Dealing with Treatment-confounder Feedback and Sparse Follow-up in Longitudinal studies - Application of a Marginal Structural Model in a Multiple Sclerosis Cohort

2020 ◽  
Author(s):  
Mohammad Ehsanul Karim ◽  
Helen Tremlett ◽  
Feng Zhu ◽  
John Petkau ◽  
Elaine Kingwell
Keyword(s):  
Multiple Sclerosis ◽  
Disease Progression ◽  
Multiple Imputation ◽  
Structural Model ◽  
Potential Effect ◽  
Hazard Ratio ◽  
Survival Advantage ◽  
Marginal Structural Model ◽  
Beta Interferon

Abstract The beta-interferons are widely prescribed platform therapies for patients with multiple sclerosis (MS). We accessed a cohort of patients with relapsing onset MS from British Columbia, Canada (1995-2013) to examine the potential survival advantage associated with beta-interferon exposure using a marginal structural model. Accounting for potential treatment-confounder feedback between comorbidity, MS disease progression and beta-interferon exposure, we found an association between beta-interferon exposure of at least 6 contiguous months and improved survival (hazard ratio (HR) = 0.63, 95% confidence interval 0.47-0.86). We also assessed potential effect modifications by sex, baseline age or baseline disease duration, and found these factors to be important effect modifiers. Sparse follow-up due to variability in patient contact with the health system is one of the biggest challenges in longitudinal analyses. We considered several single-level and multi-level multiple imputation approaches to deal with sparse follow-up and disease progression information; both types of approach produced similar estimates. Compared to ad hoc imputation approaches, such as linear interpolation (HR: 0.63), and last observation carried forward (HR: 0.65), all multiple imputation approaches produced a smaller hazard ratio (HR: 0.53), although the direction of effect and conclusions drawn concerning the survival advantage remained the same.

Brain atrophy evolution and lesion load accrual in multiple sclerosis: a 2-year follow-up study

2008 ◽  
Vol 15 (2) ◽  
pp. 204-211 ◽  
Author(s):  
G Tedeschi ◽  
D Dinacci ◽  
M Comerci ◽  
L Lavorgna ◽  
G Savettieri ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Disease Progression ◽  
Gray Matter ◽  
Brain Atrophy ◽  
Disease Duration ◽  
Lesion Load ◽  
Whole Brain ◽  
Gray Matter Atrophy

Background To investigate in a large cohort of patients with multiple sclerosis (MS), lesion load and atrophy evolution, and the relationship between clinical and magnetic resonance imaging (MRI) correlates of disease progression. Methods Two hundred and sixty-seven patients with MS were studied at baseline and two years later using the same MRI protocol. Abnormal white matter fraction, normal appearing white matter fraction, global white matter fraction, gray matter fraction and whole brain fraction, T2-hyperintense, and T1-hypointense lesions were measured at both time points. Results The majority of patients were clinically stable, whereas MRI-derived brain tissue fractions were significantly different after 2 years. The correlation between MRI data at baseline and their variation during the follow-up showed that lower basal gray matter atrophy was significantly related with higher progression of gray matter atrophy during follow-up. The correlation between MRI parameters and disease duration showed that gray matter atrophy rate decreased with increasing disease duration, whereas the rate of white matter atrophy had a constant pattern. Lower basal gray matter atrophy was associated with increased probability of developing gray matter atrophy at follow-up, whereas gray matter atrophy progression over 2 years and new T2 lesion load were risk factors for whole brain atrophy progression. Conclusions In MS, brain atrophy occurs even after a relatively short period of time and in patients with limited progression of disability. Short-term brain atrophy progression rates differ across tissue compartments, as gray matter atrophy results more pronounced than white matter atrophy and appears to be a early phenomenon in the MS-related disease progression.

Increased plasma 8,12-iso-iPF2alpha- VI levels in relapsing multiple sclerosis patients are not predictive of disease progression

2012 ◽  
Vol 18 (8) ◽  
pp. 1092-1098 ◽  
Author(s):  
CE Teunissen ◽  
M Sombekke ◽  
L van Winsen ◽  
J Killestein ◽  
F Barkhof ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Sclerosis ◽  
Disease Progression ◽  
Plasma Levels ◽  
Lesion Load ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients ◽  
In Cis

Background: Oxidative stress plays an important role in multiple sclerosis (MS). Isoprostanes are biomarkers for oxidative stress and have been related to neurological disease progression. Objective: To study whether plasma isoprostane levels were related to disease progression in MS. Methods: Plasma levels of 8,12-iso-iPF2alpha-VI were determined in 17 patients with clinically isolated syndrome (CIS), 41 relapsing–remitting MS (RRMS) patients and 5 primary progressive MS (PPMS) patients and related to MRI and clinical disease parameters. Results: Isoprostane levels were similar in CIS (60.9, interquartile range (IQR): 47.7–77.7 pg/ml) and RRMS patients (65.3, IQR: 51.9–82.8 pg/ml). The plasma levels were lower in PPMS patients (42.5, IQR: 37.1–49.9) pg/ml, p<0.05) compared to CIS and RRMS patients in this cohort, which was not confirmed in a second cohort. Baseline isoprostane levels were not related to clinical progression defined by conversion form CIS to RRMS or change in Expanded Disability Status Scale (EDSS) or MS Functional Composite (MSFC) scores during six years of follow-up (CIS + RRMS), nor to change in volume of gadolinium enhancing lesions, T2 lesion load or T1 hypointense lesion load during 2.8 years of follow-up (CIS + RRMS). Conclusion: These results do not support a strong role of 8,12-iso-iPF2alpha-VI in the prediction of disease progression in MS.

scholarly journals An assessment of the potential miscalibration of cardiovascular disease risk predictions caused by a secular trend in cardiovascular disease in England

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Alexander Pate ◽  
Tjeerd van Staa ◽  
Richard Emsley
Keyword(s):  
Cardiovascular Disease ◽  
Risk Prediction ◽  
Structural Model ◽  
Validation Cohort ◽  
Secular Trend ◽  
Marginal Structural Model ◽  
Cvd Risk ◽  
Model Framework ◽  
Statin Use

Abstract Background A downwards secular trend in the incidence of cardiovascular disease (CVD) in England was identified through previous work and the literature. Risk prediction models for primary prevention of CVD do not model this secular trend, this could result in over prediction of risk for individuals in the present day. We evaluate the effects of modelling this secular trend, and also assess whether it is driven by an increase in statin use during follow up. Methods We derived a cohort of patients (1998–2015) eligible for cardiovascular risk prediction from the Clinical Practice Research Datalink with linked hospitalisation and mortality records (N = 3,855,660). Patients were split into development and validation cohort based on their cohort entry date (before/after 2010). The calibration of a CVD risk prediction model developed in the development cohort was tested in the validation cohort. The calibration was also assessed after modelling the secular trend. Finally, the presence of the secular trend was evaluated under a marginal structural model framework, where the effect of statin treatment during follow up is adjusted for. Results Substantial over prediction of risks in the validation cohort was found when not modelling the secular trend. This miscalibration could be minimised if one was to explicitly model the secular trend. The reduction in risk in the validation cohort when introducing the secular trend was 35.68 and 33.24% in the female and male cohorts respectively. Under the marginal structural model framework, the reductions were 33.31 and 32.67% respectively, indicating increasing statin use during follow up is not the only the cause of the secular trend. Conclusions Inclusion of the secular trend into the model substantially changed the CVD risk predictions. Models that are being used in clinical practice in the UK do not model secular trend and may thus overestimate the risks, possibly leading to patients being treated unnecessarily. Wider discussion around the modelling of secular trends in a risk prediction framework is needed.

Hexosylceramides as intrathecal markers of worsening disability in multiple sclerosis

2014 ◽  
Vol 21 (10) ◽  
pp. 1271-1279 ◽  
Author(s):  
Antonio Checa ◽  
Mohsen Khademi ◽  
Daniel G Sar ◽  
Jesper Z Haeggström ◽  
Jon O Lundberg ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Progression ◽  
Neurological Diseases ◽  
Control Groups ◽  
Promising Candidate ◽  
Fatty Acid Chain ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Liquid Chromatography Tandem Mass

Background: Sphingolipids are important components of neurons and the myelin sheath whose levels are altered in multiple sclerosis (MS). Objectives: We aimed to determine if cerebrospinal fluid (CSF) sphingolipids can be used as markers of MS disease progression. Methods: Using liquid chromatography tandem mass spectrometry, we analysed sphingolipids in CSF from 134 individuals. The MS group included 65 patients divided into 41 relapsing–remitting MS (RRMS) and 24 progressive MS (ProgMS). In addition, a group of 13 early MS/clinically isolated syndrome (EarlyMS) and two control groups consisting of 38 individuals with other neurological diseases (OND) and 18 OND with signs of inflammation (iOND) were analysed. A follow-up study included 17 additional RRMS patients sampled at two time points 4.7±1.7 years apart. Results: Levels of sphingomyelin (SM)- and hexosylceramide (HexCer)-derived sphingolipids increased in the CSF of patients with MS independently of the fatty acid chain length in RRMS ( p<0.05). Levels of palmitic acid (16:0)-containing HexCer (HexCer16:0) increased significantly in ProgMS compared with the OND ( p<0.001), iOND ( p<0.05) and EarlyMS ( p<0.01) groups and correlated with Expanded Disability Status Scale in RRMS in both studies ( p=0.048; p=0.027). Conclusion: HexCer16:0 is a promising candidate marker of disease progression in MS, especially in RRMS.

scholarly journals Clinical Application of Autologous Adipose Stem Cells in Patients with Multiple Sclerosis: Preliminary Results

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Adam Stepien ◽  
Natalia L. Dabrowska ◽  
Marzena Maciagowska ◽  
Renata Piusinska Macoch ◽  
Aleksandra Zolocinska ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Progression ◽  
Progression Free Survival ◽  
Entire Group ◽  
Adipose Stem Cell ◽  
Free Survival ◽  
Inflammatory Phase ◽  
Efficacy Measures ◽  
One Year

The clinical outcome of autologous adipose stem cell (ASC) treatment of patients with multiple sclerosis (MS) was investigated following one year of observation.Methods. The clinical and MRI outcomes of 16 ASC-treated patients with RRMS and SPMS are reported after a one-year follow-up period.Results.At 18 months of follow-up, some patients showed “enticing” improvements on some exploratory efficacy measures, although a significant benefit was not observed for any measure across the entire group. Neither the progression of disability nor relapses were observed in any cases. In four patients, we found new gadolinium+ (Gd+) lesions on MRI. Our results indicate that ASC therapy is safe and does not produce any substantial side effects. Disease progression-free survival (PFS) of 18 months was seen in all patients with RRMS and SPMS. In these patients, EDSS scores did not progress above baseline scores. Gd-enhancing lesions were observed in two cases with RRMS, but these patients did not exhibit changes in EDSS score.Conclusion. Intrathecal treatment with ASCs is an attractive form of therapy for patients with MS but should be reserved for cases with aggressive disease progression, for cases that are still in the inflammatory phase, and for the malignant form.

scholarly journals Serum contactin-1 as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis

2021 ◽  
pp. 135245852110100
Author(s):  
Zoë YGJ van Lierop ◽  
Luuk Wieske ◽  
Marleen JA Koel-Simmelink ◽  
Madhurima Chatterjee ◽  
Iris Dekker ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Progression ◽  
Odds Ratio ◽  
Prognostic Biomarker ◽  
Disability Progression ◽  
Lower Baseline ◽  
Relapsing Remitting ◽  
Natalizumab Treatment

Background: Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS). Objective: To study serum contactin-1 (sCNTN1) as a novel biomarker for disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients. Methods: Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria. Results: Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04–1.45) ( p = 0.017) for progression during follow-up. Conclusion: Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.

Mini-Autologous Hematopoietic Stem Cell Transplantations as a New Treatment Modality for Multiple Sclerosis Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4454-4454
Author(s):  
Andrei A Novik ◽  
Vladimir Y Melnichenko ◽  
Denis A Fedorenko ◽  
Ruslana V Kruglina ◽  
Tatiana I Ionova ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Stem Cell ◽  
Disease Progression ◽  
Hematopoietic Stem Cell ◽  
High Dose ◽  
Base Line ◽  
Hematopoietic Stem ◽  
Patient Reported ◽  
Multiple Sclerosis Patients

Abstract Conventional therapies do not provide satisfactory control of multiple sclerosis (MS) due to their inability to eradicate self-specific T cell clones. Recently, high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) was proposed as a new and promising therapy for MS patients. Taking into account the information about high risk of transplant-related mortality and severe side effects of myeloablative conditioning regimens, the rationale to use non-myeloablative regimens sounds reasonable. The goal of our research was to study the safety and efficacy of mini-AHSCT in MS patients. Fifty three patients with MS (secondary progressive – 16 patients, primary progressive – 12, progressive-relapsing – 3 and relapsing-remitting – 22) were included in this study (mean age - 30.0, range: 17–47; male/female – 23/30). The conditioning regimen included reduced or modified BEAM. Median EDSS at base-line was 4.0 (range 1.5 – 8.0). The median follow-up duration was 7 months (range 6 – 20 months). Neurological and quality of Life (QoL) evaluation was performed at baseline, at discharge, at 3, 6, 9, 12 months, and every 6 months thereafter AHSCT. MRI examinations were performed at baseline, at 6, 12 months, and at the end of follow-up. Transplantation procedure was well tolerated by the patients with no transplant-related deaths. Among 29 patients included in the efficacy analysis 15 patients (52%) experienced clinical stabilization; 14 (48%) – improvement. EDSS improved by 0.5 points in 11 patients, by 1.0 points in 2 patients, by 2.0 points in 1 patient. One patient progressed after 6 months stabilization. No active, new or enlarging lesions were registered in patients without disease progression. Out of 27 patients included in QoL analysis 21 exhibited QoL improvement and 4 – stabilization during the follow-up; QoL worsened in 2 patients. All the patients without disease progression were off therapy throughout the post-transplant period. In conclusion, mini-AHSCT may be considered as a new, safe and effective treatment for MS. The results of mini-AHSCT in MS patients are promising both in terms of clinical and patient-reported outcomes. The collection of long-term follow-up data is worthwhile to verify these findings. The rationale of evolution from myeloablative to non-myeloablative transplant regimens should be confirmed by the further studies.

Metabolic response evaluated by 18F-FDG PET/CT as a potential tool in identifying subgroup of patients with advanced non-small cell lung cancer for immediate maintenance treatment after first-line chemotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18148-e18148
Author(s):  
Su-Hee Cho ◽  
Silvia Park ◽  
Lee Chun Park ◽  
Jun Ho Ji ◽  
Ji Yean Lee ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Disease Progression ◽  
Predictive Factors ◽  
Fdg Pet ◽  
Small Cell ◽  
Hazard Ratio ◽  
Small Cell Lung ◽  
First Line ◽  
Factors Associated

e18148 Background: Platinum-based doublet regimens have been a mainstay of first-line treatment with advanced non–small cell lung cancerand ans the present guidelines recommend four to six cycles and waiting until disease progression. However subsequent disease progression is often rapid so sequential and maintenance therapy was performed in many studies. But almost studies didn’t show the significant survival benefit. Thus, we supposed that FDG PET may be a useful to determine what subgroup have better prognosis Methods: We founded out fifty-two patients who diagnosed to underwent baseline and follow-up FDG PET after 4 cycles of first-line platinum based chemotherapy. We obstained patient's characteristics and response rate (RR), progression-free survival (PFS), and overall survival (OS) from the medical records. And we checked maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG) from FDG PET. Results: Univariate analysis showed that MTV (hazard ratio = 1.032, P = 0.007) and TLG (hazard ratio = 1.030, P = 0.001) were independent predictive factors associated with decreased PFS and gender (hazard ratio = 5.248, P = 0.026), smoking (hazard ratio = 7.798, P = 0.006), EGFR mutation (hazard ratio = 0.106, P = 0.030) and TLG (hazard ratio = 1.027, P = 0.046) were significant predictors of OS. Histopathology was a marginally significant prognostic factor (P = 0.058). Multivariate analysis showed that TLG (hazard ratio = 1.030, P = 0.001) were independent predictive factors associated with decreased PFS and smoking (hazard ratio = 10.588, P = 0.002) and TLG (hazard ratio = 1.043, P = 0.007) were significant predictors of OS. Conclusions: There is a correlation between TLG and PFS significantly. We suggest that follow-up FDG PET after 4 cycle chemotherpy can help to discriminate patients who have benefit through sequential and maintenance therapy. But it need specific value for clinical use, so more large-scale prospective study is warranted.

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