Comparison of impedance cardiography and cardiac magnetic resonance imaging for the evaluation of cardiac function in early-stage breast cancer patients.

Objective.Breast cancer treatment can negatively impact cardiac function in some breast cancer patients. Current methods (MUGA, echocardiography) used in clinical practice to detect abnormal cardiac changes as a result of treatment suffer from important limitations. Use of alternative techniques that would offer safe, inexpensive and non-invasive cardiac function assessment in this population would be highly advantageous. The aim of this study was to examine the agreement between impedance cardiography (ICG) and cardiac magnetic resonance imaging (CMR) in quantifying stroke volume (SV), cardiac output (CO) and end-diastolic volume (EDV) in this population.Approach.Sixteen breast cancer patients underwent ICG and CMR assessments at three time-points (before treatment, immediately after chemotherapy, and four months after chemotherapy). Bland-Altman analysis was used to quantify the accuracy and precision of ICG (relative to CMR) in estimating absolute values of SV, CO and EDV. Four methods (concordance rate, polar concordance rate, clinical concordance rate and trend interchangeability rate) were also used to assess ICG performance in tracking changes in these variables.Main results.Bland-Altman analysis showed that the accuracy of ICG relative to CMR was -3.1 ml (SV), 0.2 l·min-1(CO) and -26.0 ml (EDV) and precision was 13.2 ml (SV), 1.1 l·min-1(CO) and 20.1 ml (EDV), respectively. Trending ability assessment showed that (1) the concordance rate was 87% (SV), 73% (CO) and 73% (EDV), (2) the polar concordance rate was 67% (SV), 53% (CO) and 33% (EDV), (3) the clinical concordance rate was 33% (SV), 40% (CO) and 20% (EDV) and (4) the trend interchangeability rate was 29% (SV), 43% (CO) and 17% (EDV), respectively.Significance.Our findings show that, although ICG showed good accuracy for absolute SV and CO measurements and for CO and EDV changes, precision was poor for all variables in terms of both absolute measurements and trend tracking performance. This suggests that ICG cannot be used interchangeably with CMR in breast cancer patients.

Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease.

Fabry disease is one of the most common lysosomal storage disorders caused by mutations in the gene encoding lysosomal α-galactosidase A (α-Gal A) and resultant accumulation of glycosphingolipids. The sugar mimetic 1-deoxygalactonojirimycin (DGJ), an orally available pharmacological chaperone, was clinically approved as an alternative to intravenous enzyme replacement therapy. The decision as to whether a patient should be treated with DGJ depends on the genetic variant within the α-galactosidase A encoding gene (GLA). A good laboratory practice (GLP)-validated cell culture-based assay to investigate the biochemical responsiveness of the variants is currently the only source available to obtain pivotal information about susceptibility to treatment. Herein, variants were defined amenable when an absolute increase in enzyme activity of ≥3% of wild type enzyme activity and a relative increase in enzyme activity of ≥1.2-fold was achieved following DGJ treatment. Efficacy testing was carried out for over 1000 identified GLA variants in cell culture. Recent data suggest that about one-third of the variants comply with the amenability criteria. A recent study highlighted the impact of inter-assay variability on DGJ amenability, thereby reducing the power of the assay to predict eligible patients. This prompted us to compare our own α-galactosidase A enzyme activity data in a very similar in-house developed assay with those from the GLP assay. In an essentially retrospective approach, we reviewed 148 GLA gene variants from our former studies for which enzyme data from the GLP study were available and added novel data for 30 variants. We also present data for 18 GLA gene variants for which no data from the GLP assay are currently available. We found that both differences in experimental biochemical data and the criteria for the classification of amenability cause inter-assay discrepancy. We conclude that low baseline activity, borderline biochemical responsiveness, and inter-assay discrepancy are alarm signals for misclassifying a variant that must not be ignored. Furthermore, there is no solid basis for setting a minimum response threshold on which a clinical indication with DGJ can be justified.

A comparative study of different methods of estimating glomerular filtration rate in a subset of Filipinos with normal renal function

@#Kidney function is commonly quantified using the glomerular filtration rate (GFR). However, the gold standard of measuring GFR, inulin clearance, is not practical for daily clinical use. This study compares different methods of GFR estimation based on serum creatinine, plasma levels of 99mTc-diethylenetriaminepentaacetic acid (DTPA), and camera acquisition of 99mTc-DTPA uptake. Seventy-five Filipino adults between ages 20 and 35 presumed to have normal kidneys were recruited. Each subject underwent gamma camera scintigraphy using the Gates and Inoue protocols after receiving a dose of 99mTc-DTPA. Blood samples were subsequently extracted at 1 hour and 3 hours after tracer injection, and GFRs were calculated based on single- and double-plasma sampling methods (SPSM and DPSM, respectively). Serum creatinine was also measured to derive GFR using the CKD-EPI, MDRD, and CockroftGault equations. Each method was correlated with a reference standard (DPSM) based on accuracy, linear regression, bias, and precision. SPSM tends to overestimate GFR unlike the other methods evaluated, but otherwise shows the most favorable diagnostic performance among the six methods when correlated with DPSM. The Inoue method appears modestly better than the routinely utilized Gates protocol, though both methods exhibit lack of precision. The CKD-EPI formula shows similar, if not slightly superior, diagnostic properties to the MDRD and Cockroft-Gault equations, thus confirming its validity for use in this Filipino population subset. Further studies are needed, particularly involving SPSM and CKD-EPI, to determine the applicability of our findings in Filipinos with varying degrees of kidney function. It is hoped that modifications to these methods can be made that are tailor-fit to derive more accurate and population-specific GFR values.

How to evaluate agreement between quantitative measurements.

When a method comparison study is performed, the aim is to evaluate the agreement of measurements of different methods. We present the Bland-Altman plot with limits of agreement as the correct analysis methodology. We also discuss other scaled and unscaled indices of agreement and commonly used inappropriate approaches.

A framework for the meta-analysis of Bland-Altman studies based on a limits of agreement approach.

Bland-Altman method comparison studies are common in the medical sciences and are used to compare a new measure to a gold-standard (often costlier or more invasive) measure. The distribution of these differences is summarized by two statistics, the 'bias' and standard deviation, and these measures are combined to provide estimates of the limits of agreement (LoA). When these LoA are within the bounds of clinically insignificant differences, the new non-invasive measure is preferred. Very often, multiple Bland-Altman studies have been conducted comparing the same two measures, and random-effects meta-analysis provides a means to pool these estimates. We provide a framework for the meta-analysis of Bland-Altman studies, including methods for estimating the LoA and measures of uncertainty (i.e., confidence intervals). Importantly, these LoA are likely to be wider than those typically reported in Bland-Altman meta-analyses. Frequently, Bland-Altman studies report results based on repeated measures designs but do not properly adjust for this design in the analysis. Meta-analyses of Bland-Altman studies frequently exclude these studies for this reason. We provide a meta-analytic approach that allows inclusion of estimates from these studies. This includes adjustments to the estimate of the standard deviation and a method for pooling the estimates based upon robust variance estimation. An example is included based on a previously published meta-analysis. Copyright © 2017 John Wiley & Sons, Ltd.

Accurate and reproducible reconstruction of coronary arteries and endothelial shear stress calculation using 3D OCT: comparative study to 3D IVUS and 3D QCA.

BACKGROUND: Geometrically-correct 3D OCT is a new imaging modality with the potential to investigate the association of local hemodynamic microenvironment with OCT-derived high-risk features. We aimed to describe the methodology of 3D OCT and investigate the accuracy, inter- and intra-observer agreement of 3D OCT in reconstructing coronary arteries and calculating ESS, using 3D IVUS and 3D QCA as references. METHODS-RESULTS: 35 coronary artery segments derived from 30 patients were reconstructed in 3D space using 3D OCT. 3D OCT was validated against 3D IVUS and 3D QCA. The agreement in artery reconstruction among 3D OCT, 3D IVUS and 3D QCA was assessed in 3-mm-long subsegments using lumen morphometry and ESS parameters. The inter- and intra-observer agreement of 3D OCT, 3D IVUS and 3D QCA were assessed in a representative sample of 61 subsegments (n = 5 arteries). The data processing times for each reconstruction methodology were also calculated. There was a very high agreement between 3D OCT vs. 3D IVUS and 3D OCT vs. 3D QCA in terms of total reconstructed artery length and volume, as well as in terms of segmental morphometric and ESS metrics with mean differences close to zero and narrow limits of agreement (Bland-Altman analysis). 3D OCT exhibited excellent inter- and intra-observer agreement. The analysis time with 3D OCT was significantly lower compared to 3D IVUS. CONCLUSIONS: Geometrically-correct 3D OCT is a feasible, accurate and reproducible 3D reconstruction technique that can perform reliable ESS calculations in coronary arteries.

Issues and pitfalls in method comparison studies.

Method comparison studies are needed for validation of new methods of measurements, for example, non-invasive blood pressure measurements against standard reference methods. After a brief introduction into method comparison studies, this paper is organized in three sections. The first section deals with the widely, though not always appropriately, used classical Bland-Altman plot with the limits of agreement and its extensions with non-constant bias and multiple observations. The second section comments on other statistical approaches including correlation coefficients, linear regressions and sensitivities and specificities which are sometimes seen in method comparison studies. The third section proposes the usage of linear mixed effects models as a flexible way to deal with questions associated with method comparison studies.

Clinical validation of an algorithm for rapid and accurate automated segmentation of intracoronary optical coherence tomography images.

OBJECTIVES: The analysis of intracoronary optical coherence tomography (OCT) images is based on manual identification of the lumen contours and relevant structures. However, manual image segmentation is a cumbersome and time-consuming process, subject to significant intra- and inter-observer variability. This study aims to present and validate a fully-automated method for segmentation of intracoronary OCT images. METHODS: We studied 20 coronary arteries (mean length=39.7±10.0 mm) from 20 patients who underwent a clinically-indicated cardiac catheterization. The OCT images (n=1812) were segmented manually, as well as with a fully-automated approach. A semi-automated variation of the fully-automated algorithm was also applied. Using certain lumen size and lumen shape characteristics, the fully- and semi-automated segmentation algorithms were validated over manual segmentation, which was considered as the gold standard. RESULTS: Linear regression and Bland-Altman analysis demonstrated that both the fully-automated and semi-automated segmentation had a very high agreement with the manual segmentation, with the semi-automated approach being slightly more accurate than the fully-automated method. The fully-automated and semi-automated OCT segmentation reduced the analysis time by more than 97% and 86%, respectively, compared to manual segmentation. CONCLUSIONS: In the current work we validated a fully-automated OCT segmentation algorithm, as well as a semi-automated variation of it in an extensive "real-life" dataset of OCT images. The study showed that our algorithm can perform rapid and reliable segmentation of OCT images.

A "Step-Up" approach for harmonization.

According to the measurement paradigm, assays claiming the same measurand should give equivalent results within clinically relevant constraints. The key to accomplish this paradigm is standardization of assays to an SI-traceable reference measurement system. However, measurement results for complex analytes often are not expressed in SI-, but in arbitrary units, defined, for example, by an international conventional measurement standard. Traceability to such a standard mostly does not lead to among assay equivalence. To achieve this, the concept of harmonization has been proposed. We describe here the practical aspects involved with the "Step-Up" design. It essentially comprises a sequence of method comparisons with selected sets of commutable samples. The outcome of each phase allows to decide whether the step-up to the next phase can be set. The harmonization process itself uses a statistically valid location measure as surrogate reference measurement procedure. The design also foresees a protocol for sustaining the first-established harmonization status. For the design to be successful, it is essential that as many assays as possible are involved in the method comparison leading to the harmonization target, and that it can be shown that they sufficiently correlate to that target with consistency of performance over the covered measurement range.

Method comparison studies in medicine

Most of important variables measured in medicine are in numerical forms or continuous in nature. New instruments and tests are constantly being developed for the purpose of measuring various variables, with the aim of providing cheaper, non-invasive, more convenient and safe methods. When a new method of measurement or instrument is invented, the quality of the instrument has to be assessed. Agreement and reliability are both important parameters in determining the quality of an instrument. This article will discuss some issues related to methods comparison study in medicine for the benefit of medical professional and researcher. METHOD: This is a narrative review and this article review the most common statistical methods used to assess agreement and reliability of medical instruments that measure the same continuous outcome. The two methods discussed in detail were the Bland-Altman Limits of Agreement, and Intra-class Correlation Coefficient (ICC). This article also discussed some issues related to method comparison studies including the application of inappropriate statistical methods, multiple statistical methods, and the strengths and weaknesses of each method. The importance of appropriate statistical method in the analysis of agreement and reliability in medicine is also highlighted in this article. CONCLUSION: There is no single perfect method to assess agreement and reliability; however researchers should be aware of the inappropriate methods that they should avoid when analysing data in method comparison studies. Inappropriate analysis will lead to invalid conclusions and thus validated instrument might not be accurate or reliable. Consequently this will affect the quality of care given to a patient.