Hodgkin lymphoma (HL) survivors have an increased morbidity and mortality from secondary cancers ... more Hodgkin lymphoma (HL) survivors have an increased morbidity and mortality from secondary cancers and cardiovascular disease (CD). We evaluate doses with involved node radiotherapy (INRT) delivered as 3D conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), or proton therapy (PT), compared with the extensive Mantle Field (MF). For 27 patients with early-stage, mediastinal HL, treated with chemotherapy and INRT delivered as 3D CRT (30 Gy), we simulated an MF (36 Gy), INRT-VMAT and INRT-PT (30 Gy). Dose to the heart, lungs, and breasts, estimated risks of CD, lung (LC) and breast cancer (BC), and corresponding life years lost (LYL) were compared. 3D CRT, VMAT or PT significantly lower the dose to the heart, lungs and breasts and provide lower risk estimates compared with MF, but with substantial patient variability. The risk of CD is not significantly different for 3D CRT versus VMAT. The risk of LC and BC is highest with VMAT. For LYL, PT is the superior modern technique. In early-stage, mediastinal HL modern radiotherapy provides superior results compared with MF. However, there is no single best radiotherapy technique for HL-the decision should be made at the individual patient level.
The Clinical biochemist. Reviews / Australian Association of Clinical Biochemists
All results in laboratory medicine are compared to some reference for interpretation. This refere... more All results in laboratory medicine are compared to some reference for interpretation. This reference may be a previous result from the same patient, a reference population--either healthy or diseased, or both--or a decision limit recommended by an expert group. The aim for the medical laboratory is to improve the signal-to-noise ratio by increasing the signal or reducing the noise. This presentation deals with the more general tools for reduction of the noise component, and focuses on biological within-subject variation, reference intervals and decision models. Regarding biological within-subject variation, the estimation of reference change value (RCV) as a yardstick for judging measured differences within the patient over time is an important tool. Here, only type 1 errors are usually applied, but type 2 errors should also be taken into consideration. Moreover, variance homogeneity is assumed for the application of RCV, but this assumption is not always fulfilled, and erroneous in...
... 8. 9. 10. 11. 12. 13. Svendsen, P.Aa., Lauritzen, T., Soegaard, U. & Nerup, J. Glycos... more ... 8. 9. 10. 11. 12. 13. Svendsen, P.Aa., Lauritzen, T., Soegaard, U. & Nerup, J. Glycosylated haemoglobin and steady-state mean blood glucose concentration in type I (insulin-dependent). diabetes. ... In: Harris, EK, Yasaka, T., eds. Maintaining a Healthy State within the Individual. ...
The variability of the tumor markers cancer antigen (CA) 15.3, carcinoembryonic antigen (CEA) and... more The variability of the tumor markers cancer antigen (CA) 15.3, carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA) during steady state concentrations and the rate of increase during progression is described. One hundred and ninety-two patients were monitored during first-line chemotherapy for metastatic breast cancer and during follow-up. Blood specimens were sampled approximately every four weeks. Steady state concentrations were registered for 77 (CA 15.3), 96 (CEA), and 127 (TPA) patients with below cutoff level values and for 28 (CA 15.3), 25 (CEA), and 11 (TPA) patients with above cutoff level values. Clinical and marker progression was registered for 75 (CA 15.3), 62 (CEA), and 57 (TPA) patients. The coefficients of total variation of steady state concentrations (comprising the intra- and interassay analytical imprecision and the within subject biological variation) were higher below (14.9% CA 15.3, 15.4% CEA, 25.9% TPA) than above cutoffs (9.6% CA 15.3,6.0% CEA, 19.9% TPA). The variability was similar for CA 15.3 and CEA but higher for TPA. During progression the rates of increase in concentrations were similar for CA 15.3 (0.0257) and CEA (0.0214) and lower than for TPA (0.0346). Our data indicate that criteria for assessment of sequential tumor marker concentrations should consider the marker in question, the steady state variability, the cutoff value, and the rate of increase during disease progression.
The aim of this protocol is to establish a common basis for the production of reference values an... more The aim of this protocol is to establish a common basis for the production of reference values and well-defined and documented reference intervals for plasma proteins, based on common standardization, using the IFCC/BCR/CAP Certified Reference Material CRM 470. The strategy is to search for racial and environmental/geographical similarities and sources of differences in order to describe the main causes for variability among smaller or larger groups in selected societies and to estimate the sizes of differences for the different proteins according to the investigated sources. For this purpose, groups of reference individuals are selected according to race and geographical/environmental location, e.g. African Americans and Caucasians from the US. The reference individuals are groups of approximately 160 healthy male blood donors, 20 to 60 years of age. Rule-out criteria are positivity for HIV, hepatitis B and C antibodies and blood hemoglobin below the lower reference limit. Exclusion in relation to different C-reactive protein (CRP) levels will be investigated. Coagulation, storage conditions, transport, and the procedure for thawing are specified. The laboratories undertaking the measurements must have adequate analytical performance, and calibration and quality of performance are defined and documented, together with recommended control materials and procedures. Statistical models for describing distributions and for comparing groups are described. It is recommended that the data be presented as reference limits with 90% confidence intervals of those limits.
An important objective in external quality assessment (EQA) is to evaluate systematic deviations ... more An important objective in external quality assessment (EQA) is to evaluate systematic deviations between methods. However, this is not possible when noncommutable control materials are used. The aim of this study was to develop an EQA model that incorporates a method bias evaluation using native patient samples into EQA schemes in which noncommutable materials are used. The model was applied twice in a point-of-care (POC) international normalized ratio survey among 1341 and 1578 participants. To estimate bias, about 100 native patient samples for each POC method were analyzed by a selected group of "expert" primary healthcare centers and on a designated comparison method. In addition, the expert centers as well as all the other EQA participants analyzed 2 noncommutable control materials, and method-specific target values were established. Both method bias and the deviation of a single-participant result from the method target value were evaluated against analytical quality specifications, making combined assessment possible. The best-case scenario occurred when both results were within the quality specifications. Two POC methods fulfilled the quality specification for bias, whereas one did not. The best-case scenario was achieved by more than 90% of the participants using the methods with no bias, whereas none of the participants using the method with unacceptable bias achieved this result. We propose an EQA model for which the bias of POC methods can be evaluated in situations in which commutable control materials are not available.
Diagnostic decisions based on decision limits according to medical guidelines are different from ... more Diagnostic decisions based on decision limits according to medical guidelines are different from the majority of clinical decisions due to the strict dichotomization of patients into diseased and non-diseased. Consequently, the influence of analytical performance is more critical than for other diagnostic decisions where much other information is included. The aim of this opinion paper is to investigate consequences of analytical quality and other circumstances for the outcome of "Guideline-Driven Medical Decision Limits". Effects of analytical bias and imprecision should be investigated separately and analytical quality specifications should be estimated accordingly. Use of sharp decision limits doesn't consider biological variation and effects of this variation are closely connected with the effects of analytical performance. Such relationships are investigated for the guidelines for HbA1c in diagnosis of diabetes and in risk of coronary heart disease based on serum cholesterol. The effects of a second sampling in diagnosis give dramatic reduction in the effects of analytical quality showing minimal influence of imprecision up to 3 to 5% for two independent samplings, whereas the reduction in bias is more moderate and a 2% increase in concentration doubles the percentage of false positive diagnoses, both for HbA1c and cholesterol. An alternative approach comes from the current application of guidelines for follow-up laboratory tests according to clinical procedure orders, e.g. frequency of parathyroid hormone requests as a function of serum calcium concentrations. Here, the specifications for bias can be evaluated from the functional increase in requests for increasing serum calcium concentrations. In consequence of the difficulties with biological variation and the practical utilization of concentration dependence of frequency of follow-up laboratory tests already in use, a kind of probability function for diagnosis as function of the key-analyte is proposed.
... distributions. Linnet has given some critical remarks to the IFCC recommendations (9). 21-955... more ... distributions. Linnet has given some critical remarks to the IFCC recommendations (9). 21-955059 307 Page 2. ... indviduals. The latter distribution is not log-Gaussian (thin straight line) and converges to the total distribution in both ends. ...
Abstract With the increasing use of decision limits (action limits, cut-off points) specified for... more Abstract With the increasing use of decision limits (action limits, cut-off points) specified for a number of analytical components in diagnosis and for action in critical situations, formulated in national or international recommendations, the traditional interpretation of reference intervals has been uncertain, and sometimes the two concepts are being mixed up by incorporating risk calculations in the reference intervals. There is, therefore, a need to clarify the two concepts and to keep them definitely separated. Reference intervals are the 95% limits for the descriptions of the distributions of the values of analytical components measured on reference samples from reference individuals. Decision limits are based on guidelines from national and international expert groups defining specific concentrations of certain components as limits for decision about diagnosis or well-defined specific actions. Analytical quality specifications for reference intervals have been defined for bi...
Cancer antigen 125 (CA125) is used to monitor tumor burden among patients with advanced serous ep... more Cancer antigen 125 (CA125) is used to monitor tumor burden among patients with advanced serous epithelial ovarian cancer. The purpose is to compare the monitoring performance of seven previously proposed criteria. The CA125 assessment criteria were applied to simulated datasets. We investigated the ability to provide information on CA125 increments as well as their robustness against false positive signals. For baseline concentrations above cut-off, the best performing criterion was based on a confirmed increment ≥2.5-times the nadir concentration. For baseline concentrations below cut-off, the best performing criterion was based on a confirmed increment from ≤ cut-off to >two-times cut-off. Computer simulation models may be useful for a preclinical validation of criteria to be investigated in clinical trials.
Scandinavian Journal of Clinical & Laboratory Investigation, 2002
Haemoglobin A1c (HbA1c) is now the key component for monitoring glycaemic control in diabetes mel... more Haemoglobin A1c (HbA1c) is now the key component for monitoring glycaemic control in diabetes mellitus (DM), especially for its close relation to diabetes complications. However, treatment goals in terms of HbA1c concentrations have been difficult to define and compare because of lack of international standardization and lack of common reference values of HbA1c concentrations. The aims of our study were to document our HbA1c analysis and make it traceable to international reference laboratories with the aid of current reference preparations, to establish a reference interval based on a low-risk population, and to evaluate the analytical quality specifications, which could meet clinical needs. The s(analytical) of our method (Tosoh) was < 0.3 HbA1c%, and the mean bias as estimated from Dr Cas Weykamp's reference preparation was below 0.3 HbA1c. This was the same as that for participating Scandinavian and international reference laboratories. The concentrations were made traceable to results from the Diabetes Control and Complication Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS). Risk groups for DM were ruled out from a randomly selected population in Vejle County, which isolated a "low-risk" reference population. The 97.5 reference interval in this population (N=430) was from 5.07 HbA1c% (95% CI: 5.02-5.11) to 6.24 HbA1c% (95% CI: 6.19-6.30), and the 99.9 centile was 6.62 HbA1c% (95%) CI 6.55-6.71). Body mass index, age and gender contributed marginally to the level of HbA1c concentrations. A 10% delta risk estimate of DM complications was detectable with a probability of Type I error of 40%, while adoption of a significance level of 95% and consideration to biological variation needed a risk difference of at least 33% to be detected. The critical difference was 11% for changes in either direction at s(analytical) < or = 0.2 HbA1c% and a s(biological) of 0.3 HbA1c%. Based on criteria for sharing common reference intervals and clinical utility, we accepted that the bias and s(analytical) should both be < 0.3 HbA1c% at the level of 7.0 HbA1c%.
Several articles describing within-subject biological variation of fasting glucose and HbA(1c) in... more Several articles describing within-subject biological variation of fasting glucose and HbA(1c) in healthy populations have been published, but information about biological variation of glucose and HbA(1c) in patients with type 1 diabetes is scarce. It is reasonable to assume that type 1 diabetics differ from their healthy counterparts in this matter. The aim of our study was to estimate the biological variation of glucose and HbA(1c) in healthy subjects and in patients with type 1 diabetes. Fifteen healthy individuals and 15 type 1 diabetes patients were included. Biological variations were calculated based on blood samples collected weekly for 10 consecutive weeks from the healthy and the eligible of the type 1 diabetes patients. The within-subject variations of glucose were approximately 5% in healthy individuals and 30% in diabetes patients, and for HbA(1c) they were 1.2% in healthy individuals and 1.7% in diabetes patients. In conclusion, we found a high within-subject biologica...
The Stockholm conference held in 1999 on "Strategies to set global analytical quality specif... more 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 closene...
Hemoglobin A1c (HbA1c) is a proxy measure for glycemic control in diabetes. We investigated the t... more Hemoglobin A1c (HbA1c) is a proxy measure for glycemic control in diabetes. We investigated the trend for glycemic control in patients from three Danish counties using HbA1c measurements. We studied 2454 patients from a population of 807,000 inhabitants for whom routine monitoring of diabetes using HbA1c-DCCT aligned was initiated in 2001. We estimated the incidence of monitored patients in the population. The progress in patients with originally diabetic HbA1c levels was investigated by cumulative probability plots, and the individual trend in clinical outcome was investigated by a modified difference plot. The age-standardized incidence of monitored patients was <0.5% in all regions. Patients with diabetic first HbA1c concentrations (>or=6.62% HbA1c) showed on average 15% improved glycemic control in the first year. Further improvement was limited. The overall percentage above the treatment target (>or=6.62% HbA1c) was 51% in 2003 compared to 59% in 2001, and the percenta...
Hodgkin lymphoma (HL) survivors have an increased morbidity and mortality from secondary cancers ... more Hodgkin lymphoma (HL) survivors have an increased morbidity and mortality from secondary cancers and cardiovascular disease (CD). We evaluate doses with involved node radiotherapy (INRT) delivered as 3D conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), or proton therapy (PT), compared with the extensive Mantle Field (MF). For 27 patients with early-stage, mediastinal HL, treated with chemotherapy and INRT delivered as 3D CRT (30 Gy), we simulated an MF (36 Gy), INRT-VMAT and INRT-PT (30 Gy). Dose to the heart, lungs, and breasts, estimated risks of CD, lung (LC) and breast cancer (BC), and corresponding life years lost (LYL) were compared. 3D CRT, VMAT or PT significantly lower the dose to the heart, lungs and breasts and provide lower risk estimates compared with MF, but with substantial patient variability. The risk of CD is not significantly different for 3D CRT versus VMAT. The risk of LC and BC is highest with VMAT. For LYL, PT is the superior modern technique. In early-stage, mediastinal HL modern radiotherapy provides superior results compared with MF. However, there is no single best radiotherapy technique for HL-the decision should be made at the individual patient level.
The Clinical biochemist. Reviews / Australian Association of Clinical Biochemists
All results in laboratory medicine are compared to some reference for interpretation. This refere... more All results in laboratory medicine are compared to some reference for interpretation. This reference may be a previous result from the same patient, a reference population--either healthy or diseased, or both--or a decision limit recommended by an expert group. The aim for the medical laboratory is to improve the signal-to-noise ratio by increasing the signal or reducing the noise. This presentation deals with the more general tools for reduction of the noise component, and focuses on biological within-subject variation, reference intervals and decision models. Regarding biological within-subject variation, the estimation of reference change value (RCV) as a yardstick for judging measured differences within the patient over time is an important tool. Here, only type 1 errors are usually applied, but type 2 errors should also be taken into consideration. Moreover, variance homogeneity is assumed for the application of RCV, but this assumption is not always fulfilled, and erroneous in...
... 8. 9. 10. 11. 12. 13. Svendsen, P.Aa., Lauritzen, T., Soegaard, U. &amp; Nerup, J. Glycos... more ... 8. 9. 10. 11. 12. 13. Svendsen, P.Aa., Lauritzen, T., Soegaard, U. &amp; Nerup, J. Glycosylated haemoglobin and steady-state mean blood glucose concentration in type I (insulin-dependent). diabetes. ... In: Harris, EK, Yasaka, T., eds. Maintaining a Healthy State within the Individual. ...
The variability of the tumor markers cancer antigen (CA) 15.3, carcinoembryonic antigen (CEA) and... more The variability of the tumor markers cancer antigen (CA) 15.3, carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA) during steady state concentrations and the rate of increase during progression is described. One hundred and ninety-two patients were monitored during first-line chemotherapy for metastatic breast cancer and during follow-up. Blood specimens were sampled approximately every four weeks. Steady state concentrations were registered for 77 (CA 15.3), 96 (CEA), and 127 (TPA) patients with below cutoff level values and for 28 (CA 15.3), 25 (CEA), and 11 (TPA) patients with above cutoff level values. Clinical and marker progression was registered for 75 (CA 15.3), 62 (CEA), and 57 (TPA) patients. The coefficients of total variation of steady state concentrations (comprising the intra- and interassay analytical imprecision and the within subject biological variation) were higher below (14.9% CA 15.3, 15.4% CEA, 25.9% TPA) than above cutoffs (9.6% CA 15.3,6.0% CEA, 19.9% TPA). The variability was similar for CA 15.3 and CEA but higher for TPA. During progression the rates of increase in concentrations were similar for CA 15.3 (0.0257) and CEA (0.0214) and lower than for TPA (0.0346). Our data indicate that criteria for assessment of sequential tumor marker concentrations should consider the marker in question, the steady state variability, the cutoff value, and the rate of increase during disease progression.
The aim of this protocol is to establish a common basis for the production of reference values an... more The aim of this protocol is to establish a common basis for the production of reference values and well-defined and documented reference intervals for plasma proteins, based on common standardization, using the IFCC/BCR/CAP Certified Reference Material CRM 470. The strategy is to search for racial and environmental/geographical similarities and sources of differences in order to describe the main causes for variability among smaller or larger groups in selected societies and to estimate the sizes of differences for the different proteins according to the investigated sources. For this purpose, groups of reference individuals are selected according to race and geographical/environmental location, e.g. African Americans and Caucasians from the US. The reference individuals are groups of approximately 160 healthy male blood donors, 20 to 60 years of age. Rule-out criteria are positivity for HIV, hepatitis B and C antibodies and blood hemoglobin below the lower reference limit. Exclusion in relation to different C-reactive protein (CRP) levels will be investigated. Coagulation, storage conditions, transport, and the procedure for thawing are specified. The laboratories undertaking the measurements must have adequate analytical performance, and calibration and quality of performance are defined and documented, together with recommended control materials and procedures. Statistical models for describing distributions and for comparing groups are described. It is recommended that the data be presented as reference limits with 90% confidence intervals of those limits.
An important objective in external quality assessment (EQA) is to evaluate systematic deviations ... more An important objective in external quality assessment (EQA) is to evaluate systematic deviations between methods. However, this is not possible when noncommutable control materials are used. The aim of this study was to develop an EQA model that incorporates a method bias evaluation using native patient samples into EQA schemes in which noncommutable materials are used. The model was applied twice in a point-of-care (POC) international normalized ratio survey among 1341 and 1578 participants. To estimate bias, about 100 native patient samples for each POC method were analyzed by a selected group of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;expert&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; primary healthcare centers and on a designated comparison method. In addition, the expert centers as well as all the other EQA participants analyzed 2 noncommutable control materials, and method-specific target values were established. Both method bias and the deviation of a single-participant result from the method target value were evaluated against analytical quality specifications, making combined assessment possible. The best-case scenario occurred when both results were within the quality specifications. Two POC methods fulfilled the quality specification for bias, whereas one did not. The best-case scenario was achieved by more than 90% of the participants using the methods with no bias, whereas none of the participants using the method with unacceptable bias achieved this result. We propose an EQA model for which the bias of POC methods can be evaluated in situations in which commutable control materials are not available.
Diagnostic decisions based on decision limits according to medical guidelines are different from ... more Diagnostic decisions based on decision limits according to medical guidelines are different from the majority of clinical decisions due to the strict dichotomization of patients into diseased and non-diseased. Consequently, the influence of analytical performance is more critical than for other diagnostic decisions where much other information is included. The aim of this opinion paper is to investigate consequences of analytical quality and other circumstances for the outcome of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;Guideline-Driven Medical Decision Limits&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;. Effects of analytical bias and imprecision should be investigated separately and analytical quality specifications should be estimated accordingly. Use of sharp decision limits doesn&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;t consider biological variation and effects of this variation are closely connected with the effects of analytical performance. Such relationships are investigated for the guidelines for HbA1c in diagnosis of diabetes and in risk of coronary heart disease based on serum cholesterol. The effects of a second sampling in diagnosis give dramatic reduction in the effects of analytical quality showing minimal influence of imprecision up to 3 to 5% for two independent samplings, whereas the reduction in bias is more moderate and a 2% increase in concentration doubles the percentage of false positive diagnoses, both for HbA1c and cholesterol. An alternative approach comes from the current application of guidelines for follow-up laboratory tests according to clinical procedure orders, e.g. frequency of parathyroid hormone requests as a function of serum calcium concentrations. Here, the specifications for bias can be evaluated from the functional increase in requests for increasing serum calcium concentrations. In consequence of the difficulties with biological variation and the practical utilization of concentration dependence of frequency of follow-up laboratory tests already in use, a kind of probability function for diagnosis as function of the key-analyte is proposed.
... distributions. Linnet has given some critical remarks to the IFCC recommendations (9). 21-955... more ... distributions. Linnet has given some critical remarks to the IFCC recommendations (9). 21-955059 307 Page 2. ... indviduals. The latter distribution is not log-Gaussian (thin straight line) and converges to the total distribution in both ends. ...
Abstract With the increasing use of decision limits (action limits, cut-off points) specified for... more Abstract With the increasing use of decision limits (action limits, cut-off points) specified for a number of analytical components in diagnosis and for action in critical situations, formulated in national or international recommendations, the traditional interpretation of reference intervals has been uncertain, and sometimes the two concepts are being mixed up by incorporating risk calculations in the reference intervals. There is, therefore, a need to clarify the two concepts and to keep them definitely separated. Reference intervals are the 95% limits for the descriptions of the distributions of the values of analytical components measured on reference samples from reference individuals. Decision limits are based on guidelines from national and international expert groups defining specific concentrations of certain components as limits for decision about diagnosis or well-defined specific actions. Analytical quality specifications for reference intervals have been defined for bi...
Cancer antigen 125 (CA125) is used to monitor tumor burden among patients with advanced serous ep... more Cancer antigen 125 (CA125) is used to monitor tumor burden among patients with advanced serous epithelial ovarian cancer. The purpose is to compare the monitoring performance of seven previously proposed criteria. The CA125 assessment criteria were applied to simulated datasets. We investigated the ability to provide information on CA125 increments as well as their robustness against false positive signals. For baseline concentrations above cut-off, the best performing criterion was based on a confirmed increment ≥2.5-times the nadir concentration. For baseline concentrations below cut-off, the best performing criterion was based on a confirmed increment from ≤ cut-off to >two-times cut-off. Computer simulation models may be useful for a preclinical validation of criteria to be investigated in clinical trials.
Scandinavian Journal of Clinical & Laboratory Investigation, 2002
Haemoglobin A1c (HbA1c) is now the key component for monitoring glycaemic control in diabetes mel... more Haemoglobin A1c (HbA1c) is now the key component for monitoring glycaemic control in diabetes mellitus (DM), especially for its close relation to diabetes complications. However, treatment goals in terms of HbA1c concentrations have been difficult to define and compare because of lack of international standardization and lack of common reference values of HbA1c concentrations. The aims of our study were to document our HbA1c analysis and make it traceable to international reference laboratories with the aid of current reference preparations, to establish a reference interval based on a low-risk population, and to evaluate the analytical quality specifications, which could meet clinical needs. The s(analytical) of our method (Tosoh) was &lt; 0.3 HbA1c%, and the mean bias as estimated from Dr Cas Weykamp&#39;s reference preparation was below 0.3 HbA1c. This was the same as that for participating Scandinavian and international reference laboratories. The concentrations were made traceable to results from the Diabetes Control and Complication Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS). Risk groups for DM were ruled out from a randomly selected population in Vejle County, which isolated a &quot;low-risk&quot; reference population. The 97.5 reference interval in this population (N=430) was from 5.07 HbA1c% (95% CI: 5.02-5.11) to 6.24 HbA1c% (95% CI: 6.19-6.30), and the 99.9 centile was 6.62 HbA1c% (95%) CI 6.55-6.71). Body mass index, age and gender contributed marginally to the level of HbA1c concentrations. A 10% delta risk estimate of DM complications was detectable with a probability of Type I error of 40%, while adoption of a significance level of 95% and consideration to biological variation needed a risk difference of at least 33% to be detected. The critical difference was 11% for changes in either direction at s(analytical) &lt; or = 0.2 HbA1c% and a s(biological) of 0.3 HbA1c%. Based on criteria for sharing common reference intervals and clinical utility, we accepted that the bias and s(analytical) should both be &lt; 0.3 HbA1c% at the level of 7.0 HbA1c%.
Several articles describing within-subject biological variation of fasting glucose and HbA(1c) in... more Several articles describing within-subject biological variation of fasting glucose and HbA(1c) in healthy populations have been published, but information about biological variation of glucose and HbA(1c) in patients with type 1 diabetes is scarce. It is reasonable to assume that type 1 diabetics differ from their healthy counterparts in this matter. The aim of our study was to estimate the biological variation of glucose and HbA(1c) in healthy subjects and in patients with type 1 diabetes. Fifteen healthy individuals and 15 type 1 diabetes patients were included. Biological variations were calculated based on blood samples collected weekly for 10 consecutive weeks from the healthy and the eligible of the type 1 diabetes patients. The within-subject variations of glucose were approximately 5% in healthy individuals and 30% in diabetes patients, and for HbA(1c) they were 1.2% in healthy individuals and 1.7% in diabetes patients. In conclusion, we found a high within-subject biologica...
The Stockholm conference held in 1999 on "Strategies to set global analytical quality specif... more 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 closene...
Hemoglobin A1c (HbA1c) is a proxy measure for glycemic control in diabetes. We investigated the t... more Hemoglobin A1c (HbA1c) is a proxy measure for glycemic control in diabetes. We investigated the trend for glycemic control in patients from three Danish counties using HbA1c measurements. We studied 2454 patients from a population of 807,000 inhabitants for whom routine monitoring of diabetes using HbA1c-DCCT aligned was initiated in 2001. We estimated the incidence of monitored patients in the population. The progress in patients with originally diabetic HbA1c levels was investigated by cumulative probability plots, and the individual trend in clinical outcome was investigated by a modified difference plot. The age-standardized incidence of monitored patients was <0.5% in all regions. Patients with diabetic first HbA1c concentrations (>or=6.62% HbA1c) showed on average 15% improved glycemic control in the first year. Further improvement was limited. The overall percentage above the treatment target (>or=6.62% HbA1c) was 51% in 2003 compared to 59% in 2001, and the percenta...
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