Comparison of inter subject variability and reproducibility of whole brain proton spectroscopy.

The aim of these studies was to provide reference data on intersubject variability and reproducibility of metabolite ratios for Choline/Creatine (Cho/Cr), N-acetyl aspartate/Choline (NAA/Cho) and N-acetyl aspartate/Creatine (NAA/Cr), and individual signal-intensity normalised metabolite concentrations of NAA, Cho and Cr. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical Metabolic Imaging and Data Acquisition Software (MIDAS) sequences were obtained along with standard structural imaging. Metabolite maps were created and regions of interest applied in normalised space. The baseline data from all 32 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were variable across the different brain regions. The within and between session reproducibility measurements were similar for Cho/Cr, NAA/Choline, Cho and Cr (11.8%, 11.4%, 14.3 and 10.6% vs. 11.9%, 11.4%, 13.5% and 10.5% respectively), but for NAA/Creatine and NAA between session reproducibility was lower (9.3% and 9.1% vs. 10.1% and 9.9%; p <0.05). This study provides additional reference data that can be utilised in interventional studies to quantify change within a single imaging session, or to assess the significance of change in longitudinal studies of brain injury and disease.TV Veenith was supported by clinical research training fellowship from the National Institute of Academic Anaesthesia and Raymond Beverly Sackler studentship. VFJN is supported by an NIHR academic clinical fellowship. JPC was supported by Wellcome trust project grant. DKM is supported by an NIHR Senior Investigator Award. This work was supported by a Medical Research Council (UK) Program Grant (Acute brain injury: heterogeneity of mechanisms, therapeutic targets and outcome effects (G9439390 ID 65883)), the UK National Institute of Health Research Biomedical Research Centre at Cambridge, and the Technology Platform funding provided by the UK Department of Health.This article was originally published in PLoS ONE (Veenith TV, Mada M, Carter E, Grossac J, Newcombe V, et al. (2014) Comparison of Inter Subject Variability and Reproducibility of Whole Brain Proton Spectroscopy. PLoS ONE 9(12): e115304. doi:10.1371/journal.pone.0115304

Within session and between session intraclass correlation coefficient for metabolites.

<p>Data displayed are mean (95% Confidence interval) intraclass correlation coefficient for metabolite ratios (Choline (Cho)/Creatine (Cr), N Acetyl Aspartate (NAA)/Cho, NAA/Cr) and metabolites (NAA, Cho and Cr) for mixed cortical and deep grey, and white matter brain regions.</p><p>Within session and between session intraclass correlation coefficient for metabolites.</p

Variability in N Acetyl Aspartate concentration.

<p>Box and whisker plot for N Acetyl Aspartate for a selection of the regions of interest (ROI), including right (R) and left (L) corticospinal (CST), anterior thalamic radiation (ATR), thalamus, putamen, frontal lobe, hippocampus and temporal lobe. The spread of data within each ROI reflects inter subject variation, while the difference between runs 1 – 2 and 3 – 4 reflects within session reproducibility, and the change from first to second sessions reflects between session reproducibility. The central lines in each box denote median values, the lower and upper boundaries the 25th and 75th centile, the error bars the 10th and 90th centile, and the closed circles outlying data points.</p

Intersubject variability of metabolite ratios for whole brain proton spectroscopy.

<p>Intersubject variability for Choline/Creatine, N-Acetyl aspartate (NAA)/Choline and N-Acetyl aspartate/Creatine. Data displayed were obtained in 32 subjects and show mean, standard deviation (SD) and percentage coefficient of variation (CoV%) for each region of interest (ROI).</p><p>Intersubject variability of metabolite ratios for whole brain proton spectroscopy.</p

Within session and between session variability of metabolites for whole brain proton spectroscopy.

<p><i>Individual region of interest measurements for within session reproducibility obtained in the first and second imaging sessions in 17 and 16 subjects respectively, and the between session reproducibility for those 22 subjects who underwent imaging at both sessions. Data displayed are standard deviation for metabolite ratios (Choline (Cho)/Creatine (Cr), N-Acetyl aspartate (NAA)/Choline and NAA/Cr.</i></p><p>Within session and between session variability of metabolites for whole brain proton spectroscopy.</p

Metabolite parametric maps.

<p>T1 weighted magnetic resonance image in MNI152 space (2mm resolution) with a representative spectra from the right thalamus and N-acetyl aspartate (NAA), Creatine (Cr) and Choline (Cho) signal-intensity normalised metabolite concentration parametric maps. PPM (parts per million).</p

Analysis of variance table for metabolite ratios.

<p>Data were obtained from 32 volunteers using the region of interest (ROI) template for and metabolite concentrations. (Choline – Cho, Creatine – Cr, N acetyl aspartate – NAA and DF – Degrees of freedom).</p><p>Analysis of variance table for metabolite ratios.</p

Variability in N Acetyl Aspartate/Creatine ratio measurements.

<p>Box and whisker plot for N Acetyl Aspartate/Creatine ratio for a selection of the regions of interest (ROI), including right (R) and left (L) corticospinal (CST), anterior thalamic radiation (ATR), thalamus, putamen, frontal lobe, hippocampus and temporal lobe. The spread of data within each ROI reflects inter subject variation, while the difference between runs 1 – 2 and 3 – 4 reflects within session reproducibility, and the change from first to second sessions reflects between session reproducibility. The central lines in each box denote median values, the lower and upper boundaries the 25th and 75th centile, the error bars the 10th and 90th centile, and the closed circles outlying data points.</p

Analysis of variance table for metabolite ratios.

<p>Data were obtained from 32 volunteers using the region of interest (ROI) template for metabolite ratios. (Choline – Cho, Creatine – Cr, N acetyl aspartate – NAA and DF – Degrees of freedom).</p><p>Analysis of variance table for metabolite ratios.</p