BACKGROUND AND PURPOSE
GlycOxiTOD is an ambispective observational registry designed to characterize vascular and other target-organ damage in adults evaluated for increased cardiovascular risk. The registry is coordinated at the Complejo Hospitalario Universitario de Santiago de Compostela and is designed to support collaborative and multicenter studies conducted under the corresponding ethical and institutional approvals.
The registry was initially developed to study the relationship between glycation, oxidative stress, arterial biomechanics, and target-organ damage. Its scope has subsequently expanded to provide a common clinical research platform integrating hemodynamic assessment, vascular imaging, biochemical markers, optical signals, and the technical and methodological evaluation of non-invasive cardiovascular devices.
The registry does not assign treatments or alter usual clinical care. Clinical decisions remain under the responsibility of the treating health care team.
SCIENTIFIC FRAMEWORK
Cardiovascular target-organ damage includes structural or functional abnormalities affecting the arterial system, heart, kidneys, retina, and other organs. These abnormalities may develop before symptomatic cardiovascular disease and may not be fully identified by conventional risk-factor assessment alone.
GlycOxiTOD evaluates the hypothesis that target-organ damage results from the interaction of several biological and mechanical processes, including:
- Blood pressure load and variability
- Abnormal arterial biomechanics
- Atherosclerotic and arteriosclerotic changes
- Glycation and advanced glycation processes
- Oxidative and inflammatory imbalance
- Metabolic abnormalities
- Changes in vascular optical and pulse-wave signals
The registry is intended to identify clinically meaningful phenotypes rather than to study a single biomarker or device in isolation.
REGISTRY ASSESSMENTS
Assessments are selected according to the participant's clinical characteristics, the applicable protocol, and the objectives of each nested study. They may include the following domains.
Clinical and hemodynamic assessment:
- Demographic, anthropometric, epidemiological, and clinical variables
- Cardiovascular risk factors and relevant medical history
- Current cardiovascular and metabolic treatments
- Office blood pressure and heart rate
- Ambulatory blood pressure monitoring
- Pulse pressure, blood pressure variability, circadian patterns, and orthostatic response
- Clinical cardiovascular-risk estimation
Laboratory and biochemical assessment:
- Routine metabolic, renal, inflammatory, and cardiovascular laboratory variables
- Glycated hemoglobin, fructosamine, glycated albumin, and related glycation markers
- Advanced glycation and glycoxidation markers
- Oxidative stress and antioxidant-system markers
- Plasma and urinary redox biomarkers
- Additional biomarkers included in approved nested studies
Vascular and target-organ assessment:
- Carotid and peripheral vascular ultrasound
- Carotid intima-media thickness and plaque assessment
- Arterial structural and biomechanical measurements
- Quantitative vascular-image analysis
- Ankle-brachial and other non-invasive vascular indices, when available
- Renal, cardiac, retinal, or other target-organ variables obtained during clinical evaluation
- Retinal imaging, when available and applicable
Optical and signal-based assessment:
- Non-invasive photoplethysmographic recordings
- Peripheral and cervical optical pulse signals
- Red, infrared, or other approved optical acquisition modalities
- Pulse-wave morphology, amplitude, timing, stability, and derived signal features
- Comparison of signals obtained from different vascular territories
- Integration of signal-derived markers with clinical, biochemical, and imaging findings
Skin advanced glycation end products may also be assessed non-invasively using validated fluorescence-based devices when available.
CORE REGISTRY DATASET AND OPTIONAL MODULES
The registry distinguishes between a minimum core dataset and optional nested-study modules.
The minimum core dataset includes informed consent, demographic and clinical information, major cardiovascular risk factors, current treatments, office blood pressure, routine metabolic and renal laboratory data, and the protocol-defined core vascular assessment.
Additional modules may include ambulatory blood pressure monitoring, advanced glycation and glycoxidative biomarkers, skin autofluorescence, retinal imaging, quantitative vascular imaging, photoplethysmography, and device-validation procedures.
Module-specific eligibility criteria, procedures, quality requirements, and evaluable denominators are prespecified for each nested study. Participants are not classified as having a normal result when the corresponding module was not performed or did not meet technical quality criteria.
TECHNICAL AND METHODOLOGICAL VALIDATION OF DEVICES
An additional purpose of the registry is to support the technical and methodological validation of devices and measurement procedures used within the research line.
These evaluations may include devices for:
- Office, ambulatory, wearable, or cuff-based blood pressure measurement
- Vascular ultrasound and quantitative image analysis
- Photoplethysmographic and other optical cardiovascular recordings
- Arterial-function and biomechanical assessment
- Skin advanced glycation measurement
- Retinal imaging
- Other non-invasive cardiovascular measurements included in approved nested studies
Depending on the device and research question, validation procedures may assess:
- Technical feasibility
- Proportion of valid and interpretable measurements
- Signal and image quality
- Agreement with an established clinical or technical reference method
- Within-session repeatability
- Between-session reproducibility
- Interobserver and intraobserver variability
- Device-to-device or operator-related variability
- Sensitivity to positioning, contact pressure, motion, and acquisition conditions
- Calibration and measurement stability
- Robustness of signal-processing or image-analysis algorithms
- Diagnostic or discriminative performance, when supported by an appropriate sample and reference standard
Repeated measurements may be performed after repositioning the device or repeating the acquisition procedure. Technical failures, uninterpretable measurements, repeat acquisitions, acquisition time, and reasons for exclusion are recorded whenever relevant.
Device-derived variables and algorithms are evaluated according to prespecified technical criteria. Exploratory results are clearly distinguished from confirmatory validation analyses.
INDEPENDENT ASSESSMENT AND BLINDING
For diagnostic and device-validation studies, index-test processing and reference-standard assessment are performed independently whenever feasible.
Investigators processing photoplethysmography signals, quantitative image features, or investigational device outputs are blinded to the reference vascular classification during prespecified confirmatory analyses. Investigators assessing the reference standard are blinded to investigational signal-derived results.
Algorithm versions, preprocessing steps, exclusion rules, technical quality thresholds, and analysis populations are documented and locked before confirmatory validation.
NESTED STUDIES
GlycOxiTOD functions as a shared registry from which specific observational and methodological studies may be developed.
Nested studies may focus on:
- Hypertension and ambulatory blood pressure phenotypes
- Early vascular target-organ damage
- Carotid imaging and plaque characterization
- Arterial biomechanics
- Glycation, oxidative stress, and inflammatory pathways
- Non-invasive biomarkers
- Photoplethysmography and optical vascular sensing
- Validation of cardiovascular devices and analytical procedures
- Diagnostic and risk-stratification models
- Longitudinal changes in vascular or target-organ damage
- Cardiovascular outcomes during follow-up
Each nested study must be scientifically justified and conducted within the scope of the applicable ethical approval, participant information, consent, data-protection requirements, and institutional governance procedures.
FOLLOW-UP
Participants may be followed through scheduled clinical assessments and review of available medical records. Follow-up may be used to identify changes in cardiovascular risk factors, vascular abnormalities, target-organ damage, treatments, hospital use, and cardiovascular events.
The duration and specific content of follow-up depend on the applicable protocol and the objectives of each nested analysis. The registry does not require all participants to undergo every available procedure.
EVENT VERIFICATION AND ADJUDICATION
Potential cardiovascular events are verified against source medical records using prespecified definitions.
Event date, event type, source documentation, and certainty of classification are recorded separately. Where required by a nested study, events are independently reviewed according to a written adjudication charter, and disagreements are resolved by an additional reviewer.
Investigators adjudicating clinical outcomes do not use investigational photoplethysmography or novel biomarker results to classify events.
DATA QUALITY AND REGISTRY PROCEDURES
The registry uses a quality-assurance framework covering participant identification, data collection, data entry, source verification, data management, analysis, and change control.
A structured data dictionary defines the main registry variables, including:
- Variable name and definition
- Source of information
- Unit of measurement
- Permitted values and coding rules
- Clinically plausible ranges
- Missing-data categories
- Derivation rules for calculated variables
- Device or laboratory method, when relevant
Data-entry controls include predefined range and consistency rules. These checks are used to identify values that are missing, duplicated, outside an expected range, or inconsistent with related variables.
Examples include checks for:
- Chronological consistency between dates
- Physiologically implausible clinical or laboratory values
- Incompatible combinations of diagnoses, treatments, or measurements
- Incomplete device or imaging records
- Differences between recorded status and source documentation
- Duplicate participant identifiers or repeated records
Potential inconsistencies generate a data query or are reviewed by an authorized member of the research team. Corrections are made using the source record and are documented according to the applicable data-management procedure.
SOURCE DATA VERIFICATION
Selected registry variables are verified against source documentation, including:
- Electronic medical records
- Clinical reports
- Laboratory information systems
- Ambulatory blood pressure reports
- Ultrasound and imaging files
- Device-generated raw data
- Study worksheets or electronic case-report forms
Verification may be complete for critical variables and sample-based for other variables, depending on the nested study and available resources.
Critical variables may include participant eligibility, dates, target-organ damage classification, reference-standard results, principal device-derived measures, and major cardiovascular outcomes.
PERIODIC REVIEW AND MONITORING
The research team performs periodic reviews of data completeness, consistency, and protocol adherence. Reviews may include:
- Recruitment and follow-up status
- Missing or pending assessments
- Quality of imaging and signal recordings
- Consistency of derived variables
- Resolution of outstanding queries
- Completeness of critical outcomes
- Compliance with the applicable standard operating procedures
Where required by the sponsor, institution, funding body, or applicable regulation, the registry may also be subject to institutional monitoring, audit, or external review.
Quality is based on institutional governance, source verification, predefined rules, documented procedures, and periodic review.
STANDARD OPERATING PROCEDURES
Written procedures are used, when applicable, for:
- Participant recruitment and identification
- Informed-consent procedures
- Clinical and hemodynamic measurements
- Ambulatory blood pressure monitoring
- Vascular ultrasound acquisition
- Image selection and quantitative analysis
- Photoplethysmographic acquisition and signal-quality assessment
- Device positioning and repeated measurements
- Laboratory-sample collection, processing, storage, and analysis
- Data entry and source verification
- Management of missing or inconsistent data
- Dataset locking and version control
- Statistical analysis
- Reporting of incidents related to research procedures
- Protocol and data-dictionary amendments
- Documentation of analytical-code and algorithm versions
Changes affecting variable definitions, acquisition methods, or analytical procedures are documented to preserve traceability across registry versions.
DATA CONFIDENTIALITY AND GOVERNANCE
Participants are assigned a coded study identifier. Direct identifiers are kept separately from the research dataset and access is restricted to authorized personnel.
Research data are handled according to applicable European and Spanish data-protection legislation and institutional policies. Access to registry data is role-based and limited to the information necessary for each approved activity.
Use of registry data for a nested study requires scientific, ethical, and institutional authorization when applicable. Data are not made available to external collaborators without the corresponding governance, data-protection, and contractual arrangements.
MISSING AND UNINTERPRETABLE DATA
The registry distinguishes between different reasons for unavailable information, including:
- Not collected
- Not clinically indicated
- Participant unable or unwilling to complete the assessment
- Technical acquisition failure
- Uninterpretable signal or image
- Source data unavailable
- Value outside prespecified quality criteria
- Lost to follow-up
Missing or uninterpretable data are not automatically replaced during primary data entry.
The analytical approach to missing data depends on the objective, variable type, amount of missingness, and assumptions about the missing-data mechanism. Analyses may include complete-case analysis, multiple imputation, sensitivity analysis, or other appropriate methods.
Device-derived or imaging variables that fail predefined quality criteria are generally classified as non-interpretable rather than imputed, unless a specific and justified analytical procedure has been prespecified.
SAMPLE SIZE
The registry is intended to support continued recruitment and multiple scientific questions. For this reason, the overall registry size is not based on a single effect estimate.
Each confirmatory nested study includes a specific sample-size or precision assessment based on its primary objective, design, expected effect, prevalence, paired or unpaired structure, reference standard, and anticipated proportion of non-interpretable measurements.
Early technical studies may use smaller feasibility samples to evaluate whether procedures can be completed and whether usable measurements can be obtained. These studies are not used to claim diagnostic validity or clinical effectiveness.
STATISTICAL ANALYSIS
Analyses are selected according to the objectives of each nested study and are described in the corresponding statistical analysis plan.
General analytical principles may include:
- Description of participant characteristics and data completeness
- Assessment of variable distributions and measurement quality
- Correlation and association analyses
- Multivariable regression
- Longitudinal and repeated-measures models
- Paired analyses comparing vascular territories within the same participant
- Agreement analysis
- Intraclass correlation coefficients and coefficients of variation
- Bland-Altman analysis
- Diagnostic-discrimination analysis
- Receiver operating characteristic curves
- Calibration and internal validation of predictive models
- Sensitivity analyses for missing data and technical exclusions
- Adjustment for clinically relevant confounding variables
Analyses involving device or algorithm performance distinguish between development, exploratory assessment, and validation. Training and validation datasets are separated when sample size and study design permit.
Results from very small feasibility samples are reported descriptively and are not interpreted as definitive evidence of diagnostic accuracy.
REGISTRY OUTPUTS
The registry is expected to generate:
- Observational studies of cardiovascular and vascular phenotypes
- Technical and methodological validation studies
- Studies of non-invasive biomarkers
- Imaging and signal-processing methods
- Diagnostic and prognostic models
- Procedures for standardized cardiovascular phenotyping
- Collaborative and multicenter research projects
- Scientific publications, training activities, and potential translational developments
The overall purpose is to build a clinically grounded and methodologically robust platform for the early characterization of cardiovascular risk and target-organ damage.
