowel screening programmes but are being replaced by faecal immunochemical tests (FIT) for haemoglobin. gFOBT have many well-documented disadvantages and there is little evidence for their use in assessment of the symptomatic. Many laboratories have eliminated gFOBT from their approved repertoires by invoking the authoritative published guidelines. Data continue to accumulate that gFOBT are obsolete. FIT are available in two formats, qualitative and quantitative, the latter having advantages that the faecal haemoglobin concentrations are measured and cut-off concentrations that stimulate further investigation can be user-defined. There is growing evidence that FIT would be useful in a spectrum of clinical settings in addition to screening. All laboratories should have FIT in their existing repertoire. For some uses, qualitative FIT would be adequate. However, much evidence has accumulated that measurements of faecal haemoglobin concentrations are beneficial for the assessment of both disease severity and the future risk of colorectal neoplasia. Interpretation requires appreciation that faecal haemoglobin concentrations are higher in men than women and rise with age. It might well be that risk scoring systems that take gender and age into account, possibly with other factors including symptoms, will benefit individuals. Laboratories should consider how quantitative faecal haemoglobin measurements could be brought into routine practice and included in their forward planning. External quality assessment is needed. Specialists in laboratory medicine are urged to play a significant role in the research and development still required to make this a truly mature investigation.

In April of 2011, Bio-Rad Laboratories Quality System Division (Irvine, CA, USA) hosted its third annual convocation of experts on laboratory quality in the city of Salzburg, Austria. As in the past 2 years, over 60 experts from across Europe, Israel, USA and South Africa convened to discuss contemporary issues and topics of importance to the clinical laboratory. This year’s conference had EN/ISO 15189 and accreditation as the common thread for most discussions, with topics ranging from how to meet requirements like uncertainty to knowledge gained from those already accredited. The participants were divided into five discussion working groups (WG) with assigned topics. The outcome of these discussions is the subject of this summary.

Fecal immunochemical tests for hemoglobin are replacing traditional guaiac fecal occult blood tests in population screening programs for many reasons. However, the many available fecal immunochemical test devices use a range of sampling methods, differ with regard to hemoglobin stability, and report hemoglobin concentrations in different ways. The methods for sampling, the mass of feces collected, and the volume and characteristics of the buffer used in the sampling device also vary among fecal immunochemical tests, making comparisons of test performance characteristics difficult. Fecal immunochemical test results may be expressed as the hemoglobin concentration in the sampling device buffer and, sometimes, albeit rarely, as the hemoglobin concentration per mass of feces. The current lack of consistency in units for reporting hemoglobin concentration is particularly problematic because apparently similar hemoglobin concentrations obtained with different devices can lead to very different clinical interpretations. Consistent adoption of an internationally accepted method for reporting results would facilitate comparisons of outcomes from these tests. We propose a simple strategy for reporting fecal hemoglobin concentration that will facilitate the comparison of results between fecal immunochemical test devices and across clinical studies. Such reporting is readily achieved by defining the mass of feces sampled and the volume of sample buffer (with confidence intervals) and expressing results as micrograms of hemoglobin per gram of feces. We propose that manufacturers of fecal immunochemical tests provide this information and that the authors of research articles, guidelines, and policy articles, as well as pathology services and regulatory bodies, adopt this metric when reporting fecal immunochemical test results.

There are differences in practice between the US, Europe, and other countries in screening for colorectal neoplasia (1) and investigation of other common lower gastrointestinal tract problems. Colonoscopy is often considered the gold standard for detection of colorectal neoplasia, and deaths from colorectal cancer can undoubtedly be reduced through removal of adenomatous polyps (2, 3). Colonoscopy is a scarce resource in many countries, however, and it may be limited to those with comprehensive health insurance. Consequently, there is much interest in using fecal tests to decide who will truly benefit from colonoscopy, particularly because the symptoms reported for colorectal diseases overlap considerably, making clinical decision-making about whom to refer difficult. In this issue of the Journal, Kok and colleagues (4) report a study on the diagnostic accuracy of point-of-care tests (POCTs)6 for fecal calprotectin and occult blood in primary care and assessing what they term “organic bowel disease.” A qualitative immunochemical fecal occult blood test was used. We have recommended (5) that tests that use antibodies to detect fecal hemoglobin be termed “fecal immunochemical tests for hemoglobin” and that the abbreviation “FIT” be used, because guaiac-based fecal occult blood tests (gFOBTs) and FITs are very different tests. As the authors mention, FITs are rapidly superseding traditional gFOBTs because of their many advantages, including that only a single sample is generally collected, the available collection devices encourage adoption of the test, the test is more specific for lower gastrointestinal bleeding, and dietary restriction is definitely not required. Indeed, the many disadvantages of gFOBTs with respect to sample collection and handling, analysis, and interpretation of results (6) have led to the general consensus that their use is obsolete because of the much better performance characteristics of FITs. We strongly advocate that professionals in laboratory medicine (PLMs) encourage current users of …

Objectives To evaluate a two-tier reflex guaiac-based faecal occult blood test (gFOBT)/faecal immunochemical test (FIT) algorithm in screening for colorectal cancer. Setting Fourth screening round in NHS Tayside (Scotland). Methods gFOBT were sent to 50–74-year-olds. Participants with five or six windows positive were offered colonoscopy. Participants with one to four windows positive were sent a FIT and, if positive, were offered colonoscopy. Participants providing an untestable gFOBT were sent a FIT and, if positive, were offered colonoscopy. Outcomes following positive results, cancer stages and key performance indicators were assessed. Results Of 131,885 invited, 73,315 (55.6%) responded. There were 66,957 (91.3%) negative, 241 (0.3%) strong positive, 5230 (7.1%) weak positive and 887 (1.2%) untestable results. The 241 participants who had five or six windows positive had more cancers than those positive by other routes: only 3 of the 30 cancers (9.7%) were Dukes' A. Among the 983 positive results from the weak positive gFOBT then positive FIT route, there were fewer cancers and more normal colonoscopies, but more adenomas than in the group with a strong positive gFOBT. In those with an untestable gFOBT, 77 had a positive FIT result, with fewer true and more false positive results than in the other groups. Fewer males had cancer and stages were earlier than in females, but more had adenoma. The detection rate for cancer was 0.18% and the PPV for cancer and all adenomas was 41.3%. Conclusions The algorithm and FIT following a weak positive gFOBT have advantages. FIT following an untestable gFOBT warrants review.

Objective: To assess the impact of the UK colorectal cancer guaiac faecal occult blood test screening pilot studies on incidence trends, stage distribution and mortality trends. Design: Ecological study. Setting: Scotland and the West Midlands. Data: We extracted anonymised colorectal cancer (ICD-10 C18–C20) registration (1982–2006) and death records (1982–2007), along with corresponding mid-year population estimates. Intervention: Residents of the screening pilot areas, in the age group 50–69 years, were offered biennial guaiac faecal occult blood test screening from 2000 onwards. Screening was not offered routinely in non-pilot areas until the start of the roll-out of the national screening programmes in England and in Scotland in 2006 and 2007, respectively. Main outcome measures: We analysed trends in age-specific incidence and mortality rates, and Dukes’ stage distribution. Within each country/region, we compared the screening pilot areas to non-screening pilot (‘control’) areas using Chi square tests and Poisson regression modelling. Results: Following the start of the screening pilots, as expected in the prevalent round of a new screening programme, in the pilot areas there was a short-lived increase in incidence of colorectal cancer among 50–69 year olds except for females in the West Midlands. A trend towards earlier stage and less advanced disease was also observed, with males showing significant increases in Dukes’ A and corresponding decreases in Dukes’ C in the screening pilot areas (all P < 0.03). With the exception of females in the West Midlands, mortality rates for colorectal cancer decreased significantly and at a faster rate in the populations invited for screening. Conclusion: The existence of a natural control population not yet invited for screening provided a unique opportunity to assess whether the benefits of colorectal cancer screening, beyond the setting of a randomised controlled trial, could be detected using routinely collected statistics. Our analysis suggests that screening will fulfil its aim of reducing mortality from colorectal cancer.

Faecal immunochemical tests (FIT) are becoming widely used in colorectal cancer screening. Estimation of faecal haemoglobin concentration in a large group prompted an observational study on gender and age.A single estimate of faecal haemoglobin concentration was made using quantitative automated immunoturbidimetry. Potential reference intervals were calculated for men and women and for age quintiles according to the Clinical and Laboratory Standards Institute Approved Guideline. The percentages of positive results were calculated at a number of concentrations. The percentages of individuals who fell into different risk groups were assessed.The 97.5 percentiles, potential upper reference limits, were 519 ng haemoglobin/mL (90% CI: 468–575) for men and 283 ng haemoglobin/mL (90% CI: 257–316) for women. Concentrations increased with age in both genders. Decision limits have advantages over reference intervals. At any cut-off concentration, more men are declared positive than women and more older people are declared positive than younger people. Future risk of neoplasia is higher in men than in women and in older people.Faecal haemoglobin concentrations vary with gender and age. More tailored strategies are needed in screening programmes. Faecal haemoglobin concentration could be included in individual risk assessment scores. These data should assist in screening programme design.

Reference change values (RCV) provide objective tools for assessment of the significance of differences in serial results from an individual. The concept is simple and the calculation easy, since all laboratories know their analytical imprecision (CV(A)) and estimates of within-subject biological variation (CV(I)) are available for a large number of quantities. Generally, CV(I) are constant over time, geography, methodology and in health and chronic stable disease. The formula is RCV=2(1/2) · Z · (CV(A)(2) + CV(I)(2))(1/2), where Z is the number of standard deviations appropriate to the probability. Correct interpretation of the semantics describing the clinical use of RCV is vital for selection of the Z-score. Many quantities of clinically importance exist for which good estimates of RCV are unavailable. Derivation of CV(I) may be difficult for such quantities: flair and imagination are required in selecting populations with chronic but stable disease on whom CV(I) can be determined. RCV can be used for delta-checking and auto-verification and laboratory information management systems (LIMS) can be adapted to do this. Recently, log-normal transformation to obtain unidirectional RCV has been used. Gaps in knowledge of RCV still require filling since the need for measures of change is clearly expressed in guidelines.

Background: Dehydration is a common medical problem requiring heuristic evaluation. Our aim was to develop a quantitative and graphical tool based on serial changes in either plasma osmolality (Posm), urine specific gravity (Usg), or body mass (Bm) to aid in determining the probability that a person has become dehydrated. A secondary purpose was to validate use of the tool by dehydrating a group of volunteers. Methods: Basic data were obtained from a recent study of biological variation in common hydration status markers. Four reference change values (RCV) were calculated for each variable (Posm, Usg, Bm) using four statistical probabilities (0.80, 0.90, 0.95, and 0.99). The probability derived from the Z-score for any given change can be calculated from: Z=change/[21/2(CVa 2+CVi 2)1/2]. This calculation was simplified to require one input (measured change) by plotting the RCV against probability to generate both an empirical equation and a dual quantitative-qualitative graphic. Results: Eleven volunteers were dehydrated by moderate levels (–2.1% to –3.5% Bm). Actual probabilities were obtained by substituting measured changes in Posm, Usg, and Bm for X in the exponential equation, Y=1–e –K·X, where each variable has a unique K constant. Median probabilities were 0.98 (Posm), 0.97 (Usg), and 0.97 (Bm), which aligned with ‘very likely’ to ‘virtually certain’ qualitative probability categories for dehydration. Conclusions: This investigation provides a simple quantitative and graphical tool that can aid in determining the probability that a person has become dehydrated when serial measures of Posm, Usg, or Bm are made.

The Stockholm conference held in 1999 on “Strategies to set global analytical quality specifications (AQS) in laboratory medicine” reached a consensus and advocated the ubiquitous application of a hierarchical structure of approaches to setting AQS. This approach has been widely used over the last decade, although several issues remain unanswered. A number of new suggestions have been recently proposed for setting AQS. One of these recommendations is described by Haeckel and Wosniok in this issue of Clinical Chemistry and Laboratory Medicine. Their concept is to estimate the increase in false-positive results using conventional population-based reference intervals, the delta false-positive rate due to analytical imprecision and bias, and relate the results directly to the current analytical quality attained. Thus, the actual estimates in the laboratory for imprecision and bias are compared to the AQS. These values are classified in a ranking system according to the closeness to the AQS, and this combination is the new idea of the proposal. Other new ideas have been proposed recently. We wait, with great interest, as should others, to see if these newer approaches become widely used and worthy of incorporation into the hierarchy.

The format of the traditional guaiac faecal occult blood test (gFOBT), particularly the collection technique, might cause difficulties for some. A multistage evaluation of alternative tests was performed. Firstly, four tests with different faecal collection approaches were assessed: a focus group recommended further investigation of a wipe gFOBT. Secondly, 100 faecal samples were analysed using two wipe tests and the routine gFOBT: no differences were found. Thirdly, a wipe gFOBT was introduced. Over 21 months, 400 requests were made and 311 wipe kit sets were submitted for analysis: 153 (49.2%) were negative, 21 (6.8%) positive (all 3 kits positive), 96 (30.9%) weak positive (1 or 2 positive) and 41 (13.2%) un-testable. Forty-three participants were referred for colonoscopy. Outcome data were provided on 39 participants: nine declined colonoscopy, two were judged unsuitable, two did not attend, two were already in follow-up, 13 had normal colonoscopy and two normal barium enema, two had diverticular disease, two had a metaplastic polyp, four had a low-risk adenoma and one had a high-risk adenoma. No participant had cancer. Detection of significant neoplasia was small. The use of the wipe gFOBT was ceased: it cannot be recommended as a screening test for bowel cancer.

This study examined the effects of conventional doses of oral captopril on the renal responses to oral furosemide in ambulant patients with stable chronic heart failure. Twenty-five men (mean age 63 years) were randomized to one of two groups. Group 1 received placebo on days 1 and 2 before furosemide. Group 2 received placebo on day 1 before furosemide and captopril thereafter (i.e., captopril before furosemide on day 2). Urine was collected after either placebo or captopril and after furosemide (taken after placebo or captopril pretreatment). Captopril by itself did not affect renal function. Captopril did, however, significantly affect the renal response to furosemide. The increase in urine flow rate after furosemide in group 2 was decreased from 225% with placebo to 128% with captopril (p < 0.02). The increase in sodium excretion after furosemide was decreased from 623% with placebo to 242% with captopril (p < 0.001). Pretreatment with captopril abolished the increase in creatine clearance after furosemide. The increase in urinary albumin excretion (used as a marker of glomerular function) after furosemide was also significantly blunted by captopril. Conventional doses of captopril acutely inhibit the natriuretic and diuretic responses to furosemide at the glomerular level in ambulant patients with stable chronic heart failure.

Many strategies to define desirable standards for laboratory tests to fulfill medical needs have been proposed over the last three decades. Traditional approaches are based on reference (normal) values, opinions of clinicians, the state of the art, views of experts, data on biological variation, and assessment of the effect of error on clinical use. All these approaches have advantages and disadvantages, but the consensus of experts reached over a decade ago that imprecision desirably be less than one-half of the within-subject biological variation still seems to provide the best set of generally applicable performance standards. Desirable bias is less than one-quarter of the group (within-subject plus between-subject) biological variation. Recent proposals are either restatements of traditional recommendations, further empirical suggestions, or models based on assessment of clinical needs, and have not been widely accepted. Both old and new studies on clinical opinions, sought by using structured questionnaires containing clinical vignettes designed to seek views on the magnitude of significant change, are flawed in design, execution, and data analysis. Until clinicians are more aware of test-result variability and clinical chemists gain quantitative knowledge on the interpretation of test results, it will be difficult to set desirable standards that fulfill actual medical needs, except in a few well-defined screening situations.

The analytical, within-subject and between-subject components of variation were estimated for serum albumin, transthyretin, α1-acid glycoprotein, α1-antichymotrypsin, haptoglobin, β2-microglobulin and C-reactive protein in a cohort of 19 apparently healthy subjects over 20 weeks. Desirable analytical goals based on biological variation should be able to be met except for serum albumin and β2-microglobulin for which methodological improvement is warranted. All proteins showed marked individuality which casts doubt on the utility of conventional population-based reference values as interpretative criteria. The critical differences required for significance of changes in serial results differ markedly from protein to protein and the data presented allow generation of objective criteria for monitoring individuals.

SynopsisThere are many steps in the process between the clinician requesting a clinical biochemistry test and receiving a numerical result. Each of these steps must be subject to quality assurance techniques. Clinical biochemistry laboratories now have mature, integrated systems of internal quality control, external quality assessment and quality assurance to ensure that the results issued do aid in the provision of optimum patient care. The recent advent of a professionally led laboratory accreditation scheme will stimulate further improvements in quality. Enthusiastic adoption of the techniques of quality management science, in the form of total quality management systems, will focus future attention on laboratories providing services to the standards dictated by consumers. Translation of these standards into objective operational specifications will then allow laboratories to adopt appropriate comprehensive quality assurance techniques which will guarantee the quality demanded.

Many quantities assayed in clinical laboratories demonstrate age-related changes. Particularly important periods are early life, adolescence, old age, and after the menopause in females. The changes that occur until adulthood are well documented. Fewer data are available on elderly people even though they consume a large component of healthcare resources. In diagnosis, and prior to initiation of drug therapy, when no previous results are available, reference values must be available to aid interpretation. Reference intervals generated from elderly people are sometimes wider than in younger adults. It is suggested that conventional adult reference values should be used in general for the very elderly since, at least in part, the wider intervals are probably due to inclusion of individuals who are unhealthy in the reference sample group. Most quantities have marked individuality, and serial values for an individual span only a part of the reference interval. Individuals can have values which are very unusual for them but still lie within the reference limits; this implies that clinical laboratory tests will be less than ideal in the detection of latent or early disease. The average within-subject variation in healthy elderly people and younger adults is similar. Therefore, the large database on biological variation can be used, with analytical imprecision, to calculate critical differences for serial results in an elderly individual which must be exceeded before significance can be claimed. These critical differences are of value in monitoring the effects of drug therapy.

The aim of this case-control study was to explore the relation between maternal and infant angiotensin converting enzyme (ACE) activity and its genotypes in uncomplicated term pregnancies (> or =37 weeks) and pregnancies with growth-restricted infants (birthweight at or below the 5th centile). Venous cord bloods and maternal venous samples were obtained for serum ACE activity and ACE genotype. Growth-restricted infants (< or =5th centile) were more likely to be of the DD genotype compared to appropriately grown infants (42 vs. 13%, p = 0.003). There was no significant difference in the frequency of the maternal DD genotype between the two groups (33 vs. 22%, p = 0.43) and similarly no significant differences in the maternal or fetal ACE activities. Within the intrauterine growth restriction (IUGR) group, infants of the DD genotype had higher ACE activity compared to appropriately grown infants (p = 0.03). In conclusion, the DD genotype of the ACE gene appears to be associated with fetal growth and may be a factor in the increased risk of adult onset chronic diseases among growth-restricted infants.

The aim of this study was to investigate differences in maternal and infant ACE genotypes in early-onset and later-onset pre-eclampsia/toxemia (PET).We conducted a case-control study of 22 cases of early-onset pre-eclampsia (before 34 weeks gestation), 38 cases of later-onset pre-eclampsia (after 34 weeks gestation), and 108 healthy controls delivered at term (38-40 weeks gestation) within a stable Caucasian population. Maternal venous blood and cord bloods were obtained for serum angiotensin converting enzyme (ACE) activity, ACE genotype, and acid-base status.Mothers who developed early-onset PET were more likely to be homozygous for the deletion allele of the ACE genotype (DD) than mothers with late-onset PET or uncomplicated pregnancies (12/22 (55%) vs. 7/38 (18%) vs. 22/105 (21%), respectively; OR 2.96 [95% confidence intervals (CI) 1.37-6.31]. Infants of mothers with early-onset PET were more likely to be homozygous for the DD genotype than infants of mothers with late-onset PET or controls (7/19 (37%) vs. 9/36 (25%) vs. 11/78 (14%); OR 2.51 (95% CI 1.12-5.61). There were no differences in maternal or infant ACE activities in relation to onset of pre-eclampsia.Our findings suggest an association between the DD genotype of the ACE gene and early-onset but not later-onset pre-eclampsia which may give a partial explanation for the higher recurrence risk with early-onset pre-eclampsia.

Analytical goals for the performance characteristics of assays of haemaoglobin A1c (HbA1c) have been investigated using different assumptions for generation of estimates, these being based on strategies using data on biological variation and on the clinical use of results. The derived goals are highly dependent on the assumptions made. In general, in monitoring of patients (using results from the same laboratory), the analytical imprecision is the most demanding, whereas bias (inaccuracy) is the most important characteristic when strategies for several centres (laboratories) to achieve similar results are invoked. Goals for analytical quality should be given in a form in which both analytical imprecision and bias (or systematic error) are specified. When several goals are to be considered (for different relevant assumptions), the most demanding should be used.