Blinded sample size recalculation in multiple composite population designs with normal data and baseline adjustments.

The increasing interest in subpopulation analysis has led to the development of various new trial designs and analysis methods in the fields of personalized medicine and targeted therapies. In this paper, subpopulations are defined in terms of an accumulation of disjoint population subsets and will therefore be called composite populations. The proposed trial design is applicable to any set of composite populations, considering normally distributed endpoints and random baseline covariates. Treatment effects for composite populations are tested by combining p-values, calculated on the subset levels, using the inverse normal combination function to generate test statistics for those composite populations while the closed testing procedure accounts for multiple testing. Critical boundaries for intersection hypothesis tests are derived using multivariate normal distributions, reflecting the joint distribution of composite population test statistics given no treatment effect exists. For sample size calculation and sample size, recalculation multivariate normal distributions are derived which describe the joint distribution of composite population test statistics under an assumed alternative hypothesis. Simulations demonstrate the absence of any practical relevant inflation of the type I error rate. The target power after sample size recalculation is typically met or close to being met.

Systematic Assessment of 10 Biomarker Candidates Focusing on α-Synuclein-Related Disorders.

BACKGROUND: Objective diagnostic biomarkers are needed to support a clinical diagnosis. OBJECTIVES: To analyze markers in various neurodegenerative disorders to identify diagnostic biomarker candidates for mainly α-synuclein (aSyn)-related disorders (ASRD) in serum and/or cerebrospinal fluid (CSF). METHODS: Upon initial testing of commercially available kits or published protocols for the quantification of the candidate markers, assays for the following were selected: total and phosphorylated aSyn (pS129aSyn), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), tau protein (tau), ubiquitin C-terminal hydrolase L1 (UCHL-1), glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), soluble triggering receptor expressed on myeloid cells 2 (sTREM-2), and chitinase-3-like protein 1 (YKL-40). The cohort comprised participants with Parkinson's disease (PD, n = 151), multiple system atrophy (MSA, n = 17), dementia with Lewy bodies (DLB, n = 45), tau protein-related neurodegenerative disorders (n = 80, comprising patients with progressive supranuclear palsy (PSP, n = 38), corticobasal syndrome (CBS, n = 16), Alzheimer's disease (AD, n = 11), and frontotemporal degeneration/amyotrophic lateral sclerosis (FTD/ALS, n = 15), as well as healthy controls (HC, n = 20). Receiver operating curves (ROC) with area under the curves (AUC) are given for each marker. RESULTS: CSF total aSyn was decreased. NfL, pNfH, UCHL-1, GFAP, S100B, and sTREM-2 were increased in patients with neurodegenerative disease versus HC (P < 0.05). As expected, some of the markers were highest in AD (i.e., UCHL-1, GFAP, S100B, sTREM-2, YKL-40). Within ASRD, CSF NfL levels were higher in MSA than PD and DLB (P < 0.05). Comparing PD to HC, interesting serum markers were S100B (AUC: 0.86), sTREM2 (AUC: 0.87), and NfL (AUC: 0.78). CSF S100B and serum GFAP were highest in DLB. CONCLUSIONS: Levels of most marker candidates tested in serum and CSF significantly differed between disease groups and HC. In the stratification of PD versus other tau- or aSyn-related conditions, CSF NfL levels best discriminated PD and MSA. CSF S100B and serum GFAP best discriminated PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression.

BACKGROUND: The objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker. METHODS: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. RESULTS: In the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 ± 7.2 pg/mL) than in controls (12 ± 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. CONCLUSIONS: Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Validation of the extended thrombolysis in cerebral infarction score in a real world cohort.

BACKGROUND: A thrombolysis in cerebral infarction (TICI) score of 2b is defined as a good recanalization result although the reperfusion may only cover 50% of the affected territory. An additional mTICI2c category was introduced to further differentiate between mTICI scores. Despite the new mTICI2c category, mTICI2b still covers a range of 50-90% reperfusion which might be too imprecise to predict neurological improvement after therapy. AIM: To compare the 7-point "expanded TICI" (eTICI) scale with the traditional mTICI in regard to predict functional independence at 90 days. METHODS: Retrospective review of 225 patients with large artery occlusion. Angiograms were graded by 2 readers according the 7-point eTICI score (0% = eTICI0; reduced clot = eTICI1; 1-49% = eTICI2a, 50-66% = eTICI2b50; 67-89% = eTICI2b67, 90-99% = eTICI2c and complete reperfusion = eTICI3) and the conventional mTICI score. The ability of e- and mTICI to predict favorable outcome at 90days was compared. RESULTS: Given the ROC analysis eTICI was the better predictor of favorable outcome (p-value 0.047). Additionally, eTICI scores 2b50, 2b67 and 2c (former mTICI2b) were significantly superior at predicting the probability of a favorable outcome at 90 days after endovascular therapy with a p-value of 0.033 (probabilities of 17% for mTICI2b50, 24% for mTICI2b67 and 54% for mTICI2c vs. 36% for mTICI2b). CONCLUSIONS: The 7-point eTICI allows for a more accurate outcome prediction compared to the mTICI score because it refines the broad range of former mTICI2b results.