Category: Statistics

Alzheimers Dement. 2024 Dec;20 Suppl 6:e084775. doi: 10.1002/alz.084775.

ABSTRACT

Numerous drugs (including disease-modifying therapies, cognitive enhancers and neuropsychiatric treatments) are being developed for Alzheimer’s and related dementias (ADRD). Emerging neuroimaging modalities, and genetic and other biomarkers potentially enhance diagnostic and prognostic accuracy. These advances need to be assessed in real-world studies (RWS). Currently, there are several national and two emerging international ADRD registries that differ in their data requirements. For instance, most existing registries do not routinely capture safety data. Outcome harmonisation would facilitate collaboration between international and national registries and, in turn, support interoperability, and enhance the statistical power and external validity of RWS. In response, the International Registry for Alzheimer’s Disease and other Dementias (InRAD) convened a Steering Committee of leaders and investigators from registries in Europe, Asia and Australia to define a harmonised minimum dataset (MDS) and extended dataset (EDS) that enables collaboration. A wider stakeholder group, including patient representatives, regulators, payors and industry, will validate the agreed MDS and EDS (Figure 1). The harmonised MDS and EDS will form the basis of data captured in InRAD, which can also form the foundation of collaboration in future RWS within and across registries (Figures 2 and 3). The harmonised MDS and EDS reflect the needs of two user levels. Firstly, the MDS and EDS should inform differential diagnosis and clinical decision making by presenting longitudinal data in a graphical dashboard summarising important outcomes at the point of care. The harmonised MDS will encompass demographics, functional and cognitive instruments, and rating scales. The harmonised EDS can answer specific questions and/or include additional functional and cognitive instruments to, for example, reflect local clinical practice and patient-reported outcomes. Secondly, harmonised MDS and EDS facilitate collaboration between registries to, for example, benchmark, assess efficacy and important safety outcomes, and to inform health technology assessments. The harmonised data sets will be as lean as practical, undergo comprehensive beta-testing by InRAD and the results shared with stakeholders. The presentation will explore the background to and need for data harmonisation across registries, the latest iteration of the harmonised MDS and EDS, and InRAD’s overall progress.

PMID:39782525 | DOI:10.1002/alz.084775

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086492. doi: 10.1002/alz.086492.

ABSTRACT

BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with neuroinflammation and heightened production of reactive oxygen species (ROS) in the brain from overactive NADPH Oxidase 2 (NOX2). The current study examines whether administration of a novel, brain-penetrant NOX2 inhibitor (CPP11G & CPP11H) reduces amyloid plaque load and improves AD-associated vascular dysfunction in a male APP-PS1 mouse model of AD.

METHOD: Intraperitoneal injections of CPP11G (n = 1) or CPP11H (n = 2) three times per week began at 9-10 months of age in the treatment APP-PS1 group (15 mg/kg). The control group of age-matched APP-PS1 mice received no treatment (n = 7). All mice were implanted with a 5mm cranial window for awake optical imaging at least 2 weeks prior to onset of treatment. Two-photon microscopy was performed to assess longitudinal changes in amyloid plaque deposition after weekly Methoxy-04 administration (1 mg/kg). Changes in plaque load were quantified weekly and averaged monthly. Additionally, wide-field optical imaging at 620nm was performed with a 90s, 8% CO2 hypercapnic challenge. This imaging wavelength is sensitive to changes in blood oxygenation (OIS-BOLD) to capture changes in vascular reactivity over time.

RESULT: Treatment with CPP11G/H shows a trend toward reduction in cortical plaque load when compared to an untreated cohort (Fig. 1). OIS-BOLD results for vascular reactivity studies show a slight trend of improved vascular function over time with CPP11G/H treatment (Fig. 2).

CONCLUSION: Our preliminary findings show a strong trend in amyloid plaque reduction with ongoing CPP11G/H treatment in older-aged AD mice and improved vascular function. Ongoing studies to increase the size of the treated cohort will reveal the reliability and statistical significance of CPP11G/H’s therapeutic benefits. We are also examining the impact of treatment on microglia activation and gliosis in APP-PS1::CX3CR1-GFP mice (Fig. 3).

PMID:39782524 | DOI:10.1002/alz.086492

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086975. doi: 10.1002/alz.086975.

ABSTRACT

BACKGROUND: Randomized placebo-controlled trials (RCTs) are the gold standard to evaluate efficacy of new drug treatments for Alzheimer’s disease. For example, the United States FDA approved the brain amyloid-targeting drug lecanemab following CLARITY AD, Biogen and Eisai’s Phase 3 RCT. However, recruiting enough participants for a high-powered and demographically representative trial is difficult and expensive. Fortunately, historical patient data from existing external observational studies of a disease can help populate RCTs [Thorlund et al. (2020). https://doi.org/10.2147/CLEP.S242097]. We propose a new trial framework that uses an external study to source “digital twins” for each trial participant. Using computer-simulated trials mimicking CLARITY AD’s demographics and 18-month duration, we show that our digital twin trial (DTT) has increased power compared to a conventional RCT.

METHOD: A continuous time linear mixed model tracked CDRSB change-from-baseline (CDRSBΔbl) trajectories in 670 ADNI participants satisfying CLARITY AD inclusion criteria [clinicaltrials.gov/study/NCT03887455]. To simulate an RCT, we resampled and added noise to participants’ data, generating a desired sample size of “recruited” participants who we randomized 1:1 to “drug” and “placebo” groups. We calculated participants’ CDRSBΔbl scores at 18 months and simulated the drug effect as a 25% reduction in CDRSBΔbl. For each participant in our DTT, we used Gower’s distance on demographic and clinical baseline variables to identify 20 most-similar real ADNI participants (the digital twins) from our original 670. Each original ADNI participant’s 18-month CDRSBΔbl was calculated using the model. A z-score was then calculated for each DTT participant’s 18-month CDRSBΔbl relative to their digital twins. T-tests were used to evaluate DTT drug vs. placebo group difference in mean z-score and, separately, RCT group difference in mean 18-month CDRSBΔbl. We simulated each trial 1,000 times. Power is the proportion of simulations with a statistically significant treatment group difference.

RESULT: Figure 1 shows that 90% power is reached with approximately 500 fewer recruited participants in simulated DTTs (∼1,600 participants) compared to RCTs (∼2,100 participants).

CONCLUSION: DTTs might require substantially fewer recruited participants to achieve the same power as conventional RCTs. This sample size reduction could facilitate recruitment for trials on Alzheimer’s and in rare diseases with low patient numbers.

PMID:39782519 | DOI:10.1002/alz.086975

Alzheimers Dement. 2024 Dec;20 Suppl 6:e085863. doi: 10.1002/alz.085863.

ABSTRACT

BACKGROUND: Cognitive impairment, a common aging-related pathology, is a risk factor for dementia. Echinacoside (ECH), derived from the traditional Chinese medicine Cistanche deserticola, shows anti-aging properties including anti-inflammation, oxidative stress reduction, and neuronal protection. Despite its benefits, the beneficial impact of ECH on age-related cognitive decline remains unclear. Senescence accelerated mouse-prone 8 (SAMP8) mice, known for rapid aging and related pathologies in the brain like glial activation, neuro-inflammation, neuron loss, and cognitive decline, are ideal for this study. The purpose of this study is to investigate the effect of ECH effects on cognitive functions in SAMP8 mice.

METHODS: Six-month-old male SAMP8 mice (n = 8∼9) were used as the model group, while age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice were used as normal controls. After adaptation in the specific pathogen free (SPF) room for one week, we administered ECH intragastrically to the SAMP8 mice daily for two months, and the control group was administered with saline. Behavioral tests, including open field test and Morris water maze, were performed to assess the mood and memory function of the SAMP8 mice. After that, all mice were sacrificed by intraperitoneal perfusion to extract brain tissues for western blotting and immunofluorescence.

RESULTS: ECH-treated SAMP8 mice showed significantly reduced escape latency in the Morris water maze compared to controls, indicating improved cognitive abilities (P<0.05). ECH also tended to lower beta-amyloid and phosphorylated Tau levels in the hippocampus of SAMP8 mice, though not statistically significant due to small sample sizes (n = 3). SAMP8 mice had higher microglia and astroglia activation than SAMR1 mice, but ECH notably inhibited this in SAMP8 mice (Figure 1).

CONCLUSIONS: Our study demonstrates that ECH intervention can markedly enhance the memory function in SAMP8 mice and inhibits microglial and astroglial activation. These findings suggest a beneficial role of ECH in alleviating cognitive decline in SAMP8 mice by reducing glia-related inflammation.

PMID:39782511 | DOI:10.1002/alz.085863

Alzheimers Dement. 2024 Dec;20 Suppl 6:e083432. doi: 10.1002/alz.083432.

ABSTRACT

An overview is given of surrogate marker evaluation, starting from the original definition of Prentice and his criteria, the estimation framework of Freedman, the meta-analytic framework, and the evaluation of surrogate endpoints from a causal inference point of view. Attention will be given, in particular, to evaluating tau-PET as a reasonably likely surrogate in Alzheimer’s Disease. A meta-analytic surrogate marker evaluation approach will be followed, for a continuous surrogate and a continuous true endpoint. Provisions are made to use both clinical trial data as well as natural history (real world) data. The statistical analysis consists of two steps: (1) a federated step where every site analyzes its own data, according to this protocol and the software provided; (2) a central step where the data hub processes the model outputs from the first step. The federated data analysis is a framework. As such, it can be applied based on a variety of choices made. Such choices pertain to patient population (e.g., early versus later stage), cognitive scale used (or, alternatively, sub-scale or custom-made item set), and particular tau PET measurement used (e.g., with variation over region of interest). A number of possible extensions are discussed too, as well as a single-trial evaluation method to complement the federated meta-analysis.

PMID:39782495 | DOI:10.1002/alz.083432

Alzheimers Dement. 2024 Dec;20 Suppl 6:e084076. doi: 10.1002/alz.084076.

ABSTRACT

BACKGROUND: Recent preclinical studies have revealed a significant reduction in amyloid-β plaques and pro-inflammatory cytokines in Alzheimer’s disease (AD) mouse models following low-dose radiation therapy (LDRT). This phase II, multicenter, prospective, single-blinded, randomized controlled trial (NCT05635968, funding from Korea Hydro & Nuclear Power: Grant No. A21IP11) aims to investigate the efficacy and safety of whole-brain LDRT in patients with AD.

METHOD: Probable AD dementia patients (MMSE 13-24 & CDR 0.5-1) with evidence of amyloid pathology (confirmed by a positive 18F-flutemetamol PET scan) were randomly assigned to one of three groups. They received a total of six fractions of LDRT: Group A with total 0 cGy (sham irradiation), Group B with 24 cGy, and Group C with 300 cGy. The effectiveness of LDRT was assessed through 18F-flutemetamol PET, brain MRI and neurocognitive function tests at baseline, and at 6 and 12 months post-LDRT. The primary endpoint was the change in the ADAS-K-cog score. The secondary endpoints included the changes in 18F-flutemetamol PET, brain MRI, and scores of K-MMSE, CDR, CGA-NPI and K-iADL.

RESULT: A total of 15 patients (5 in each group) who completed 6 months post-LDRT follow-up were analyzed in this interim analysis. Baseline ADAS-K-cog (mean values in the order of group A, B, and C: 40.8 vs. 30.2 vs. 37.4, p = 0.111), CDR (1.0 vs 0.7 vs. 0.8, p = 0.141), K-MMSE (19.6 vs. 22.4 vs. 19.2, p = 0.125) scores were not statistically different across the three groups. After 6 months, mean differences in cognitive test scores compared to baseline were 3.4 vs. 0.2 vs 0.4 (ADAS-K-cog, p = 0.369), 0.6 vs 0.0 vs 0.0 (CDR, p = 0.089), and -1.8 vs. 0.8 vs. 1.2 (K-MMSE, p = 0.081). Compared to Group A, more subjects in experimental groups (B+C) showed improvement in K-iADL (0/5 in Group A vs. 4/10 in Group B+C) and CGA-NPI (0/5 in Group A vs. 5/10 in Group B+C). LDRT was well-tolerated in all patients without any adverse events.

CONCLUSION: Whole-brain LDRT for patients with AD was tolerable and demonstrated potential benefits in neurocognitive function tests. Quantitative imaging analysis will follow, and final results with the planned follow-up are awaited.

PMID:39782493 | DOI:10.1002/alz.084076

Alzheimers Dement. 2024 Dec;20 Suppl 6:e093562. doi: 10.1002/alz.093562.

ABSTRACT

BACKGROUND: Alzheimer’s disease (AD) clinical trials led to the recent successes with monoclonal antibodies targeting amyloid, which opens up many new directions for research into treatment for AD in the future. Gaining greater understanding from these successes and failures will help researchers to focus their efforts on avenues that have the highest potential benefit.

METHOD: We performed a meta-analysis of over a hundred studies of 70+ AD treatments. A global statistical test (GST) combining ADAS-cog, ADCS-ADL and CDR-sb was used to assess the overall efficacy in these studies, in a fair way across multiple outcomes. Disease modifying treatment effects and symptomatic effects impacting all disease symptoms will perform better on this GST than treatments impacting only one symptom. In addition, a false positive effect is less likely to occur on all 3 outcomes simultaneously, making the GST a more reliable outcome for detecting true treatment effects. Composite scores, ADCOMS and iADRS, were used to target true disease progression in the lecanemab and donanemab phase 2 studies, respectively, and have similar advantages to a GST. A similar approach would have possibly averted much of the controversy surrounding the aducanumab approval.

RESULT: Some studies that were previously determined to be failures show some indication of positive effects. And conversely, some studies previously thought to be promising are shown to be more clearly failures. Meta-analyses combining similar treatments across programs illuminate overlooked mechanisms as well as more conclusive failures.

CONCLUSION: The success and failure of Alzheimer’s treatments is partly hidden by including 3 different domains of clinical efficacy: cognition, function and global. True treatment efficacy and true lack of efficacy are much easier to detect with multiple, combined outcomes.

PMID:39782484 | DOI:10.1002/alz.093562

J Cardiothorac Surg. 2025 Jan 8;20(1):46. doi: 10.1186/s13019-024-03227-3.

ABSTRACT

OBJECTIVES: Despite the advances in medicine, aortic dissection remains a cardiac surgery emergency with high mortality and morbidity rates. This study examined the effects of the Glue + Felt technique, which uses biological glue and felt to repair the proximal anastomotic site, on the outcomes of patients with acute type A aortic dissection.

METHODS: A total of 108 patients who underwent surgery for acute type A aortic dissection at our clinic between 2007 and 2020 were included in the study. The patients were divided into two groups: the “Glue + Felt Technique” and the “Bentall-De Bono” groups, based on the surgical technique used for the aortic root. The effects of these two techniques on the development of intraoperative and postoperative complications and survival rates were statistically analyzed.

RESULTS: The Glue + Felt technique was used for 76 patients, while the Bentall-De Bono technique was used for 32 patients. The Kaplan-Meier analysis revealed significant differences in survival rates between the two groups over the entire follow-up period, both with and without propensity score matching (p < 0.001 and p = 0.02, respectively). However, no significant differences were observed in comparisons beyond the first 30 days of follow-up, either with or without propensity score matching (p = 0.573 and p = 0.561, respectively). The main factors contributing to this difference were the duration of cardiopulmonary bypass and aortic cross-clamp time (p < 0.05). During the average follow-up period of 46.2 ± 31.6 months, no re-intervention was required in patients from the Glue-Felt technique group.

CONCLUSIONS: The mortality rate in aortic dissection surgery is higher with more extensive surgical intervention as the duration of cardiopulmonary bypass and aortic cross-clamp time increases. Repairing the lumen and reducing operation time in suitable patients using the Glue-Felt technique for the proximal anastomotic site positively impacts postoperative complications and improves in-hospital and 30-day survival rates, without increasing long-term re-intervention rates.

PMID:39780221 | DOI:10.1186/s13019-024-03227-3

J Orthop Surg Res. 2025 Jan 9;20(1):23. doi: 10.1186/s13018-025-05454-3.

ABSTRACT

BACKGROUND: Osteoporosis, a skeletal disorder affecting nearly 20% of the global population, poses a significant health concern, with osteoporotic vertebral body fractures (VBF) representing a common clinical manifestation. The impact of osteoporotic sintering fractures in the thoracolumbar spine on the sagittal lumbar profile is incompletely understood and may lead to the onset of clinical symptoms in previously asymptomatic patients.

METHODS: This retrospective single-center study analyzed data from patients presenting with osteoporotic spine fractures between 2017 and 2022. Patient selection involved stringent inclusion and exclusion criteria, focusing on radiologically documented osteoporotic sintering fractures in the thoracolumbar junction (TH11-L2). Clinical parameters were recorded and analyzed, alongside lateral-view radiographic assessments utilizing the IDS 7-PACS^®-System (Sectra, Linköping, Sweden). Measurements included total lumbar lordosis, lordosis caudal to the fracture, kyphosis of the fractured vertebra, and sacral slope. Statistical analysis was conducted using SPSS 27 (IBM, Armonk, USA).

RESULTS: Thirty patients (73.3% female, 26.7% male) met the inclusion criteria, with an average age of 82.4 years. Analysis revealed a significant increase in kyphosis of the fractured vertebra in the thoracolumbar spine (p < 0.0001) following further sintering of osteoporotic VBF with increased lordosis caudal to the fracture (p < 0.0001). Total lumbar lordosis remained unchanged, alongside sacral slope measurements (p = 0.612 and p = 0.863, respectively).

CONCLUSION: Progressive sintering of osteoporotic fractures in the thoracolumbar junction accentuates lordosis in underlying segments, potentially exacerbating degenerative changes and symptomatic manifestations. Thus, prioritizing interventions aimed at preventing progressive sintering and restoring sagittal balance is paramount in optimizing treatment outcomes for affected individuals.

PMID:39780214 | DOI:10.1186/s13018-025-05454-3

BMC Med Educ. 2025 Jan 8;25(1):33. doi: 10.1186/s12909-025-06642-9.

ABSTRACT

BACKGROUND: Visual Thinking Strategies (VTS) is an evidence-based pedagogical approach that uses art analysis and structured inquiry to enhance observation, critical thinking, and teamwork, especially in medical training for clinical skills development. This study aimed to compare the short-term and delayed follow-up effects of integrating Visual Thinking Strategies and Visual Thinking Activity (VTA) tasks based on the PRISM Model with Observation Exercises (OE) on medical students’ observation skills, including the number of observations, number of words used, and time spent describing observations.

METHOD: This pre- and post-test experimental study with a control group was conducted among first-year medical students at Gonabad University of Medical Sciences during the 2023-2024 academic year. Forty-four students participated in the intervention group, receiving VTS and VTA tasks, while 45 students formed the control group, engaging in OE alone. Observation skills were assessed using standardized art images (short-term) and real-world clinical exposure (delayed follow-up) through measures of total observations, number of words used, and time spent describing observations. Descriptive statistics, analysis of one-way ANOVA/ANCOVA, and independent t-tests were employed for data analysis.

RESULTS: In the short-term evaluation, the intervention group demonstrated significantly higher performance in the total number of observations (p = 0.001, Adjusted Partial Eta2 = 0.12), number of words used to describe art images (p = 0.001, Adjusted Partial Eta2 = 0.21), and time spent analyzing images (p < 0.001, Adjusted Partial Eta2 = 0.17) compared to the control group. However, after one month in a clinical exposure, no significant differences were found between the groups in the total number of observations (p = 0.62) and number of words used (p = 0.64). Nevertheless, the intervention group spent significantly more time describing their clinical observations (p = 0.04, Effect Size = 0.44).

CONCLUSION: The findings highlight the significant role of VTS in enhancing medical students’ observation skills. While both interventions were equally effective in the delayed follow-up and real-world settings regarding the total number of observations and words used, the VTS and VTA approach led to a notable increase in the time spent on observation descriptions. This conclusion warrants further investigation in future studies.

PMID:39780206 | DOI:10.1186/s12909-025-06642-9