Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix® HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotyp

The size of the treatment effect: do patients and proxies agree?

Background: This study examined whether MS patients and proxy respondents agreed on change in disease impact, which was induced by treatment. This may be of interest in situations when patients suffer from limitations that interfere with reliable self-assessment, such as cognitive impairment.Methods: MS patients and proxies completed the Multiple Sclerosis Impact Scale (MSIS-29) before and after intravenous steroid treatment. Analyses focused on patient-proxy agreement between MSIS-29 change scores. Transition ratings were used to measure the patient's judgement of change and whether this change was reflected in the MSIS-29 change of patients and proxies. Receiver operating characteristic (ROC) analyses were also performed to examine the diagnostic properties of the MSIS-29 when completed by patients and proxies.Results: 42 patients and proxy respondents completed the MSIS-29 at baseline and follow-up. Patient-proxy differences between change scores on the physical and psychological MSIS-29 subscale were quite small, although large variability was found. The direction of mean change was in concordance with the transition ratings of the patients. Results of the ROC analyses of the MSIS-29 were similar when completed by patients (physical scale: AUC = 0.79, 95% CI: 0.65 - 0.93 and 0.66, 95% CI: 0.48 - 0.84 for the psychological scale) and proxies (physical scale: 0.80, 95% CI: 0.72 - 0.96 and 0.71, 95% CI: 0.56 - 0.87 for the psychological scale)Conclusion: Although the results need to be further explored in larger samples, these results do point towards possible use of proxy respondents to assess patient perceived treatment change at the group level

Longitudinal proxy measurements in multiple sclerosis: patient-proxy agreement on the impact of MS on daily life over a period of two years

Background: The use of self- report measurements in clinical settings is increasing. However, in patients with limitations that interfere with reliable self- assessment such as cognitive impairment or mood disturbances, as may be the case in multiple sclerosis ( MS), data collection might be problematic. In these situations, information obtained from proxy respondents ( e. g. partners) may replace self- ratings. The aim of this study was to examine the value of proxy ratings at separate points in time and to assess patient- proxy agreement on possible changes in disease impact of MS. Methods: Fifty- six MS patients and their partners completed the Multiple Sclerosis Impact Scale ( MSIS- 29) at baseline and follow- up, two years later. Patient- proxy agreement was assessed at both time points by calculating intraclass correlation coefficients ( ICCs), exact and global agreement and the mean directional differences between groups. Agreement of change over time was assessed by calculating ICCs between change scores. In parallel, global ratings of both patients and proxy respondents of the extent to which the patient had improved or deteriorated over the past two years were collected to validate possible changes on the MSIS- 29. Results: At both time points, agreement on the physical scale was higher than agreement on the psychological scale ( ICCs at baseline were 0.81 for the physical scale and 0.72 for the psychological scale; at follow- up, the ICC values were 0.86 and 0.65 respectively). At follow- up, statistically significant mean differences between patients and proxies were noted for the physical scale (- 4.8 +/- 12.7, p = 0.006) and the psychological scale (- 8.9 +/- 18.8, p = 0.001). Agreement between change scores on the MSIS- 29 was fair ( ICC < 0.60). Our analyses suggest that the validity of measuring changes over time might be better for proxy respondents compared to patients. Conclusion: Proxy respondents could act as a reliable source of information in cross- sectional studies. Moreover, results suggested that agreement on change over time might be better for proxy respondents compared to patients. Although this remarkable finding should be interpreted cautiously because of several limitations of the study, it does plead for further investigation of this important topic

Multiple sclerosis patients show lower bioavailable 25(OH)D and 1,25(OH)2D, but no difference in ratio of 25(OH)D/24,25(OH)2D and FGF23 concentrations

Vitamin D (VitD) insufficiency is common in multiple sclerosis (MS). VitD has possible anti-inflammatory effects on the immune system. The ratio between VitD metabolites in MS patients and the severity of the disease are suggested to be related. However, the exact effect of the bone-derived hormone fibroblast-growth-factor-23 (FGF23) and VitD binding protein (VDBP) on this ratio is not fully elucidated yet. Therefore, the aim is to study differences in total, free, and bioavailable VD metabolites and FGF23 between MS patients and healthy controls (HCs). FGF23, vitD (25(OH)D), active vitD (1,25(OH)2D), inactive 24,25(OH)D, and VDBP were measured in 91 MS patients and 92 HCs. Bioavailable and free concentrations were calculated. No difference in FGF23 (p = 0.65) and 25(OH)D/24.25(OH)2D ratio (p = 0.21) between MS patients and HCs was observed. Bioavailable 25(OH)D and bioavailable 1.25(OH)2D were lower (p < 0.01), while VDBP concentrations were higher in MS patients (p = 0.02) compared with HCs, specifically in male MS patients (p = 0.01). In conclusion, FGF23 and 25(OH)D/24.25(OH)2D did not differ between MS patients and HCs, yet bioavailable VitD concentrations are of potential clinical relevance in MS patients. The possible immunomodulating role of VDBP and gender-related differences in the VD-FGF23 axis in MS need further study

Multiple sclerosis patients show lower bioavailable 25(OH)D and 1,25(OH)2D, but no difference in ratio of 25(OH)D/24,25(OH)2D and FGF23 concentrations

Vitamin D (VitD) insufficiency is common in multiple sclerosis (MS). VitD has possible anti-inflammatory effects on the immune system. The ratio between VitD metabolites in MS patients and the severity of the disease are suggested to be related. However, the exact effect of the bone-derived hormone fibroblast-growth-factor-23 (FGF23) and VitD binding protein (VDBP) on this ratio is not fully elucidated yet. Therefore, the aim is to study differences in total, free, and bioavailable VD metabolites and FGF23 between MS patients and healthy controls (HCs). FGF23, vitD (25(OH)D), active vitD (1,25(OH)2D), inactive 24,25(OH)D, and VDBP were measured in 91 MS patients and 92 HCs. Bioavailable and free concentrations were calculated. No difference in FGF23 (p = 0.65) and 25(OH)D/24.25(OH)2D ratio (p = 0.21) between MS patients and HCs was observed. Bioavailable 25(OH)D and bioavailable 1.25(OH)2D were lower (p < 0.01), while VDBP concentrations were higher in MS patients (p = 0.02) compared with HCs, specifically in male MS patients (p = 0.01). In conclusion, FGF23 and 25(OH)D/24.25(OH)2D did not differ between MS patients and HCs, yet bioavailable VitD concentrations are of potential clinical relevance in MS patients. The possible immunomodulating role of VDBP and gender-related differences in the VD-FGF23 axis in MS need further study

Clinician-patient communication during the diagnostic workup: The ABIDE project

Introduction: We aimed to describe clinician-patient communication in the diagnostic process of memory clinics, specifically clinician behavior known to facilitate knowledgeable participation of patients during consultations. Methods: In this multicenter, observational study, we audio-recorded routine diagnostic consultations of 41 clinicians and 136 patients/caregivers at eight memory clinics. Patients/caregivers completed surveys after each audiotaped consultation. We used a study-specific coding scheme to categorize communication behavior. Results: Clinicians often provided information on (results of) diagnostic testing. They infrequently invited questions and/or checked understanding. Clinician behavior to involve patients in decision-making about diagnostic testing was limited. Of note, patients/caregivers rarely expressed their information or involvement preferences. Yet, approximately, one quarter of them would have liked to receive more information. Discussion: Involving patients more explicitly by means of shared decision-making could benefit the quality of care provided in memory clinics because it enables clinicians to attune the diagnostic workup to the individual patient's needs

Clinician-patient communication during the diagnostic workup: The ABIDE project

Introduction: We aimed to describe clinician-patient communication in the diagnostic process of memory clinics, specifically clinician behavior known to facilitate knowledgeable participation of patients during consultations. Methods: In this multicenter, observational study, we audio-recorded routine diagnostic consultations of 41 clinicians and 136 patients/caregivers at eight memory clinics. Patients/caregivers completed surveys after each audiotaped consultation. We used a study-specific coding scheme to categorize communication behavior. Results: Clinicians often provided information on (results of) diagnostic testing. They infrequently invited questions and/or checked understanding. Clinician behavior to involve patients in decision-making about diagnostic testing was limited. Of note, patients/caregivers rarely expressed their information or involvement preferences. Yet, approximately, one quarter of them would have liked to receive more information. Discussion: Involving patients more explicitly by means of shared decision-making could benefit the quality of care provided in memory clinics because it enables clinicians to attune the diagnostic workup to the individual patient's needs