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The International Journal of Behavioral... Oct 2011The International Physical Activity Questionnaire-Short Form (IPAQ-SF) has been recommended as a cost-effective method to assess physical activity. Several studies... (Review)
Review
BACKGROUND
The International Physical Activity Questionnaire-Short Form (IPAQ-SF) has been recommended as a cost-effective method to assess physical activity. Several studies validating the IPAQ-SF have been conducted with differing results, but no systematic review of these studies has been reported.
METHODS
The keywords "IPAQ", "validation", and "validity" were searched in PubMed and Scopus. Studies published in English that validated the IPAQ-SF against an objective physical activity measuring device, doubly labeled water, or an objective fitness measure were included.
RESULTS
Twenty-three validation studies were included in this review. There was a great deal of variability in the methods used across studies, but the results were largely similar. Correlations between the total physical activity level measured by the IPAQ-SF and objective standards ranged from 0.09 to 0.39; none reached the minimal acceptable standard in the literature (0.50 for objective activity measuring devices, 0.40 for fitness measures). Correlations between sections of the IPAQ-SF for vigorous activity or moderate activity level/walking and an objective standard showed even greater variability (-0.18 to 0.76), yet several reached the minimal acceptable standard. Only six studies provided comparisons between physical activity levels derived from the IPAQ-SF and those obtained from objective criterion. In most studies the IPAQ-SF overestimated physical activity level by 36 to 173 percent; one study underestimated by 28 percent.
CONCLUSIONS
The correlation between the IPAQ-SF and objective measures of activity or fitness in the large majority of studies was lower than the acceptable standard. Furthermore, the IPAQ-SF typically overestimated physical activity as measured by objective criterion by an average of 84 percent. Hence, the evidence to support the use of the IPAQ-SF as an indicator of relative or absolute physical activity is weak.
Topics: Exercise; Humans; Physical Exertion; Physical Fitness; Reproducibility of Results; Surveys and Questionnaires; Validation Studies as Topic; Walking
PubMed: 22018588
DOI: 10.1186/1479-5868-8-115 -
BMJ (Clinical Research Ed.) May 2016To provide an overview of prediction models for risk of cardiovascular disease (CVD) in the general population. (Review)
Review
OBJECTIVE
To provide an overview of prediction models for risk of cardiovascular disease (CVD) in the general population.
DESIGN
Systematic review.
DATA SOURCES
Medline and Embase until June 2013.
ELIGIBILITY CRITERIA FOR STUDY SELECTION
Studies describing the development or external validation of a multivariable model for predicting CVD risk in the general population.
RESULTS
9965 references were screened, of which 212 articles were included in the review, describing the development of 363 prediction models and 473 external validations. Most models were developed in Europe (n=167, 46%), predicted risk of fatal or non-fatal coronary heart disease (n=118, 33%) over a 10 year period (n=209, 58%). The most common predictors were smoking (n=325, 90%) and age (n=321, 88%), and most models were sex specific (n=250, 69%). Substantial heterogeneity in predictor and outcome definitions was observed between models, and important clinical and methodological information were often missing. The prediction horizon was not specified for 49 models (13%), and for 92 (25%) crucial information was missing to enable the model to be used for individual risk prediction. Only 132 developed models (36%) were externally validated and only 70 (19%) by independent investigators. Model performance was heterogeneous and measures such as discrimination and calibration were reported for only 65% and 58% of the external validations, respectively.
CONCLUSIONS
There is an excess of models predicting incident CVD in the general population. The usefulness of most of the models remains unclear owing to methodological shortcomings, incomplete presentation, and lack of external validation and model impact studies. Rather than developing yet another similar CVD risk prediction model, in this era of large datasets, future research should focus on externally validating and comparing head-to-head promising CVD risk models that already exist, on tailoring or even combining these models to local settings, and investigating whether these models can be extended by addition of new predictors.
Topics: Cardiovascular Diseases; Female; Humans; Male; Models, Theoretical; Predictive Value of Tests; Risk Assessment; Risk Factors
PubMed: 27184143
DOI: 10.1136/bmj.i2416 -
Journal of Biomedical Informatics May 2020This review aims to: 1) evaluate the quality of model reporting, 2) provide an overview of methodology for developing and validating Early Warning Score Systems (EWSs)... (Review)
Review
OBJECTIVES
This review aims to: 1) evaluate the quality of model reporting, 2) provide an overview of methodology for developing and validating Early Warning Score Systems (EWSs) for adult patients in acute care settings, and 3) highlight the strengths and limitations of the methodologies, as well as identify future directions for EWS derivation and validation studies.
METHODOLOGY
A systematic search was conducted in PubMed, Cochrane Library, and CINAHL. Only peer reviewed articles and clinical guidelines regarding developing and validating EWSs for adult patients in acute care settings were included. 615 articles were extracted and reviewed by five of the authors. Selected studies were evaluated based on the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) checklist. The studies were analyzed according to their study design, predictor selection, outcome measurement, methodology of modeling, and validation strategy.
RESULTS
A total of 29 articles were included in the final analysis. Twenty-six articles reported on the development and validation of a new EWS, while three reported on validation and model modification. Only eight studies met more than 75% of the items in the TRIPOD checklist. Three major techniques were utilized among the studies to inform their predictive algorithms: 1) clinical-consensus models (n = 6), 2) regression models (n = 15), and 3) tree models (n = 5). The number of predictors included in the EWSs varied from 3 to 72 with a median of seven. Twenty-eight models included vital signs, while 11 included lab data. Pulse oximetry, mental status, and other variables extracted from electronic health records (EHRs) were among other frequently used predictors. In-hospital mortality, unplanned transfer to the intensive care unit (ICU), and cardiac arrest were commonly used clinical outcomes. Twenty-eight studies conducted a form of model validation either within the study or against other widely-used EWSs. Only three studies validated their model using an external database separate from the derived database.
CONCLUSION
This literature review demonstrates that the characteristics of the cohort, predictors, and outcome selection, as well as the metrics for model validation, vary greatly across EWS studies. There is no consensus on the optimal strategy for developing such algorithms since data-driven models with acceptable predictive accuracy are often site-specific. A standardized checklist for clinical prediction model reporting exists, but few studies have included reporting aligned with it in their publications. Data-driven models are subjected to biases in the use of EHR data, thus it is particularly important to provide detailed study protocols and acknowledge, leverage, or reduce potential biases of the data used for EWS development to improve transparency and generalizability.
Topics: Adult; Early Warning Score; Humans; Intensive Care Units; Models, Statistical; Prognosis; Vital Signs
PubMed: 32278089
DOI: 10.1016/j.jbi.2020.103410 -
Journal of Medical Systems Jan 2022In clinical practice, assessing digital health literacy is important to identify patients who may encounter difficulties adapting to digital health using digital...
In clinical practice, assessing digital health literacy is important to identify patients who may encounter difficulties adapting to digital health using digital technology and service. We developed the Digital Health Technology Literacy Assessment Questionnaire (DHTL-AQ) to assess the ability to use digital health technology, services, and data. The DHTL-AQ was developed in three phases. In the first phase, the conceptual framework and domains and items were generated from a systematic literature review using relevant theory and surveys. In the second phase, a cross-sectional survey with 590 adults age ≥ 18 years was conducted at an academic hospital in Seoul, Korea in January and February 2020 to test face validity of the items. Then, psychometric validation was conducted to determine the final items and cut-off scores of the DHTL-AQ. The eHealth literacy scale, the Newest Vital Sign, and 10 mobile app task ability assessments were examined to test validity. The final DHTL-AQ includes 34 items in two domains (digital functional and digital critical literacy) and 4 categories (Information and Communications Technology terms, Information and Communications Technology icons, use of an app, evaluating reliability and relevance of health information). The DHTL-AQ had excellent internal consistency (overall Cronbach's α = 0.95; 0.87-0.94 for subtotals) and acceptable model fit (CFI = 0.821, TLI = 0.807, SRMR = 0.065, RMSEA = 0.090). The DHTL-AQ was highly correlated with task ability assessment (r = 0.7591), and moderately correlated with the eHealth literacy scale (r = 0.5265) and the Newest Vital Sign (r = 0.5929). The DHTL-AQ is a reliable and valid instrument to measure digital health technology literacy.
Topics: Adolescent; Adult; Biomedical Technology; Cross-Sectional Studies; Digital Technology; Humans; Psychometrics; Reproducibility of Results; Surveys and Questionnaires
PubMed: 35072816
DOI: 10.1007/s10916-022-01800-8 -
European Urology Focus Nov 2021Early detection of kidney cancer improves survival; however, low prevalence means that population-wide screening may be inefficient. Stratification of the population... (Review)
Review
CONTEXT
Early detection of kidney cancer improves survival; however, low prevalence means that population-wide screening may be inefficient. Stratification of the population into risk categories could allow for the introduction of a screening programme tailored to individuals.
OBJECTIVE
This review will identify and compare published models that predict the risk of developing kidney cancer in the general population.
EVIDENCE ACQUISITION
A search identified primary research reporting or validating models predicting the risk of kidney cancer in Medline and EMBASE. After screening identified studies for inclusion, we extracted data onto a standardised form. The risk models were classified using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines and evaluated using the PROBAST assessment tool.
EVIDENCE SYNTHESIS
The search identified 15 281 articles. Sixty-two satisfied the inclusion criteria; performance measures were provided for 11 models. Some models predicted the risk of prevalent undiagnosed disease and others future incident disease. Six of the models had been validated, two using external populations. The most commonly included risk factors were age, smoking status, and body mass index. Most of the models had acceptable-to-good discrimination (area under the receiver-operating curve >0.7) in development and validation. Many models also had high specificity; however, several had low sensitivity. The highest performance was seen for the models using only biomarkers to detect kidney cancer; however, these were developed and validated in small case-control studies.
CONCLUSIONS
We identified a small number of risk models that could be used to stratify the population according to the risk of kidney cancer. Most exhibit reasonable discrimination, but a few have been validated externally in population-based studies.
PATIENT SUMMARY
In this review, we looked at mathematical models predicting the likelihood of an individual developing kidney cancer. We found several suitable models, using a range of risk factors (such as age and smoking) to predict the risk for individuals. Most of the models identified require further testing in the general population to confirm their usefulness.
Topics: Biomarkers; Humans; Kidney Neoplasms; Mass Screening; Prognosis; Risk Factors
PubMed: 32680829
DOI: 10.1016/j.euf.2020.06.024 -
Clinical Microbiology and Infection :... Aug 2021Only clinically validated HPV assays can be accepted in cervical cancer screening. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Only clinically validated HPV assays can be accepted in cervical cancer screening.
OBJECTIVES
To update the list of high-risk HPV assays that fulfil the 2009 international validation criteria (Meijer-2009).
DATA SOURCES
PubMed/Medline, Embase, Scopus, references from selected studies; published in January 2014 to August 2020.
STUDY ELIGIBILITY CRITERIA
HPV test validation studies and primary screening studies, involving testing with an index HPV test and a comparator HPV test with reporting of disease outcome (occurrence of histologically confirmed cervical precancer; CIN2+).
PARTICIPANTS
Women participating in cervical cancer screening.
INTERVENTIONS
Testing with an index and a comparator HPV test of clinician-collected cervical specimens and assessment of disease outcome (
validation guidelines, or tests with consistent previous validations. METHODS
Assessment of relative clinical accuracy (including non-inferiority statistics index vs comparator assay) and test reproducibility in individual studies; random effects meta-analyses of the relative clinical sensitivity and specificity of index vs comparator tests.
RESULTS
Seven hrHPV DNA tests consistently fulfilled all validation criteria in multiple studies using predefined test positivity cut-offs (Abbott RealTime High Risk HPV, Anyplex II HPV HR Detection, BD Onclarity HPV Assay, Cobas 4800 HPV Test, HPV-Risk Assay, PapilloCheck HPV-Screening Test and Xpert HPV). Another assay (Alinity m HR HPV Assay) was fully validated in one validation study. The newer Cobas 6800 HPV Test, was validated in two studies against Cobas 4800. Other tests partially fulfilled the international validation criteria (Cervista HPV HR Test, EUROArray HPV, Hybribio's 14 High-Risk HPV, LMNX Genotyping Kit GP HPV, MALDI-TOF, RIATOL qPCR and a number of other in-house developed assays) since the non-inferior accuracy was reached after a posteriori cut-off optimization, inconsistent accuracy findings in different studies, and/or insufficient reproducibility assessment. The APTIMA HPV Assay targeting E6/E7 mRNA of hrHPV was fully validated in one formal validation study and showed slightly lower pooled sensitivity but higher specificity than the standard comparator tests in seven screening studies. However, the current international validation criteria relate to DNA assays. The additional requirement for longitudinal performance data required for non-DNA based HPV assays was not assessed in this review.
CONCLUSIONS
Eleven hrHPV DNA assays fulfil all requirements for use in cervical cancer screening using clinician-collected specimens.
Topics: Alphapapillomavirus; Early Detection of Cancer; Female; Genotyping Techniques; Humans; Papillomaviridae; Papillomavirus Infections; Reproducibility of Results; Sensitivity and Specificity; Uterine Cervical Neoplasms
PubMed: 33975008
DOI: 10.1016/j.cmi.2021.04.031 -
Neuropsychobiology 2023The utility of heart rate variability (HRV) for characterizing psychological stress is primarily impacted by methodological considerations such as study populations,... (Review)
Review
The utility of heart rate variability (HRV) for characterizing psychological stress is primarily impacted by methodological considerations such as study populations, experienced versus induced stress, and method of stress assessment. Here, we review studies on the associations between HRV and psychological stress, examining the nature of stress, ways stress was assessed, and HRV metrics used. The review was performed according to the PRISMA guidelines on select databases. Studies that examined the HRV-stress relationship via repeated measurements and validated psychometric instruments were included (n = 15). Participant numbers and ages ranged between 10 and 403 subjects and 18 and 60 years, respectively. Both experimental (n = 9) and real-life stress (n = 6) have been explored. While RMSSD was the most reported HRV metric (n = 10) significantly associated with stress, other metrics, including LF/HF (n = 7) and HF power (n = 6) were also reported. Various linear and nonlinear HRV metrics have been utilized, with nonlinear metrics used less often. The most frequently used psychometric instrument was the State-Trait Anxiety Inventory (n = 10), though various other instruments have been reported. In conclusion, HRV is a valid measure of the psychological stress response. Standard stress induction and assessment protocols combined with validated HRV measures in different domains will improve the validity of findings.
Topics: Humans; Adult; Heart Rate; Stress, Psychological
PubMed: 37290411
DOI: 10.1159/000530376 -
The reliability and validity of ultrasound to quantify muscles in older adults: a systematic review.Journal of Cachexia, Sarcopenia and... Oct 2017This review evaluates the reliability and validity of ultrasound to quantify muscles in older adults. The databases PubMed, Cochrane, and Cumulative Index to Nursing and... (Meta-Analysis)
Meta-Analysis Review
This review evaluates the reliability and validity of ultrasound to quantify muscles in older adults. The databases PubMed, Cochrane, and Cumulative Index to Nursing and Allied Health Literature were systematically searched for studies. In 17 studies, the reliability (n = 13) and validity (n = 8) of ultrasound to quantify muscles in community-dwelling older adults (≥60 years) or a clinical population were evaluated. Four out of 13 reliability studies investigated both intra-rater and inter-rater reliability. Intraclass correlation coefficient (ICC) scores for reliability ranged from -0.26 to 1.00. The highest ICC scores were found for the vastus lateralis, rectus femoris, upper arm anterior, and the trunk (ICC = 0.72 to 1.000). All included validity studies found ICC scores ranging from 0.92 to 0.999. Two studies describing the validity of ultrasound to predict lean body mass showed good validity as compared with dual-energy X-ray absorptiometry (r = 0.92 to 0.96). This systematic review shows that ultrasound is a reliable and valid tool for the assessment of muscle size in older adults. More high-quality research is required to confirm these findings in both clinical and healthy populations. Furthermore, ultrasound assessment of small muscles needs further evaluation. Ultrasound to predict lean body mass is feasible; however, future research is required to validate prediction equations in older adults with varying function and health.
Topics: Age Factors; Aged; Aged, 80 and over; Body Composition; Humans; Muscle, Skeletal; Organ Size; Reproducibility of Results; Sarcopenia; Ultrasonography
PubMed: 28703496
DOI: 10.1002/jcsm.12210 -
The Cochrane Database of Systematic... Jan 2018Endoscopic assessment of mucosal disease activity is routinely used to determine eligibility and response to therapy in clinical trials of ulcerative colitis. The... (Review)
Review
BACKGROUND
Endoscopic assessment of mucosal disease activity is routinely used to determine eligibility and response to therapy in clinical trials of ulcerative colitis. The operating properties of the existing endoscopic scoring indices are unclear.
OBJECTIVES
A systematic review was undertaken to evaluate the development and operating characteristics of endoscopic scoring indices for the evaluation of ulcerative colitis.
SEARCH METHODS
We searched MEDLINE, Embase and CENTRAL from inception to 5 July 2016. We also searched references and conference proceedings (Digestive Disease Week, United European Gastroenterology Week, European Crohn's and Colitis Organization).
SELECTION CRITERIA
Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated endoscopic indices for evaluation of ulcerative colitis disease activity were considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with ulcerative colitis using conventional clinical, radiologic and endoscopic criteria.
DATA COLLECTION AND ANALYSIS
Two authors independently reviewed the studies identified from the literature search. These authors also independently extracted and recorded data on the number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as reliability (intra-rater and inter-rater), validity (content, construct, criterion), responsiveness and feasibility. Any disagreements regarding study inclusion or data extraction were resolved by discussion and consensus with a third author. Risk of bias was assessed by determining whether assessors were blinded to clinical information and whether assessors scored the endoscopic index independently. We also assessed the methodological quality of the validation studies using the COSMIN checklist MAIN RESULTS: A total of 23 reports of 20 studies met the pre-defined inclusion criteria and were included in the review. Of the 20 included validation studies, 19 endoscopic scoring indices were assessed, including the Azzolini Classification, Baron Score, Blackstone Endoscopic Interpretation, Chinese Grading System of Ulcerative Colitis, Endoscopic Activty Index, Jeroen Score, Magnifying Colonoscopy Grade, Matts Score, Mayo Clinic Endoscopic Subscore, Modified Baron Score, Modified Mayo Clinic Endoscopic Subscore, Osada Score, Rachmilewtiz Endoscopic Score, St. Mark's Index, Ulcerative Colitis Colonoscopic Index of Serverity (UCCIS), endoscopic component of the Ulcerative Colitis Disease Activity Index (UCDAI), Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Witts Sigmoidoscopic Score and Watson Grade. The individuals who performed the endoscopic scoring were blinded to clinical and/or histologic information in ten of the included studies, not blinded to clinical and/or histologic information in one of the included studies, and it was unclear whether blinding occurred in the remaining nine included studies. Independent observation was confirmed in four of the included studies, unclear in five of the included studies, and non-applicable (since inter-rater reliability was not assessed) in the remaining eleven included studies. The methodological quality (COSMIN checklist) of most of the included studies was rated as 'good' or 'excellent'. One study that assessed responsiveness was rated as 'fair'. The inter-rater reliability of nine endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Endoscopic Activity Index, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS, UCEIS, Watson Grade was assessed in seven studies, with estimates of correlation, ƙ, ranging from 0.44 to 0.97. The iIntra-rater reliability of seven endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS and UCEIS was assessed in three studies, with estimates of correlation, ƙ, ranging from 0.41 to 0.86. No studies assessed content validity. Three studies evaluated the criterion validity of three endoscopic scoring indices including the Rachmilewitz Endoscopic Score, Magnifying Colonoscopy Grade and the UCCIS. These indices were correlated with objective markers of disease activity including albumin, blood leukocytes, C-reactive protein, fecal calprotectin, hemoglobin, mucosal interleukin-8 concentration and platelet count. Correlation estimates ranged from r = -0.19 to 0.83. Thirteen endoscopic scoring indices were tested for construct validity in 13 studies. Estimates of correlation between the endoscopic scoring indices and other measures of disease activity ranged from r = 0.27 to 0.93. Two studies explored the responsiveness of four endoscopic scoring indices including the Mayo Endoscopic Subscore, Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS. One study concluded that the Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS had similar responsiveness for detecting disease change in ulcerative colitis. The other included study concluded that the UCEIS may be the most accurate endoscopic scoring tool. None of the included studies formally assessed feasibility.
AUTHORS' CONCLUSIONS
While the UCEIS, UCCIS and Mayo Clinic Endoscopic Subscore have undergone extensive validation, none of these instruments have been fully validated and only two studies assessed responsiveness. Further research on the operating properties of these indices is needed given the lack of a fully-validated endoscopic scoring instrument for the evaluation of disease activity in ulcerative colitis.
Topics: Colitis, Ulcerative; Colonoscopy; Humans; Reproducibility of Results; Severity of Illness Index; Sigmoidoscopy
PubMed: 29338066
DOI: 10.1002/14651858.CD011450.pub2 -
BMJ (Clinical Research Ed.) Sep 2021To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes.
OBJECTIVES
To identify and assess the quality and accuracy of prognostic models for nephropathy and to validate these models in external cohorts of people with type 2 diabetes.
DESIGN
Systematic review and external validation.
DATA SOURCES
PubMed and Embase.
ELIGIBILITY CRITERIA
Studies describing the development of a model to predict the risk of nephropathy, applicable to people with type 2 diabetes.
METHODS
Screening, data extraction, and risk of bias assessment were done in duplicate. Eligible models were externally validated in the Hoorn Diabetes Care System (DCS) cohort (n=11 450) for the same outcomes for which they were developed. Risks of nephropathy were calculated and compared with observed risk over 2, 5, and 10 years of follow-up. Model performance was assessed based on intercept adjusted calibration and discrimination (Harrell's C statistic).
RESULTS
41 studies included in the systematic review reported 64 models, 46 of which were developed in a population with diabetes and 18 in the general population including diabetes as a predictor. The predicted outcomes included albuminuria, diabetic kidney disease, chronic kidney disease (general population), and end stage renal disease. The reported apparent discrimination of the 46 models varied considerably across the different predicted outcomes, from 0.60 (95% confidence interval 0.56 to 0.64) to 0.99 (not available) for the models developed in a diabetes population and from 0.59 (not available) to 0.96 (0.95 to 0.97) for the models developed in the general population. Calibration was reported in 31 of the 41 studies, and the models were generally well calibrated. 21 of the 64 retrieved models were externally validated in the Hoorn DCS cohort for predicting risk of albuminuria, diabetic kidney disease, and chronic kidney disease, with considerable variation in performance across prediction horizons and models. For all three outcomes, however, at least two models had C statistics >0.8, indicating excellent discrimination. In a secondary external validation in GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland), models developed for diabetic kidney disease outperformed those for chronic kidney disease. Models were generally well calibrated across all three prediction horizons.
CONCLUSIONS
This study identified multiple prediction models to predict albuminuria, diabetic kidney disease, chronic kidney disease, and end stage renal disease. In the external validation, discrimination and calibration for albuminuria, diabetic kidney disease, and chronic kidney disease varied considerably across prediction horizons and models. For each outcome, however, specific models showed good discrimination and calibration across the three prediction horizons, with clinically accessible predictors, making them applicable in a clinical setting.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42020192831.
Topics: Aged; Albuminuria; Calibration; Clinical Decision Rules; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Predictive Value of Tests; Prognosis; Renal Insufficiency, Chronic; Reproducibility of Results; Risk Assessment; Risk Factors
PubMed: 34583929
DOI: 10.1136/bmj.n2134