Indirect comparisons of siponimod with fingolimod and ofatumumab in multiple sclerosis: assessing the feasibility of propensity score matching analyses

Background: Natalizumab and fingolimod were approved for treatment of active relapsing-remitting multiple sclerosis (RRMS) in Denmark in 2006 and 2011, respectively. There have been no randomized head-to-head studies comparing the two drugs. Objective: To compare the clinical efficacy of natalizumab and fingolimod. Methods: Data on all Danish RRMS patients who started their first second-line treatment with natalizumab or fingolimod from July 2011 to March 2015 were prospectively recorded in the Danish Multiple Sclerosis (MS) Treatment Register. The two treatment arms were 1:1 propensity score matched by baseline covariates using ‘nearest neighbour’ method. Results: Propensity score matching left 928 of 1309 RRMS cases, 464 in each treatment group. The on-treatment annualized relapse rate was 0.296 (95% confidence interval (CI): 0.26–0.34) for natalizumab and 0.307 (95% CI: 0.27–0.35) for fingolimod. The adjusted relapse rate ratio was 0.93 (95% CI: 0.74–1.17; p = 0.53). Mean time to first relapse was 2.55 and 2.56 years, respectively ( p = 0.76). There was no difference in change of Expanded Disability Status Scale (EDSS). Conclusion: We found no differences in clinical disease activity between natalizumab- and fingolimod-treated RRMS patients in this real-life observational study. However, the lack of magnetic resonance imaging (MRI) data for the propensity score matching may conceal a higher efficacy of natalizumab.

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Extensive Healthy Donor Age/Gender Adjustments and Propensity Score Matching Reveal Physiology of Multiple Sclerosis through Immunophenotyping

10.1101/2020.05.26.20113902 ◽

2020 ◽

Author(s):

Paavali A. Hannikainen ◽

Peter Kosa ◽

Christopher Barbour ◽

Bibiana Bielekova

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Propensity Score ◽

Propensity Score Matching ◽

Immune Cells ◽

Biological Fluids ◽

Physiological Age ◽

High Efficacy ◽

Adaptive Immune Cells ◽

Cellular Abnormalities

AbstractQuantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal fluid (CSF) flow cytometry in neuroimmunological disorders such as multiple sclerosis (MS), previous studies did not contain enough healthy donors (HD) to derive age- and gender-related normative data and sufficient heterogeneity of other inflammatory neurological diseases (OIND) controls to identify MS specific changes.The goals of this blinded, training and validation study of MS patients and embedded controls, representing 1240 prospectively-acquired paired CSF/blood samples from 588 subjects was: 1. To define physiological age/gender-related changes in CSF cells; 2. To define/validate cellular abnormalities in blood and CSF of untreated MS through disease duration (DD) and determine which are MS-specific; 3. To compare effect(s) of low-efficacy (i.e., interferon-beta [IFN-beta] and glatiramer acetate [GA]) and high-efficacy drugs (i.e., natalizumab, daclizumab and ocrelizumab) on MS-related cellular abnormalities using propensity score matching.Physiological gender differences are less pronounced in the CSF compared to blood, while age- related changes suggest decreased immunosurveillance of CNS by activated, HLA-DR+ T cells associated with natural aging. Results from patient samples support concept of MS being immunologically single disease evolving in time. Initially, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. With progression, T cells (CD8+ > CD4+), NK cells and myeloid dendritic cells are depleted from blood as they continue to accumulate, together with B cells, in the CSF and migrate to CNS tissue forming compartmentalized inflammation. All MS drugs inhibit non-physiological accumulation of immune cells in the CSF. While low efficacy drugs tend to normalize it, high efficacy drugs overshoot some aspects of CSF physiology suggesting impairment of CNS immunosurveillance. Comparable inhibition of MS-related CSF abnormalities advocates changes within CNS parenchyma responsible for differences in drug’s efficacy on MS disability progression.Video summarizing all results may become useful educational tool.

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Extensive Healthy Donor Age/Gender Adjustments and Propensity Score Matching Reveal Physiology of Multiple Sclerosis Through Immunophenotyping

Frontiers in Neurology ◽

10.3389/fneur.2020.565957 ◽

2020 ◽

Vol 11 ◽

Author(s):

Paavali A. Hannikainen ◽

Peter Kosa ◽

Christopher Barbour ◽

Bibiana Bielekova

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Propensity Score ◽

Propensity Score Matching ◽

Immune Cells ◽

Biological Fluids ◽

Physiological Age ◽

High Efficacy ◽

Adaptive Immune Cells ◽

Cellular Abnormalities

Quantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal fluid (CSF) flow cytometry in neuroimmunological disorders, such as multiple sclerosis (MS), previous studies did not contain enough healthy donors (HD) to derive age- and gender-related normative data and sufficient heterogeneity of other inflammatory neurological disease (OIND) controls to identify MS specific changes.The goals of this blinded training and validation study of MS patients and embedded controls, representing 1,240 prospectively acquired paired CSF/blood samples from 588 subjects was (1) to define physiological age-/gender-related changes in CSF cells, (2) to define/validate cellular abnormalities in blood and CSF of untreated MS through disease duration (DD) and determine which are MS-specific, and (3) to compare effect(s) of low-efficacy (i.e., interferon-beta [IFN-beta] and glatiramer acetate [GA]) and high-efficacy drugs (i.e., natalizumab, daclizumab, and ocrelizumab) on MS-related cellular abnormalities using propensity score matching.Physiological gender differences are less pronounced in the CSF compared to blood, and age-related changes suggest decreased immunosurveillance of CNS by activated HLA-DR+T cells associated with natural aging. Results from patient samples support the concept of MS being immunologically single disease evolving in time. Initially, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. With progression, T cells (CD8+ > CD4+), NK cells, and myeloid dendritic cells are depleted from blood as they continue to accumulate, together with B cells, in the CSF and migrate to CNS tissue, forming compartmentalized inflammation. All MS drugs inhibit non-physiological accumulation of immune cells in the CSF. Although low-efficacy drugs tend to normalize it, high-efficacy drugs overshoot some aspects of CSF physiology, suggesting impairment of CNS immunosurveillance. Comparable inhibition of MS-related CSF abnormalities advocates changes within CNS parenchyma responsible for differences in drug efficacy on MS disability progression.Video summarizing all results may become useful educational tool.

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Superiority of serum NFL in predicting Multiple Sclerosis severity

10.1101/2021.05.07.21256836 ◽

2021 ◽

Author(s):

Peter Kosa ◽

Ruturaj R Masvekar ◽

Mika Komori ◽

Jonathan Phillips ◽

Vighnesh Ramesh ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Linear Regression ◽

Propensity Score ◽

Propensity Score Matching ◽

Validation Cohort ◽

Cns Injury ◽

Neurofilament Light Chain ◽

Cord Injury ◽

Mlr Model

Objective: Serum neurofilament light chain (sNFL) is becoming an important biomarker of neuroaxonal injury. While sNFL correlates with cerebrospinal fluid NFL (cNFL), 40-60% of variance remains unexplained. Assuming that for diseases of the central nervous system (CNS), such as multiple sclerosis (MS), the cNFL better reflects CNS injury, our goal was to develop and validate adjustment of sNFL for relevant confounders, to strengthen cNFL-sNFL correlations. Methods: We used 1,378 matched cNFL-sNFL pairs divided into training and validation cohort with matching data on 11 confounders, neuroexam, and magnetic resonance imaging (MRI). The effect of confounders on cNFL-sNFL relationship was tested using multiple linear regression (MLR) model. Propensity score matching was used to identify effect of spinal cord damage on sNFL levels. Results: In the training cohort (n=898) we correlated 11 confounders with the residuals from cNFL-sNFL linear regression. Four non-overlapping confounders explaining highest proportion of variance (12%: age, 8.7%: blood urea nitrogen, 3%: alkaline phosphatase, and 3.9%: weight) were used in MLR model. The model strengthened the cNFL-sNFL correlation from R2 = 0.52 to 0.64 in the independent validation cohort and strengthened correlation of adjusted sNFL with number of contrast-enhancing lesions (from R2 0.11 to 0.18). However, only sNFL, but not cNFL correlated with MS severity outcomes. Using propensity score matching, we demonstrated that subjects with proportionally higher sNFL to cNFL levels have significantly higher clinical and radiological evidence of spinal cord injury. Interpretation: Superiority of sNFL likely resides in the release of NFL from axons of lower motor or dorsal ganglia neurons directly to blood.

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A propensity-matched comparison of long-term disability worsening in patients with multiple sclerosis treated with dimethyl fumarate or fingolimod

Therapeutic Advances in Neurological Disorders ◽

10.1177/17562864211021177 ◽

2021 ◽

Vol 14 ◽

pp. 175628642110211

Author(s):

Amber Salter ◽

Samantha Lancia ◽

Gary Cutter ◽

Ruth Ann Marrie ◽

Jason P. Mendoza ◽

...

Keyword(s):

Multiple Sclerosis ◽

Sensitivity Analysis ◽

Propensity Score ◽

Propensity Score Matching ◽

Cox Regression ◽

Dimethyl Fumarate ◽

The United States ◽

Significant Difference ◽

Previously Treated

Background: Although the aggregate of data among patients with multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY), most studies have not assessed long-term worsening of disability. We compared long-term disability worsening over 5 years, as assessed by the Patient-Determined Disease Steps (PDDS), among participants with MS treated with DMF or FTY. Methods: We identified individuals in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry who had relapsing-remitting MS (RRMS), residing in the United States (Spring 2011 to Spring 2018), who initiated treatment with DMF ( n = 689) or FTY ( n = 565) and had ⩾1 year follow-up on index treatment. Participants receiving DMF who were previously treated with FTY and those on FTY previously treated with DMF were excluded. Propensity score matching at baseline was used to match FTY-treated to DMF-treated participants. Time to 6-month confirmed disability worsening (⩾1-point increase on PDDS, sustained for ⩾6 months) was estimated using Cox regression. A sensitivity analysis was conducted to account for differences in the duration of index exposure between DMF and FTY groups. Results: After propensity score matching, 468 DMF-treated participants were matched with 468 FTY-treated participants. Median treatment duration was 3.0 years for DMF and 4.0 years for FTY. At 5 years, 68.3% [95% confidence interval (CI): 62.4–73.5] of DMF-treated participants and 63.3% (95% CI: 59.6–70.1) treated with FTY were free from 6-month confirmed PDDS worsening [hazard ratio (HR) 1.01 (95% CI: 0.79–1.28); p = 0.95]. Results were similar in the sensitivity analysis: 70.5% (95% CI: 61.8–77.6) of DMF-treated participants and 72.7% (95% CI: 65.4–78.6) of FTY-treated participants were free from 6-month confirmed PDDS worsening [HR: 1.04 (95% CI: 0.71–1.51); p = 0.84]. Conclusions: In participants with MS from the NARCOMS registry, there was no significant difference in confirmed disability (PDDS) worsening over 5 years between those treated with DMF versus FTY.

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Differences in employment concerns between Hispanic and Caucasian persons with multiple sclerosis: A propensity score matching analysis

Journal of Vocational Rehabilitation ◽

10.3233/jvr-201115 ◽

2020 ◽

pp. 1-10

Author(s):

Phillip D. Rumrill ◽

Jennifer Sánchez ◽

Jia-Rung Wu ◽

Stuart Rumrill ◽

Kanako Iwanaga ◽

...

Keyword(s):

Multiple Sclerosis ◽

Propensity Score ◽

Propensity Score Matching ◽

Hispanic Americans ◽

Rehabilitation Counseling ◽

Legal Rights ◽

Group Differences ◽

Future Research ◽

Propensity Score Matching Analysis ◽

Caucasian Americans

BACKGROUND: Little is known about the experiences and concerns of Hispanic Americans with multiple sclerosis (MS), especially how their experiences and concerns compare to those of Caucasian Americans with MS. OBJECTIVE: The purpose of this study was to examine differences in satisfaction with the overall employment situation between two matched samples of adults with MS, namely, Hispanics and Caucasians. METHODS: Participants in this study responded to a national survey of the employment and community living concerns of people with MS. A propensity score matching (PSM) procedure was used to match participants based on demographic and MS-related variables. RESULTS: A two-sample Hotelling T 2 test revealed no statistically significant between-group differences on satisfaction regarding fair treatment in the workplace but between-group differences were observed on satisfaction regarding legal rights and personal-environmental resources related to work. CONCLUSIONS: Implications for future research and clinical practice in rehabilitation counseling in the COVID-19 era are discussed.

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Besondere Förderung von Kern- kompetenzen an Spezialgymnasien?

Zeitschrift für Pädagogische Psychologie ◽

10.1024/1010-0652/a000001 ◽

2010 ◽

Vol 24 (1) ◽

pp. 5-22 ◽

Cited By ~ 7

Author(s):

Jürgen Baumert ◽

Michael Becker ◽

Marko Neumann ◽

Roumiana Nikolova

Keyword(s):

Propensity Score ◽

Propensity Score Matching

Der vorliegende Beitrag geht der Frage nach, ob Schülerinnen und Schüler, die nach der vierten Klasse in Berlin in ein grundständiges Gymnasium wechseln, in Abhängigkeit vom Profil des besuchten Gymnasiums im Vergleich zu Grundschülern mit vergleichbaren Lernvoraussetzungen unterschiedliche Lernzuwächse im Leseverständnis, in Mathematik und Englisch erreichen. Auf der Datengrundlage der ELEMENT-Studie wurde die Leistungsentwicklung von Schülerinnen und Schülern an grundständigen Gymnasien (N = 1758) und Grundschulen (N = 3169) während der 5. und 6. Jahrgangsstufe mithilfe von Propensity Score Matching-Analysen (PSM) modelliert. Nach Kontrolle von leistungsrelevanten Unterschieden zwischen den Schülergruppen am Ende der 4. Jahrgangsstufe zeigten sich für das Leseverständnis am Ende der 6. Klasse keine statistisch signifikanten Unterschiede. Für die Mathematikleistung ließen sich Unterschiede lediglich zugunsten eines grundständigen Gymnasiums, das zum Untersuchungszeitpunkt noch kein spezifisches Profil entwickelt hatte, nachweisen. In der Domäne Englisch, in der die curricularen Unterschiede zwischen den Schulzweigen stärker akzentuiert sind, wurden positive Ergebnisse im Vergleich zu den Grundschulen für die so genannten Schnellläuferzüge, die englisch-bilingualen Klassen und das grundständige Gymnasium ohne spezifisches Profil ermittelt. Die Lernstände am Ende der 6. Klasse in den altsprachlichen Gymnasien fielen dagegen im Vergleich zu den Grundschulen geringer aus. Die Befunde widersprechen der Annahme, dass mit dem frühen Übergang auf ein grundständiges Gymnasium automatisch eine besondere Förderung der Lesefähigkeit und des mathematischen Verständnisses besonders leistungsfähiger Schülerinnen und Schüler erreicht werde. Die Ergebnisse zu den Englischleistungen weisen hingegen darauf hin, dass Unterschiede in der Leistungsentwicklung auftreten können, sofern die Aufteilung auf Schulen mit unterschiedlichen Bildungsprogrammen mit curricularen Unterschieden im Unterricht einhergeht. Methodische und inhaltliche Implikationen der Befunde und Grenzen ihrer Generalisierbarkeit werden diskutiert.

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Validating Four Standard Scales in Spiritually Practicing and Nonpracticing Samples Using Propensity Score Matching

European Journal of Psychological Assessment ◽

10.1027/1015-5759.24.3.165 ◽

2008 ◽

Vol 24 (3) ◽

pp. 165-173 ◽

Cited By ~ 8

Author(s):

Niko Kohls ◽

Harald Walach

Keyword(s):

Propensity Score ◽

Propensity Score Matching ◽

Repeated Measures ◽

Propensity Scores ◽

Total Sample ◽

Experimental Manipulation ◽

Brief Symptom Inventory ◽

Time Interaction ◽

Social Support Scale ◽

Lower Test

Validation studies of standard scales in the particular sample that one is studying are essential for accurate conclusions. We investigated the differences in answering patterns of the Brief-Symptom-Inventory (BSI), Transpersonal Trust Scale (TPV), Sense of Coherence Questionnaire (SOC), and a Social Support Scale (F-SoZu) for a matched sample of spiritually practicing (SP) and nonpracticing (NSP) individuals at two measurement points (t1, t2). Applying a sample matching procedure based on propensity scores, we selected two sociodemographically balanced subsamples of N = 120 out of a total sample of N = 431. Employing repeated measures ANOVAs, we found an intersample difference in means only for TPV and an intrasample difference for F-SoZu. Additionally, a group × time interaction effect was found for TPV. While Cronbach’s α was acceptable and comparable for both samples, a significantly lower test-rest-reliability for the BSI was found in the SP sample (rSP = .62; rNSP = .78). Thus, when researching the effects of spiritual practice, one should not only look at differences in means but also consider time stability. We recommend propensity score matching as an alternative for randomization in variables that defy experimental manipulation such as spirituality.

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