Overview of outcome measures and corresponding data collection methods
| Primary exposure and outcomes | Data collection methods | Outcome variables | Justification of methods | |
| Primary ovarian insufficiency | Blood sample | Hormone level | If indicated for routine care: level of follicle-stimulating hormone in mIU/mL | Routine care—diagnostic value |
| Questionnaire | Date of last menstruation, menopausal age | |||
| Medical record | Date of last menstruation, menopausal age | |||
| Bone mineral density | Medical test | DEXA scan of lumbar spine and hip by means of Hologic Delphi densitometer (VUmc) or General Electric Scanner (LUMC) | BMD values in g/cm2 T-scores and Z-scores Presence of osteopenia (defined as T-scores of −1 to −2.5) Presence of osteoporosis (defined as T-scores of ≥−2.5) | Routine care—diagnostic value The DEXA scan is most widely used in clinical practice to screen for osteoporosis and regarded as the ‘golden standard’ |
| Instant vertebral assessment (IVA) by Hologic Delphi densitometer (VUmc) or General Electric Scanner (LUMC) | Vertebral height reduction in % Presence of clinical and non-clinical vertebral fractures | There is a strong additive value of IVA compared with DEXA alone78–80 | ||
| Anthropomorphic measurements | Height in cm and weight in kg | |||
| Blood sample | Bone turnover markers | Bone formation by P1NP—mean value in ng/mL Bone resorption by β-CTX—mean value in pg/mL | These markers have been used in previous studies and are recommended for research purposes81 | |
| Vitamin D | Level of 25-hydroxyvitamin D in serum in nmol/L | Vitamin D has been associated with bone turnover markers, BMD, fracture risk and risk of falling82–84 | ||
| Questionnaire | Food frequency questionnaire (FFQ) | Mean score of calcium intake | The FFQ is a validated questionnaire62 Reference values are available63 | |
| General questionnaire | Previous fractures, use of calcium and vitamin D supplements use of glucocorticoids, family history of osteoporosis | |||
| Medical record | Earlier DEXA scans (yes, no), if applicable treatment plan for osteoporosis such as vitamin D supplementation, recommendations for lifestyle changes | |||
| Cardiovascular status | Medical test | Echocardiogram If contraindicated: cardiac MRI | Abnormalities in heart structure Left ventricular function by E/A ratio, deceleration time, isovolumic relaxation time, left ventricular ejection fraction, diastolic and systolic diameter and volume, E/e′ ratio Right ventricular function: tricuspid annular plane systolic excursion Presence of mitral, aortic or tricuspid valve defects, that is, insufficiencies or stenoses Wall motion score index | Routine care—diagnostic value |
| ECG | Sinus rhythm, QRS complex, ST morphology (elevation or depression), PQ interval and left ventricle hypertrophy | Routine care—diagnostic value | ||
| Coronary computer tomography angiography (CCTA) by a 320-detector row volumetric scanner (Aquilion ONE) (LUMC) and 256 Scanner Philips (VUmc) | Coronary artery calcium score according to Agatston Presence of luminal narrowing and if applicable: type of narrowing and number of plaques for the left main coronary artery, left anterior descending, circumflex artery and right coronary artery | High sensitivity and specificity85 Most valid alternative method for detecting significant coronary disease (golden standard is invasive coronary angiography)86 | ||
| Vascular measurements | Presence of atherosclerosis by carotid intima–media thickness (IMT) and femoral IMT in mm Arterial stiffness (VUmc only) | Predictors of future cardiovascular events71 87 88 | ||
| Blood pressure | Mean of three consecutive measurements in mm Hg | |||
| Anthropomorphic measurements | Height in cm, weight in kg, Body Mass Index in kg/cm2, hip circumference in cm, waist circumference in cm, waist-hip ratio | |||
| Blood sample | Biomarkers | Left ventricular function and presence of ischaemia and infarction by NT-pro-BNP in pmol/L Chronic inflammation (associated with atherosclerosis) by CRP in mg/L | In general population: strong predictor of coronary heart disease89 90 | |
| Lipid spectrum | Total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides | Established risk factors for CVD | ||
| Glucose | Fasting blood glucose | Established risk factor for diabetes | ||
| Kidney function | Creatinine, estimated glomerular filtration rate | Routine care before CCTA | ||
| Questionnaire | General questionnaire | (Family) history of CVD and risk factors for CVD and if applicable date of diagnosis and treatment | ||
| Medical record | Cardiovascular risk score based on SCORE chart and Framingham chart, adjusted for age Cardiovascular history, contraindications for echocardiogram | |||
| Neurocognitive function | Neurocognitive test | 15 Words test | Verbal memory in total number of words | These tests were selected based on their reliability, validity and availability of reference norms. The domains examined are potentially sensitive for the effect of oestrogens48 78–83 |
| Trail Making Test A and B | Information processing speed in seconds to complete | |||
| COWA verbal fluency test | Verbal fluency in total number of words | |||
| Letter–number sequencing | Working memory in total number of correct trials | |||
| WAIS III Digit span | Measures concentration in total number of items/lists correctly repeated; can be converted to a scaled score, which is an age-based, norm-referenced score for each subject | |||
| Dutch Adult Reading Test (NART) | Verbal intelligence in mean IQ estimate | |||
| Quality of life | Questionnaire | SF-12 | General health | Shortened version of the validated questionnaire SF-36, which has been previously used in Dutch studies91 |
| MOS cognitive functioning scale | Cognitive functioning | Frequently used questionnaire92 | ||
| Hospital Anxiety and Depression Scale (HADS) | Anxiety and depression | Valid and reliable Dutch reference values are available93 | ||
| Sexual Activity Questionnaire (SAQ) | Sexual functioning | The SAQ is a valid, reliable and acceptable measure for describing the sexual functioning of women in terms of activity, pleasure and discomfort. It is quick and easy to administer and has good face validity discriminating between the sexual functioning of premenopausal and postmenopausal women94 | ||
| Shortened fatigue questionnaire (VVV) | Fatigue | Reliable and validated questionnaire95 | ||
β-CTX, Beta-carboxy-terminal collagen crosslinks; COWA, Controlled Oral Word Association Test; CRP, C-reactive protein; CVD, cardiovascular disease;DEXA, dual-energy X-ray absorptiometry; LUMC, Leiden University Medical Center; NT-pro-BNP, N-terminal prohormone of brain natriuretic peptide; SF-12, 12-Item Short Form Health Survey; SF-36, 36-Item Short Form Health Survey; MOS, Medical Outcomes Study; VUmc, VU University Medical Center; WAIS, Wechsler Adult Intelligence Scale.