The gold standard method for the assessment of vascular aging is carotid–femoral pulse wave velocity (cfPWV). cfPWV can be estimated from 2 commonly assessed clinical variables—age and blood pressure. This analysis uses data from the Health and Retirement Study to examine the relationship between estimated pulse wave velocity (ePWV) and mortality among 9,293 middle age and older adults.Cox proportional hazard models were used to predict mortality occurring over a 10- to 12-year period. Controls were included for sociodemographic characteristics , health status , health behaviors , and CVD-related biomarkers .By 2018, 26.19% of the weighted analytic sample were reported as deceased. In the fully specified models that control for age, age-squared, systolic and diastolic blood pressure, sociodemographic variables, health status and behaviors, and biomarkers, ePWV was associated with a greater likelihood of mortality.An estimate of PWV derived from age and blood pressure is independently associated with an increased likelihood of death in a representative sample of middle age and older adults in the United States. Translational Significance: This study demonstrates an association between an estimate of vascular aging derived from chronological age and blood pressure (estimated pulse wave velocity [ePWV]) and all-cause mortality in 9,293 U.S. older adults in the Health and Retirement Study. As gold standard measures of vascular aging require in-person data collection with expensive equipment and high operator technical proficiency, ePWV holds promise as an easily obtained estimate of vascular aging that can be integrated into large cohort studies that measure age and blood pressure.From 2014 to the onset of the coronavirus disease 2019 (COVID-19) pandemic, U.S. life expectancy declined as a result of an increase in all-cause mortality concentrated in midlife . Some ofThe stiffening of arteries is considered a hallmark of human aging in context. Even in the absence of overt heart disease, as people age, their large central arteries, such as the aorta, lose elasticity and stiffen . Vascular aging is a dynamic process that may, at the individual level, occur at a different rate than chronological aging . VariatiThe gold standard method for the assessment of arterial stiffness is the measurement of carotid–femoral pulse wave velocity cfPWV; . Althougr = 0.31) and White adults  is computed using equations that only require age and mean blood pressure inputs and may be useful as a measure of vascular aging in research studies. Preliminary evidence suggests that ePWV may be a reasonable proxy for cfPWV, with correlations between the two measures ranging from 0.52 to 0.67 in various studies . Other rTo date, the small number of studies that have explored ePWV as a predictor of mortality have done so in European cohorts, and have not adequately taken gender, race, and ethnicity into account. Specifically, in some of these studies, participation has been limited to men , and theWe analyze data from the Health and Retirement Study (HRS), which is a nationally representative prospective, longitudinal study of U.S. adults who are older than the age of 50. Started in 1992, the HRS was designed to explore patterns of later-life work, aging, and retirement in order to inform public policy . The HRSThe HRS is approved by the institutional review board (IRB) of the University of Michigan, and all participants provide written informed consent. All of the data used in this study are deidentified, and most of the data are publicly available. The blood biomarker data are considered sensitive health data, and we were required to submit an application to use them. This study was determined to be exempt from review by the Syracuse University Office of Research and Integrity/IRB because all of the data were deidentified at the point that we had access to them.N = 4,046). These measures are described in more detail later. In addition, participants were considered outliers and excluded if their age was 50 or younger (N = 349), body mass index (BMI) was <16 kg/m2 (N = 2), or systolic or diastolic blood pressure was <40 mmHg (N = 44). Participants who did not self-identify as White or Black  or as being of Hispanic ethnicity (among those reporting Black or White race) were also excluded because the sample was deemed by us to be too small to retain in the analysis (N = 214). Finally, participants with a zero on the survey weight variable in 2006 or 2008 were also excluded (N = 229). With these exclusions implemented, the analytic sample for this study includes 9,293 participants.For this study, baseline data were taken from nonproxy participants in 2006 and 2008 as the biomarker data were initially collected from half the sample during each of those years. HRS participants were excluded if there were missing data on any of the sociodemographic, health behavior, health conditions, or biomarker measures included in this analysis  is calculated as follows: ([diastolic blood pressure] + [0.4 × (systolic blood pressure − diastolic blood pressure)]). MBP was calculated using a form factor of 0.4, rather than the traditional “1/3rd” approach, given that the derivation of MBP in previous ePWV equations utilized this same approach .The model we estimate includes exogenous sociodemographic variables, as well as several potentially confounding measures of socioeconomic attainment. Together, these social determinants of health anchor life-course processes of cumulative inequality that may be variably associated with health behavior, disease development, and vascular aging. The exogenous sociodemographic variables that we include are gender  and a combined measure of racial and ethnic identity . Socioeconomic attainment is measured with three variables: education ; household income (in dollars); and household wealth (in dollars).2). The health conditions that are included are history of heart disease ; history of type 2 diabetes (yes/no); and history of stroke (yes/no). We also include associated medication use, including antihypertensive medications (yes/no), diabetes medications (yes/no), and cholesterol medications (yes/no).The model also includes several self-reported health behaviors and health conditions that are correlated with vascular aging and mortality. The health behaviors that are included are physical activity  and current smoker (yes/no). Anthropometric status/body habitus is determined as BMI  cholesterol, as a measure of lipid metabolism; glycated hemoglobin A1c, as a measure of glucose control; cystatin c, as a measure of global kidney function; and C-reactive protein (CRP), as a measure of systemic low-grade inflammation. To account for assay and laboratory variability in biomarker values, HRS data are released with NHANES equivalent assay values , which wWe estimate Cox proportional hazard models predicting death between 2006/2008 and 2018 for the total analytic sample. This approach takes time to the event and censoring into account. We present results from three successive models with adjustments for additional covariates in each model. The first model includes continuous measures of systolic and diastolic blood pressure, as well as continuous measures of age and age-squared. In the second model, we add ePWV to determine the extent to which it contributes to the risk of mortality after taking into account the influences of its constituent components. In the final model, we add the sociodemographic variables, health behavior and conditions, medication use, and biomarker variables. In addition to presenting results from the fully specified model for the full analytic sample, we estimate models respectively stratified by gender and by race and ethnicity. Model 1 includes age, age-squared, systolic blood pressure, diastolic blood pressure, and ePWV. Model 2 adds the self-reported sociodemographic variables, health behaviors and conditions, and medication use. Model 3 adds CVD biomarkers . We conducted all analyses with HRS-provided weights using Stata/IC 16.0 for Windows .Considering the exogenous sociodemographic characteristics and baseline socioeconomic status, approximately 56% identified as female individuals, and more than three-quarters identified as non-Hispanic White individuals. Just over 8.3% identified as non-Hispanic Black individuals, and approximately 7.6% identified as either Hispanic White or Black individuals. The majority (nearly 54%) had graduated high school; 24% had attained a college degree or higher education. Mean income was $73,450, and mean wealth was $551,942.2, which is slightly higher than the ideal individual-level BMI of 25–27 kg/m2 for older adults . Diastolic blood pressure remains significant and negative in Model 2. However, with the addition of ePWV to the model, the coefficient on systolic blood pressure changes from positive to negative and is statistically significant.Model 2 adds ePWV to Model 1. Net of age, age-squared, and the direct measures of blood pressure, ePWV has a large, positive, statistically significant association with mortality. Model 2 fits better than Model 1 . Moreover, Model 3 fits better than a model that includes all of the covariates except ePWV , which indicates that ePWV makes a unique contribution to explaining the risk of mortality. The results observed in Model 2 for ePWV, age, age-squared, systolic blood pressure, and diastolic blood pressure remain relatively unchanged, while these other variables have independent associations with mortality in the expected directions. Mortality is significantly higher among males, current smokers, and persons with: heart disease, diabetes, stroke, higher cystatin c, and higher CRP. Mortality is significantly lower among persons who: identify as Hispanic; have a college/graduate degree; have higher income; and exercise more than once a week. BMI has a nonlinear association with mortality, which can be characterized as an inverted J-shaped curve.Model 3 adds the exogenous sociodemographic and potentially confounding variables to Model 2. Model 3 fits better than Model 2 . While there was no statistically significant gender interaction, the interaction between non-Hispanic Black and ePWV was statistically significant and anomalous. Specifically, among non-Hispanic Blacks, at higher levels of ePWV, the risk of mortality was attenuated. To expand upon these preliminary analyses, p < .10). Addition of the CVD biomarkers in Model 3 further attenuates the association of ePWV with mortality among men by 23.4% and reduces it to marginal statistical significance (p < .10). Among women, the association becomes nonsignificant due to a slight decrease in the size of the coefficient and a further increase in the standard error.The results indicate ePWV has a strong, positive, statistically significant association with mortality among both men and women following adjustment for ePWV’s constituent components—age, age-squared, and blood pressure. Among men, controlling for socioeconomic status, health behaviors , comorbid disease conditions, and medication use in Model 2 reduce the association between ePWV and mortality by 12.5%, but the association remains statistically significant. By contrast, among women, the coefficient in Model 2 is slightly larger but relatively unchanged, the standard error increases, and the association becomes marginally significant , systemic inflammation (CRP), and kidney function (cystatin c) is a novel contribution of this study. However, this study also has several limitations that point to directions for future research. First, we only used the baseline levels of blood pressure to calculate ePWV even though blood pressure changes over time . Future Our results support a complex relationship between blood pressure and mortality in older adults that may be modified by vascular aging. Specifically, when entering ePWV into our second model that includes its constituent elements, the coefficient on systolic blood pressure changes from positive to negative and is statistically significant, while chronological age is no longer significantly associated with mortality. In the HRS, it has been shown that low systolic and diastolic blood pressure is associated with a higher risk of mortality among older adults with a history of CVD (and likely accelerated vascular aging), and that those with low systolic blood pressure have the poorest survival . The joiThis study provides evidence that an estimate of PWV derived from chronological age and blood pressure is independently associated with all-cause mortality in a representative sample of middle age and older adults in the United States. We conclude that ePWV may be useful as a measure of vascular aging in large cohort studies that include the direct measurement of blood pressure or valid measures of blood pressure linked from medical records systems or other sources.


Background: Evidence for kidney function monitoring intervals in primary care is weak, and based mainly on expert opinion. In the absence of trials of monitoring strategies, an approach combining a model for the natural history of kidney function over time combined with a cost-effectiveness analysis offers the most feasible approach for comparing the effects of monitoring under a variety of policies. This study aimed to create a model for kidney disease progression using routinely collected measures of kidney function.Methods: This is an open cohort study of patients aged ≥18 years, registered at 643 UK general practices contributing to the Clinical Practice Research Datalink between 1 April 2005 and 31 March 2014. At study entry, no patients were kidney transplant donors or recipients, pregnant or on dialysis. Hidden Markov models for estimated glomerular filtration rate (eGFR) stage progression were fitted to four patient cohorts defined by baseline albuminuria stage; adjusted for sex, history of heart failure, cancer, hypertension and diabetes, annually updated for age.Results: Of 1,973,068 patients, 1,921,949 had no recorded urine albumin at baseline, 37,947 had normoalbuminuria (<3mg/mmol), 10,248 had microalbuminuria (3–30mg/mmol), and 2,924 had macroalbuminuria (>30mg/mmol). Estimated annual transition probabilities were 0.75–1.3%, 1.5–2.5%, 3.4–5.4% and 3.1–11.9% for each cohort, respectively. Misclassification of eGFR stage was estimated to occur in 12.1% (95%CI: 11.9–12.2%) to 14.7% (95%CI: 14.1–15.3%) of tests. Male gender, cancer, heart failure and age were independently associated with declining renal function, whereas the impact of raised blood pressure and glucose on renal function was entirely predicted by albuminuria.Conclusions: True kidney function deteriorates slowly over time, declining more sharply with elevated urine albumin, increasing age, heart failure, cancer and male gender. Consecutive eGFR measurements should be interpreted with caution as observed improvement or deterioration may be due to misclassification. The guideline suggests increasing the intensity of monitoring according to the current level of eGFR and albumin-creatinine ratio, stating that monitoring should be tailored according to i) the underlying cause of CKD and ii) past patterns of eGFR and albumin-creatinine ratio, comorbidities, changes to treatments such as reninangiotensin-aldosterone system antagonists, inter-current illness and whether the patient has chosen conservative management of CKD. One of the objectives of monitoring eGFR is to detect progression of CKD, which could precede end-stage renal disease (ESRD). ESRD is associated with substantial morbidity and mortality, with cardiovascular disease mortality rates 10 to 30 times higher in patients on dialysis than in the general population. Yet, kidney function declines slowly with age and ESRD is rare, even for people with moderately impaired renal function (eGFR 30–59 ml/min/1.73m2). In a study of 58,000 people with CKD stage 3 who were followed for 10 years, the cumulative incidence was 40 per 1,000 people. It follows that recommendations to monitor everyone annually or more frequently in a community setting for progressive kidney function loss will have a poor yield. Furthermore, as eGFR is a noisy measurement, with a within-person coefficient of variation estimated to be approximately 5.5%, it is likely two consecutive eGFR measurements may appear to indicate declining renal function when underlying renal function is stable , or stable renal function when underlying renal function has deteriorated . Finally, it is arguable as to whether there are any actions that can be taken to halt the deterioration of renal function if progressive CKD is found, as there is currently very little evidence that “catching” CKD early produces any benefit.The National Institute for Health and Care Excellence recommend monitoring kidney function using estimated glomerular filtration rate (eGFR) in people with, or at risk of, chronic kidney disease (CKD) and recommendations for how frequently monitoring should take place are based on expert opinion. In the absence of trials, an approach combining a model for the natural history of kidney function over time combined with a cost-effectiveness analysis offers the most feasible approach for comparing the effects of monitoring under a variety of policies. The aim of this study was to create a model for kidney disease progression using routine measures of kidney function. Our approach simultaneously estimates the true rate of kidney function loss and the probability of misclassification that inevitably occurs from using eGFR. Our study is conducted in a general primary care population and our results will be useful in guiding future recommendations for the timing of monitoring eGFR in primary care.There have been no trials of screening or monitoring for CKDThe protocol for this research was approved by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Agency (protocol number 14_150R). Ethical approval for observational research using the Clinical Practice Research Datalink with approval from the Independent Scientific Adisory Committee has been granted by a National Research Ethics Service committee . to construct an open cohort of adults (≥18 years of age) registered at practices deemed to have “acceptable” patient records (termed “up-to-standard” in CPRD). We included patient records starting from 1 April 2005, post-dating the publication of the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines for the classification of CKD in 2002 and the introduction of Quality and Outcomes Framework targets in UK primary care in 2004. The study end date was 31 March 2014. Eligible patients had to be registered with their practice for a minimum of 12 months before study entry to ensure adequate recording of baseline covariates. We excluded patients who, in the 12 months before study entry, were pregnant, were receiving dialysis, or were living kidney donors or recipients. Follow-up ended at the study end date, unless preceded by the date of death, transfer out of CPRD, the last available linked data, or (where applicable) pregnancy, renal transplantation/donation, or dialysis.We used the UK Clinical Practice Research Practice Datalink (CPRD) were fitted to four patient cohorts defined by baseline albuminuria stage: 1) no albuminuria measurement (unmeasured), 2) normoalbuminuria (<3 mg/mmol), 3) microalbuminuria (3–30 mg/mmol), and 4) macroalbuminuria (>30 mg/mmol). Models were adjusted for sex, heart failure, cancer, hypertension and diabetes, and annually updated age.To model decline in kidney function, hidden Markov models (HMMs)The HMMs comprised two components, a multi-state model governing the ‘true’ underlying progression of CKD, and a second model for the probability of misclassification to allow for the variability in eGFR. The underlying model for CKD was parametrised as uni-directional, in which true kidney function could only deteriorate over time (no spontaneous improvement). The outcome was eGFR stage based on the criteria used for the diagnosis of CKD, i.e. G1–G5. We combined stages G1 and G2 for the purposes of improving model fit. Death from any cause was assumed to be an absorbing state. A representation of the HMMs is depicted in2 we specified the model so that a single measurement of eGFR could fall within a G3a or G3b category due to measurement error and biological variation, but not G4 or G5. For a person with true eGFR in stage G3b, a single measurement of eGFR could be misclassified as either G1/2, G3a, G4 or G5. Death was the only state assumed to be always classified correctly.The HMMs were specified so that it was possible for misclassification to occur in neighbouring eGFR categories. Hence, for a person with true GFR >60 ml/min/1.73mExtended data).To assess model fit, we used a split-sample approach. Although this is a weak procedure for low-variance methods, such as the Cox proportional hazards model or logistic regression, it is useful for a model that can be over-parametrised or exhibit convergence issues (such as a HMM). We split the data using pseudo-random numbers into equal size training and testing data sets. The model was fit in the training data set and then used to predict trajectories of eGFR for patients in the testing data set, based on their measurement times and covariates. Calibration plots were used to compare the predicted and observed proportion of tests falling within each eGFR category over time. Annual transition rates for kidney function loss and death from any cause were estimated from the model, along with the misclassification probabilities and transition rate multipliers for age, sex, heart failure and cancer, and presented as state model diagrams. The models were used to estimate the probability of progression to a higher stage within six, 12 or 36 months, along with the probability that an eGFR test taken at that time would detect the change (true positive), and the probability that a change in eGFR stage would occur in a person in whom true kidney function had not changed , for all cohorts for baseline stages G3a and G3b; see Supplementary Tables S18–21  and the proportion of times the observed was a higher stage than predicted (over-grading), and then added these together to calculate the total number of misclassified tests across cohorts.Finally, we estimated global misclassification probabilities for the four cohorts using the Viterbi algorithm, with HMMs fit using version 1.6.7 of themsm package. Scripts used in these analyses are available (seeSoftware availability).All analyses were performed in R version 3.6.1 (“Action of the Toes”)The initial data set comprised 3,338,526 patients. A total of 1,365,458 patients whose records contained fewer than three eGFR tests were excluded, leaving 1,973,068 patients eligible for analysis: 1,921,949 without a urine albumin test on record, 37,947 with normoalbuminuria (<3 mg/mmol), 10,248 with microalbuminuria (3–30 mg/mmol), and 2,924 with macroalbuminuria (>30 mg/mmol). Each of the four cohorts were split into two halves and nominated as training and testing data sets. Due to the computational demands of the statistical method used, we randomly selected a sub-cohort of 50,000 patients to fit the model in the cohort without a urine albumin test on record. Summary statistics of patient characteristics from the four cohorts are presented inExtended data).Six state continuous time HMMs adjusted for sex, heart failure, cancer, hypertension and diabetes, and annually updated age were fit on the four training data sets. Hypertension and diabetes were subsequently removed from the models as they were unable to predict eGFR stage progression or death. All models converged to their respective maximum likelihood estimates, with positive definitive Hessian matrices permitting confidence interval estimation for all parameters. Intensity, transition and misclassification matrices for these models are given in Supplementary Tables S2—13  as this is a contributing factor to CKD, but the addition of this non-absorbing state with pathways back to each state resulted in over-parametrisation of the model. Furthermore, data on urine albumin, body mass index and ethnicity is missing in a large number of patients in CPRD. To overcome this, we created a sub-group of patients in whom urine albumin was not recorded. The omission of ethnicity in this model is a limitation as kidney function decline is considered to differ between ethnic groups. We were not able to adjust our models for ethnicity, as historically, ethnicity has been poorly recorded in CPRD.. Even so, our model calibrates well with reports of progression to ESRD from different stages. For example, Tangriet al. reported that three from 2,014 people with CKD stage 3 at baseline progressed to ESRD after three years of follow-up. Assuming this population contained an equal proportion of people with CKD stage 3a and 3b, then our model, based on the unmeasured urine albumin cohort, would predict that just one person would reach stage 5 after three years. Using the model for patients with normoalbuminuria, it would be three people. From the same study, 22 of 826 people progressed from stage 4 at baseline to kidney failure after three years. Our models predict 25 people with unmeasured urine albumin and 46 people with normoalbuminuria would reach stage 4. In a study reporting on sex differences in CKD progression, the rate of ESRD per 100 person-years was 3.1 in women and 3.8 in men. Based on our model for patients with normoalbuminuria our equivalent estimates are 1.9 and 2.3, but 2.07 and 2.13 for patients with microalbuminuria and 3.0 and 3.2 for patients with macroalbuminuria. Our study shows that kidney function deteriorates slowly in most patients with average sojourn times in decades rather than years. Whilst eGFR is widely used to measure kidney function we estimate that the potential for misclassification is large and clinically relevant, with implications for monitoring for rapid kidney function loss or pharmacovigilance. For example, of 1,741 people with CKD stage 3 recruited for a study from 32 primary care practices in the UK, 496 were in remission at baseline  and of these, 157 were back to CKD stage 3 at one year, with a further 132 returning to stage 3 CKD by five years. This type of pattern is consistent with our model, in which underlying kidney function only deteriorates but is observed with error. If our model is correct, then it is clear to see how monitoring CKD periodically will confuse and might lead to inappropriate action. The assumption that true underlying kidney function only deteriorates with age is a fundamental part of the model and further research could investigate alternative models for underlying kidney progression and their impact monitoring recommendations.It is likely that once a patient’s kidney function has been observed in stage 4 or 5, they are referred to specialist care, with subsequent kidney function testing occurring outside the CPRD database. Hence, these patients’ records are missing from our study, which potentially explains why transition rates slow down rather than increase, as might be expected. Our study design means that we would also miss patients with ESRD who had not engaged in primary care. In a study of electronic health records data from Pennsylvania, a similar model was fit to eGFR records, and reported that transition probabilities between kidney function stages generally increased as stage increased for all but stage 3. Future work in this field could look to validate this model in another primary care population, ideally one in which patients are followed throughout including stages 4 and 5.We have developed a model to predict decline in kidney function and used it to assess different monitoring strategies and screening programmes. The model takes into account stage progression and test error, which were recently identified as important for future economic evaluations of CKD testing The revised version includes no new or revised analyses.  So this Version 2 report deals entirely with the authors' responses to my Version 1 Report and the edits in their Discussion. I repeat the positive aspects of this manuscript summarised in the first two paragraphs of my Version 1 Report, dealing with the importance of the issue raised by the authors, the almost total absence of evidence on the utility of measurement of eGFR and proteinuria in a population of subjects similar to those followed in UK General Practices, the availability of the nearly unique set of data from the Clinical Practice Research Datalink, and the authors' competence in performing their Hidden Markov Model analysis.  My reservations dealt mostly with the authors' choice of analytic model. The authors' rationale for their use of their Hidden Markov Model is that it permits adjustment for the well-documented degree of CKD stage misclassification that is revealed when estimates of eGFR are compared with directly measured GFR . But their Hidden Markov Model also makes assumptions that may well not hold in reality.  There are two specific issues with the authors' Markov assumptions: a. that eGFR once "lost" cannot be recovered, and b: that the history of prior changes in renal function is not informative once a Markov transition has occurred.  This model seems to be based on an assumption that reduction of eGFR is mostly associated with irreversible changes in renal structure or physiology.  This assumption is particularly risky in subjects with relatively well preserved renal function and absent or trace proteinuria -- demonstrably the large majority of subjects in the authors' cohort and evidently the primary focus of their broader project.  In these subjects, the likelihood of a transient reduction of eGFR due to any episode leading to dehydration may well be greater than of an event causing an irreversible loss of function (conflicting with the assumption that "true" [hidden] eGFR cannot increase following a drop in eGFR).  Further, subjects with prior episodes of AKI are known to have greater subsequent chance of progressing to ESRD, and subjects receiving treatment with any of the three classes of treatment shown to be effective in delaying progression  are all associated with immediate reductions of eGFR that are associated with later slower risk of subsequent progression.  These facts conflict with the assumption that past changes in eGFR leading to a Markov stage transition are not informative of the chance of subsequent loss of eGFR.  I suggested using an alternative model -- joint modeling -- that deals similarly with the issue of errors in measurement of proposed predictors by estimating a true but "hidden" path of eGFR over time from the observed values and uses estimates from that model at relevant time points as the estimated "true" current value for the joint survival model.  This technique permits use of all the continuous primary data without collapsing it into categories, makes no assumption excluding increases of eGFR, and permits many options for assumptions about the impact of earlier values. Additionally, this approach would permit direct evaluation of the concordance and the rate of classification error of the relevant primary outcomes -- ESRD or death. In my Version 1 report, I noted that "Given the huge amount of information available for this analysis, the inefficiency of the hidden Markov model may be overcome in the analysis of the overall community estimates of rate of progression."  This seems to be the case in the paper cited in their response to my critique, and I agree that their analytic method is useful for evaluation of choice of overall or group policy.  I suspect, though, that alternative analytic methods permitting use of all of the continuous data might be more powerful in refining predictions, and therefore permitting individualized recommendations or guidelines applicable to specific patients.   In their response to my Version 1 report, the authors' have included new text recognizing the limitations of the Markov approach and recognized that "Further research could include assessing the impact of the Markov assumption on predicting kidney function decline using HMMs."  Given this addition, I now approve this manuscript.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?NoIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:Nephrology, Epidemiology, Statistics, Clinical trial design, performance, and analysis.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. I have no further comments.Is the work clearly and accurately presented and does it cite the current literature?PartlyIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?NoIs the study design appropriate and is the work technically sound?NoAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Renal epidemiologyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The authors of this manuscript report on the long-term rate of progression of chronic kidney disease (CKD) in a very large cohort of UK general practice patients followed as part of the Clinical Practice Research Datalink in the time between 1 April 2005 and 31 March 2014. Progression of kidney disease over each patient's course was assessed as the rate of progression from one stage to the next across the six currently standard KDOQI/KDIGO "stages" of renal insufficiency , which are defined by ranges of estimated glomerular filtration rate (eGFR). The rate of progression from one stage to the next was modeled as a Hidden Markov Model, which assumes that subjects are at "true" eGFR stages at each evaluation point, but that these stages may be misclassified based on random error of the eGFR estimate, so that the "observed" transitions may be misidentified. The overall conclusions of the authors are: a) that progression of renal disease to renal failure occurs quite slowly in general, with only a small fraction of patients that progress to kidney failure, and b) that progression of kidney disease as evidenced by [exclusive] use of progression in the KDOQI/KDIGO Stage of CKD, though generally reflective of the average course of kidney disease in the community, is associated with significant error when applied to an individual. Though the authors don't say this, the implication is that use of their analysis may not be very helpful in establishing guidelines as to in whom, and at what repeated intervals, eGFR determinations would be cost effective. The major strength of this study is the almost unique test bed offered by access to the data of almost 2,000,000 UK qualified general practice patients from Clinical Practice Research Datalink with "up-to-standard" data collection. Given the choice of analytic method, the authors' analysis is technically entirely competent. The assumptions and methods are well described. The results are clearly explained and put in appropriate context in the Discussion Section. The major limitation of the available data is that patients with the more advanced Stages of kidney disease are likely to have been referred to specialist providers, so that data on the more advanced stages of kidney disease, where progression is generally both more rapid and more clinically important, are more limited and more susceptible to bias. The authors clearly acknowledge this. Further, the issue addressed by this manuscript is potentially important, at least from a health economics point of view. Current policy recommendations uniformly encourage periodic assessment of renal function "in people with, or at risk of, chronic kidney disease (CKD)." But as noted above, in general kidney disease progresses quite slowly and only a small minority of subjects even with documented kidney disease ever progress to chronic renal failure. There is almost no empirical data upon which to make any data-based recommendation about in whom or how often the "periodic assessments" should be done. 2) to close to 0. The reduction of this range of values to a classification with 6 levels is associated with massive information loss. Markov models deal with chances of transition from one state to another, and all members of one state are considered to be interchangeable, so that a patient with an eGFR of 100 (at Stage 1/2 with the combination of these two stages) is treated as equivalent to one with an eGFR of 62. But surely the chance of progression from an eGFR of 100 to an eGFR < 60 (Stage 3a) is much lower than the chances of progression from a value of 62 to < 60 . Similarly, it is intuitively likely  that a subject with a history of rapid loss of eGFR in the past will have more rapid progression in the future. But with a Markov model, all history is lost, and only the current stage, and not the prior history is taken into account. Given the huge amount of information available for this analysis, the inefficiency of the hidden Markov model may be overcome in the analysis of the overall community estimates of rate of progression. But these results will be of almost no use in prediction of the progression of kidney disease in the individual patient. And it is the individual patient's progress, not the average rate of progression in the community, that we are trying to clarify in recommending individual testing eGFR and setting repeat testing intervals.  But the choice of analytic method is subject to criticism. The continuous variable eGFR may range from over 100 , error due to the underlying determination of serum creatinine (Scr) which is increased at low levels of Scr because of its inverse relationship with eGFR, or variability in timing of the underlying measurements of serum creatinine). Mixed methods also permit specification of alternative models of change over time, permitting exploration of the hypotheses that progression is not linear. They would also facilitate development of time dependent models, allowing input of changes to patient's diabetes, hypertension, and cancer status over time, rather than limiting those variables to the baseline analysis. Most important, this sort of analysis might permit identification of the subset of individuals for whom the risk of progression is the highest -- that might be most benefited by careful follow-up of eGFR, and might give better guidance as to cost-effective testing intervals. An alternative approach would have been to use a hierarchical ("mixed") analytic method  to evaluate the overall community rate of progression while estimating the distribution of individual rates of progression. Mixed models deal automatically with the problem that eGFR is measured with error  If the authors felt constrained by these requirements, they have performed a reasonable, if inefficient, analysis. But they and the authors of reference 29 might have done better to request and perform a more efficient analysis using the underlying eGFR data rather than the derived CKD Stages to develop their model, and then abstracted stage specific recommendations from the more efficient model, rather than the other way around.  In sum, the analysis as performed using the specified analytic model was competently done, and the overall conclusions are justified - that the rate of progression of renal insufficiency is slow on average, and that dependence on this model would be associated with potentially significant error. But these limited conclusions don't exclude the possibility that more clinically reliable and useful data might be obtained by use of a method that didn't throw away so much of the available data.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?NoIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:Nephrology, Epidemiology, Statistics, Clinical trial design, performance, and analysis.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Reviewer: The authors of this manuscript report on the long-term rate of progression of chronic kidney disease (CKD) in a very large cohort of UK general practice patients followed as part of the Clinical Practice Research Datalink in the time between 1 April 2005 and 31 March 2014. Progression of kidney disease over each patient's course was assessed as the rate of progression from one stage to the next across the six currently standard KDOQI/KDIGO "stages" of renal insufficiency , which are defined by ranges of estimated glomerular filtration rate (eGFR). The rate of progression from one stage to the next was modeled as a Hidden Markov Model, which assumes that subjects are at "true" eGFR stages at each evaluation point, but that these stages may be misclassified based on random error of the eGFR estimate, so that the "observed" transitions may be misidentified. The overall conclusions of the authors are: a) that progression of renal disease to renal failure occurs quite slowly in general, with only a small fraction of patients that progress to kidney failure, and b) that progression of kidney disease as evidenced by [exclusive] use of progression in the KDOQI/KDIGO Stage of CKD, though generally reflective of the average course of kidney disease in the community, is associated with significant error when applied to an individual. Though the authors don't say this, the implication is that use of their analysis may not be very helpful in establishing guidelines as to in whom, and at what repeated intervals, eGFR determinations would be cost effective.Authors: We disagree. We believe our model  permits analysis that correctly considers the misclassification that commonly occurs when monitoring kidney function using estimated GFR. This is important because when a person is misclassified into a higher stage treatment may represent a cost but provide less benefit than expected and in the opposite scenario a misclassification into a lower stage  would not incur costs from direct treatment but would render the patient at a higher risk for longer. Attempts to model the cost-effectiveness of monitoring without taking this into account are potentially misleading. The work presented in this manuscript formed part of a wider research project, which is intended to assess the cost effectiveness of kidney function monitoring. The health economics study using the outputs from this paper can be found athttps://doi.org/10.1371/journal.pmed.1003478. The Health and Technology Assessment programme this work feeds into can be found athttps://www.journalslibrary.nihr.ac.uk/programmes/pgfar/RP-PG-1210-12003.Reviewer: The major strength of this study is the almost unique test bed offered by access to the data of almost 2,000,000 UK qualified general practice patients from Clinical Practice Research Datalink with "up-to-standard" data collection. Given the choice of analytic method, the authors' analysis is technically entirely competent. The assumptions and methods are well described. The results are clearly explained and put in appropriate context in the Discussion Section. The major limitation of the available data is that patients with the more advanced Stages of kidney disease are likely to have been referred to specialist providers, so that data on the more advanced stages of kidney disease, where progression is generally both more rapid and more clinically important, are more limited and more susceptible to bias. The authors clearly acknowledge this. Further, the issue addressed by this manuscript is potentially important, at least from a health economics point of view. Current policy recommendations uniformly encourage periodic assessment of renal function "in people with, or at risk of, chronic kidney disease (CKD)." But as noted above, in general kidney disease progresses quite slowly and only a small minority of subjects even with documented kidney disease ever progress to chronic renal failure. There is almost no empirical data upon which to make any data-based recommendation about in whom or how often the "periodic assessments" should be done.Authors: We would like that thank the Reviewer for the very positive comments and we agree that patients with more advanced stages of kidney disease might have been referred to specialist care. We would like to emphasise that the main aim of this study was estimate the rate of progression of kidney function decline before they enter end-stage renal disease, requiring specialist care. Therefore, there is a plethora of data, on which to make data-based recommendations regarding the frequency of periodic assessments. Tables S17–20 show that where such recommendations have been made, these have ‘only’ been for patients in eGFR stages G3a and G3b. Patients in these stages are still monitored within primary care, as opposed to specialist care. Moreover, as general practices are financially incentivised by the Quality and Outcomes Framework (QOF) to monitor such patients, there is no shortage of data for these patients as demonstrated in Table 1. Furthermore, it’s also worth noting that Table 1 represents the baseline values for patients from an open cohort spanning the years 2005–2014. During this time, there were two substantial changes to QOF that increased the frequency of serum creatinine and proteinuria testing—one in 2006 and another in 2009. The effect of these changes can be seen in Figure 3. This figure shows that serum creatinine testing increased in subjects with CKD stages ≥2 from 2005 to 2008, where it reached a new plateau, and proteinuria testing increased in subjects with CKD stages ≥4 from 2008 to 2010, where it too reached a new plateau. A significant number of patients would have entered our study cohort prior to these dates, making Table 1 a poor reflection of the general quality of the testing data https://doi.org/10.1136/bmjopen-2018-028062. This figure shows that serum creatinine testing increased in subjects with CKD stages ≥ 2 from 2005 to 2008, where it reached a new plateau, and proteinuria testing increased in subjects with CKD stages ≥ 4 from 2008 to 2010, where it too reached a new plateau. A significant number of patients would have entered our study cohort prior to these dates, making Table 1 a poor reflection of the general quality of the testing data.Reviewer: But the choice of analytic method is subject to criticism. The continuous variable eGFR may range from over 100 (mL/min/1.73 m2) to close to 0. The reduction of this range of values to a classification with 6 levels is associated with massive information loss. Markov models deal with chances of transition from one state to another, and all members of one state are considered to be interchangeable, so that a patient with an eGFR of 100 (at Stage 1/2 with the combination of these two stages) is treated as equivalent to one with an eGFR of 62. But surely the chance of progression from an eGFR of 100 to an eGFR < 60 (Stage 3a) is much lower than the chances of progression from a value of 62 to < 60. Similarly, it is intuitively likely  that a subject with a history of rapid loss of eGFR in the past will have more rapid progression in the future. But with a Markov model, all history is lost, and only the current stage, and not the prior history is taken into account. Given the huge amount of information available for this analysis, the inefficiency of the hidden Markov model may be overcome in the analysis of the overall community estimates of rate of progression. But these results will be of almost no use in prediction of the progression of kidney disease in the individual patient. And it is the individual patient's progress, not the average rate of progression in the community, that we are trying to clarify in recommending individual testing eGFR and setting repeat testing intervals.Authors: The Reviewer is correct in stating that the Markov assumption means that each subject’s transition to a more severe eGFR stage depends only upon their current stage. We agree that this assumption may be an oversimplification of reality, as it would be likely that an individual who has progressed rapidly through previous stages will continue to do so, and vice versa. As for the reviewers point about likelihood of progression being different if eGFR was 100 vs 62 ml/min/1.73m2, we do not disagree that progression to a next stage would be different, but we would emphasise the problem of knowing what true eGFR is. For example, someone in whom true eGFR is 80 ml/min/1.73m2, their observed eGFR could be anywhere between 70 and 90 ml/min/1.73m2. So, by categorising eGFR into six levels there is some loss in information, but we have a more robust inference. We strongly disagree that these models will be almost of no use. Our models provide average progression times conditional on eGFR stage and presence of albuminuria, and other co-morbidities, e.g., heart failure. The same problem would exist for mixed effect models in as much as you can only provide aggregated rates of decline. We have added the following paragraph to the Discussion section:We could be criticised for using an approach that categorises kidney function rather than a method that models continuous eGFR, such as generalised linear mixed models. This is because categorisation can lead to loss of information and reduced statistical power. However, such information loss is typically small when the number of categories is large , as was the case in our study. Furthermore, the use of categories that naturally aligned with clinically meaningful eGFR stages added to the interpretability of our findings. In addition, HMMs assume that all individuals within a state are interchangeable, and that the chance of progression to subsequent states depends only on the current state. This assumption may not hold if a patient whose kidney function has previously rapidly declined continues along this trajectory. To mitigate this, we have included updated risk factor information in our model and stratified by baseline albuminuria status. Further research could include assessing the impact of the Markov assumption on predicting kidney function decline using HMMs.” “Reviewer: An alternative approach would have been to use a hierarchical ("mixed") analytic method  to evaluate the overall community rate of progression while estimating the distribution of individual rates of progression. Mixed models deal automatically with the problem that eGFR is measured with error 1, error due to the underlying determination of serum creatinine (Scr) which is increased at low levels of Scr because of its inverse relationship with eGFR, or variability in timing of the underlying measurements of serum creatinine). Mixed methods also permit specification of alternative models of change over time, permitting exploration of the hypotheses that progression is not linear. They would also facilitate development of time dependent models, allowing input of changes to patient's diabetes, hypertension, and cancer status over time, rather than limiting those variables to the baseline analysis. Most important, this sort of analysis might permit identification of the subset of individuals for whom the risk of progression is the highest -- that might be most benefited by careful follow-up of eGFR and might give better guidance as to cost-effective testing intervals.Authors: The reviewer is correct, there are alternative statistical models to the approach we led with in this paper. Our initial intention was to model eGFR (or log eGFR) using mixed effect models, but we decided against it for two reasons: the trajectories of eGFR are not linear or necessarily even monotonic in time; more flexible modelling is limited by the fact that for many people only a few eGFR measurements existed in their health record. The models that we did fit did not meet the assumptions of normality implicit in the random effects approach and this, we believe, led to poor predictive performance of these models. It is possible that in an alternative data set, it would be possible to fit these models, but this was not our experience using routinely collected GP data. We would like to stress that we used updated covariates in all the HMMs used in this study and did not condition on only the baseline values of these.Reviewer: The authors' choice of analytic methods in this analysis should be put into perspective. The authors were evidently motivated to undertake this analysis so that cost-effectiveness studies could be done specifically in terms of the KDOQI/KDIGO CKD staging mechanism -- presumably to make it easier to develop easily followed guidelines for testing frequency.  If the authors felt constrained by these requirements, they have performed a reasonable, if inefficient, analysis. But they and the authors of reference 29 might have done better to request and perform a more efficient analysis using the underlying eGFR data rather than the derived CKD Stages to develop their model, and then abstracted stage specific recommendations from the more efficient model, rather than the other way around.Authors: The reviewer is not entirely correct. This model was one part of a larger funded project which included a cost-effectiveness study using the outputs from this model, but it is not true that we felt or were constrained by this. Our initial plan was to model eGFR as a continuous measure, but we did not for reasons explained in the previous response. We feel the objective of our work is quite the opposite to the reviewer and we would prioritise models than fit clinical practice over and above statistical efficiency.Reviewer: In sum, the analysis as performed using the specified analytic model was competently done, and the overall conclusions are justified - that the rate of progression of renal insufficiency is slow on average, and that dependence on this model would be associated with potentially significant error. But these limited conclusions don't exclude the possibility that more clinically reliable and useful data might be obtained by use of a method that didn't throw away so much of the available data.Authors: We disagree with the assertion made by the reviewer that our method “threw so much of the data away”. We agree that categorisation can result in loss of information, but this is most likely to occur when continuous measures are split in two (dichotomisation) and applied to small data sets. The thresholds for categorisation should also not be defined post-hoc. Neither of these are true in our case. To cite Altman and Royston “using multiple categories  is generally preferable to dichotomising. With four or five groups the loss of information can be quite small, but there are complexities in analysis” (seehttps://doi.org/10.1136/bmj.332.7549.1080). Moreover, we have provided calibration plots in Figures S1–4 that demonstrate the accuracy of the predictions made by the models. The authors used CPRD records to inform a multistate model on progression of kidney disease. They appropriately considered that there could be measurement error and allowed for this to some extent.  They used outcome variables that have not been validated for incident analyses in CPRD. The underlying model for 'true' but unobserved kidney disease assumed that kidney disease could only get worse over time but not better - but this is not supported by actual data which suggest that transient decreases can improve over time and may not necessarily need to be permanent (though such changes may be a risk marker for later decline). Here the authors should discuss more about the chronicity assumption within the CKD definition and how they parametrised this in their data. Then there was a model for measurement error, but this seems to be a static model, i.e. assuming that measurement error does not vary over time - did I understand this correctly? Because over time in the UK the way creatinine gets measured and reported has changed dramatically during the study period. This change in reporting of calibrated creatinines in effect hides progression over time when crude analyses are used as different labs shifted to calibration and reporting of creatinine to IDMS at different points in time - thereby shifting the entire creatinine distribution down by 5% over the years prior to 2014 (i.e. hiding a decrease in kidney function over time). Did the authors recalculate eGFR from the creatinines (which then requires some thought about time-dependent measurement error which varies by lab and time) - or use reported eGFRs ? Dependent on whether the authors used creatinine or eGFR they have discussed further biases in their design and explicitly allow for such biases in their model. Then there is the overall study design which is a somewhat odd cohort as it is dependent on having three or more eGFR (or creatinine?) tests and that is not representative of the general population - the survey and CPRD validated prevalence of reduced eGFR in the UK population is about 6% and here the numbers are much higher  simply because these represent an enriched sample as GPs had a reason to test more than once but indeed three times. Does this enriched sample really represent 'a model for kidney disease progression'? The authors should discuss this and whether people who should have been tested but weren't tested may be a high risk group. The sample here represents a group of patients who engage with the health service but the people who progress in truth may be not fully captured. This needs to be discussed more. There were real financial reasons for testing e.g. annual testing for diabetes (started in 2004), and less so for other illnesses, but risk factors for CKD determine testing rates and especially repeat testing as reported by the UK National CKD Audit, and there is some understanding from this audit how testing schemes are carried out. So I would disagree with "A major strength of this study is that we have taken a very large and unselected sample of patients from a database that has been shown to be representative of the wider UK population" as stated in the discussion - this is a selected sample and not representative of what happens overall in terms of kidney function decline as not all are tested the same way. I would have stratified by underlying comorbidity and not simply adjusted for it. I totally agree with the authors about the selective loss to follow-up with loss of people who are managed by other specialities including renal in secondary care.  Overall this is an interesting analysis, but more work is needed to convince me that this model should be used for economic modelling.Is the work clearly and accurately presented and does it cite the current literature?PartlyIf applicable, is the statistical analysis and its interpretation appropriate?PartlyAre all the source data underlying the results available to ensure full reproducibility?NoIs the study design appropriate and is the work technically sound?NoAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Renal epidemiologyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Reviewer: They used outcome variables that have not been validated for incident analyses in CPRD .Authors: We did not model or attempt to estimate the incidence of dialysis or transplantation. We have included patients who would be candidate for dialysis or transplantation (patients with stage 4/5 CKD), but we censored patients at the first code relating to dialysis or transplantation from hospital or GP records. Moreover, we excluded patients with history of renal replacement therapy. It is unlikely that a significant number of patients would have received either dialysis or renal replacement therapy without there being a code to identify it in the data.Reviewer: The underlying model for 'true' but unobserved kidney disease assumed that kidney disease could only get worse over time but not better - but this is not supported by actual data which suggest that transient decreases can improve over time and may not necessarily need to be permanent (though such changes may be a risk marker for later decline). Here the authors should discuss more about the chronicity assumption within the CKD definition and how they parametrised this in their data.Authors: It is true that kidney function, albeit measured by an imperfect test  has been observed to improve and whilst this might be true, observed improvements in kidney function could also be as a result of measurement error or intervention. For simplicity, and with the agreement of the clinicians on the paper (DL and CO’C), we thought the unidirectional model for true underlying kidney function to be biologically plausible. We did perform a sensitivity analysis in which we allowed underlying kidney function to spontaneously (without intervention) improve. We concluded that this model did not fit the data as well as the progression only model. We have added the following text to the eighth paragraph of the Discussion section:The assumption that true underlying kidney function only deteriorates with age is a fundamental part of the model and further research could investigate alternative models for underlying kidney progression and their impact monitoring recommendations.” “Reviewer: Then there was a model for measurement error, but this seems to be a static model, i.e. assuming that measurement error does not vary over time - did I understand this correctly? Because over time in the UK the way creatinine gets measured and reported has changed dramatically during the study period. This change in reporting of calibrated creatinines in effect hides progression over time when crude analyses are used as different labs shifted to calibration and reporting of creatinine to IDMS at different points in time - thereby shifting the entire creatinine distribution down by 5% over the years prior to 2014 (i.e. hiding a decrease in kidney function over time).Authors: This is a valid point, relating to a problem we have encountered in routine health record data sets. However, we feel that this issue is likely to have minimal impact to our study, as apart from the last 3.25 years, our data pre-dates the use of IDMS as the changes took place in 2010. Furthermore, we conducted this study in an open cohort (CRPD-Vision) that has been decreasing in size (https://doi.org/10.1136/bmjopen-2017-020738), further attenuating the pool of potentially affected tests.Reviewer: Did the authors recalculate eGFR from the creatinines (which then requires some thought about time-dependent measurement error which varies by lab and time) - or use reported eGFRs ? Dependent on whether the authors used creatinine or eGFR they have discussed further biases in their design and explicitly allow for such biases in their model.Authors: In this study, we used all testing sources available to obtain eGFR, including pre-derived eGFR values. Unfortunately, the data source used provides no information on the techniques used to measure serum creatinine levels or to estimate eGFR. We also no longer have access to this data. Hence, we cannot say whether the calculation of a particular eGFR value was performed using laboratory methods or via an estimating equation in a GP practice. However, we estimated the overwhelming majority of eGFR values from raw serum creatinine values. Hence, any bias present from the use of pre-derived eGFR values is likely to be minimal. The method we used to calculate eGFR from serum creatinine was the CKD-EPI equation. We are aware that better method for the calculation of eGFR exist, however, the one we used would have been the one predominantly in use in UK clinical practice throughout the study period.Reviewer: Then there is the overall study design which is a somewhat odd cohort as it is dependent on having three or more eGFR (or creatinine?) tests and that is not representative of the general population - the survey and CPRD validated prevalence of reduced eGFR in the UK population is about 6% and here the numbers are much higher  simply because these represent an enriched sample as GPs had a reason to test more than once but indeed three times. Does this enriched sample really represent 'a model for kidney disease progression'? The authors should discuss this and whether people who should have been tested but weren't tested may be a high risk group. The sample here represents a group of patients who engage with the health service but the people who progress in truth may be not fully captured. This needs to be discussed more.Authors: The requirement of three serum creatinine tests was imposed to establish a reliable baseline eGFR status (requiring two tests) and to estimate change over time. We concede that the population present in this sample is not representative of a general UK population so much as a UK general practice population, and we have amended the wording of the fourth paragraph of the Discussion section of the manuscript to reflect this. This reads:Inclusion into the study was conditional upon having three or more serum creatinine measurements, but creatinine is commonly measured in UK general and not necessarily for the purpose of monitoring kidney function or diagnosing kidney disease.” “ … and later in the eighth paragraph of the Discussion section:Our study design means that we would also miss patients with ESRD who had not engaged in primary care.” “ The degree to which this could bias our results is open to some conjecture, and we have also made such comments in the Discussion section of the manuscript. Furthermore, others  who have studied the underlying mechanisms for requesting kidney function testing have concluded that the only mechanism by which testing may bias estimates of transition rates is that of patient-driven testing, which we feel is possible, but unlikely.Reviewer: There were real financial reasons for testing e.g. annual testing for diabetes (started in 2004), and less so for other illnesses, but risk factors for CKD determine testing rates and especially repeat testing as reported by the UK National CKD Audit, and there is some understanding from this audit how testing schemes are carried out. So I would disagree with "A major strength of this study is that we have taken a very large and unselected sample of patients from a database that has been shown to be representative of the wider UK population" as stated in the discussion – this is a selected sample and not representative of what happens overall in terms of kidney function decline as not all are tested the same way. I would have stratified by underlying comorbidity and not simply adjusted for it.Authors: When we wrote the section of text in question, we were referring to the non-selected nature of any one individual appearing in the dataset, i.e., their presence was only determined through virtue of their general practice opting into the database. However, as per our previous response, the population used in this study is still representative of a GP patient cohort, which is the setting in which we anticipate these results to be generalised. We have endeavoured to ensure that our study population was as non-specific as possible, but he nature of our study meant that patients needed to have creatinine measures present in their medical history for us to draw any kind of inference on their kidney function decline. We would also add that, contrary to the reviewer’s comments, we have stratified our analysis by the factors most important in determining the rate of kidney function decline, being the initial albuminuria stage. This is in line with the findings of other studies in this area .


Low back pain (LBP) remains one of the most common and incapacitating health conditions worldwide. Clinical guidelines recommend exercise programs after the acute phase, but clinical effects are modest when assessed at a population level. Research needs to determine who is likely to benefit from specific exercise interventions, based on clinical presentation. This study aimed to derive clinical prediction rules (CPRs) for treatment success, using a lumbar stabilization exercise program (LSEP), at the end of treatment and at six-month follow-up. The eight-week LSEP, including clinical sessions and home exercises, was completed by 110 participants with non-acute LBP, with 100 retained at the six-month follow-up. Physical  and psychological (related to fear-avoidance and home-exercise adherence) measures were collected at a baseline clinical exam. Multivariate logistic regression models were used to predict clinical success, as defined by ≥50% decrease in the Oswestry Disability Index. CPRs were derived for success at program completion (T8) and six-month follow-up (T34), negotiating between predictive ability and clinical usability. The chosen CPRs contained four (T8) and three (T34) clinical tests, all theoretically related to spinal instability, making these CPRs specific to the treatment provided (LSEP). The chosen CPRs provided a positive likelihood ratio of 17.9 (T8) and 8.2 (T34), when two or more tests were positive. When applying these CPRs, the probability of treatment success rose from 49% to 96% at T8 and from 53% to 92% at T34. These results support the further development of these CPRs by proceeding to the validation stage. Low back pain (LBP) remains one of the most incapacitating health conditions worldwide, and one for which the majority of suffers cannot be given a reliable diagnosis of the cause(s) of their pain . This diLumbar stabilization exercise programs (LSEP) target motor control and coordination of the paraspinal and abdominal musculature, and may also progressively overload muscles to enhance trunk muscle endurance –5. This Another research group has published preliminary work, at the derivation stage, on the development of CPRs for an LSEP . The conThe aim of the present study was to perform the derivation stage of CPRs for treatment success using an LSEP, for adult patients with non-acute low back pain. The LSEP was a hybrid between the McGill and Australian approaches, using exercises specific to motor control and to isometric endurance/strengthening. The primary goal was to extend previous positive findings  by usingA prospective one-arm study involving three assessments taken during the intervention and a six-month follow-up was carried out in a single patient group . While sThis study design allows us to pursue two objectives, namely to 1. to derive two CPRs (treatment success at the end of treatment and at six-month follow-up) using practical  measures obtained during the initial clinical examination and 2. to identify the mechanisms involved in this exercise program through an expanded battery of measures, thus allowing the specific effects of the treatment to be described. The present study will address the first objective (CPRs’ derivation), using physical (PHY) and psychological (PSY) measures collected at T0 and primary clinical outcome measures (OUT) collected at T0, T8 and T34 . The othUsing preliminary findings  derived Participants were recruited through newspaper advertisements and from physiotherapy clinics in Montreal, Quebec, Canada, and were assessed from July 2012 to August 2016 (preliminary study or phase 1) and from July 2018 to October 2020 (phase 2). They were French- or English-speaking, aged between 18 and 65 years, had lumbar or lumbosacral pain, with or without radicular pain, for at least four weeks (non-acute phase) and a minimum score of 12% on the Oswestry Disability Index (ODI) , thus alAll procedures and the informed written consent were approved by the ethics committees of the Centre for Interdisciplinary Research in Rehabilitation of Greater Montreal (CRIR) .Guide du dos: ISBN: 978-2-923465-03-6), was given to patients at their first clinical visit. The booklet aimed to change beliefs and behaviours (resuming activities) related to back pain. Physiotherapists received a one-day training session explaining how to describe the study (1 hour) and, more importantly, how to teach patients the exercises (8 hours).The 8-week LSEP was implemented by 15 physiotherapists from private physiotherapy clinics in the Montreal area, without any co-interventions , except for medications . In order to standardize the information given to patients on their condition, the Back Book booklet , or its The exercise program, which has been previously detailed  physical therapist (N.R.). The exam was comprised of tests that can be theoretically related to lumbar segmental instability (LSI) or motor control impairments (MCI) , 33, 34 As detailed in Three subgroups of patients were defined according to their level of success using ODI at T8 or T34: 1. success, 2. clinically significant improvement, and 3. failure, similar to Hicks, Fritz . For thiSuccess: ΔODI% ≥ 50Clinically significant improvement: ΔODI% < 50%, but ΔODI ≥ 10Failure: ΔODI% < 50% and ΔODI < 10Logistic regression models were developed to define, on the basis of the initial measures (PHY and PSY measures at T0), the characteristics of the patients who had therapeutic success at T8 and then at T34.The steps in these processes are briefly described as follows:Six methods were used to identify the most informative cut-off points of our continuous variables to discriminate between the success and failure groups. Method 1 (ROC) is deduced from the ROC curve (Receiver Operating characteristic); the plot representing the rate of true positives to the rate of false positives. Method 2 (Md) reports a simple cut-off of the series at its median value. Method 3 (YI) uses the maximum value of the Youden index as the informative point . Method The use and crossing of these different methods allowed us to better probe our variables and select the most informative cut points. Joint investigations were also carried out to examine the selected cut points in clinical and physiological terms, and their concordance with the available literature, if any. The statistical and functional characteristics of the selected variables were also examined in light of the information provided by sensitivity, specificity, and likelihood ratios, as well as their discriminatory abilities expressed by the area under the ROC curve and the negotiation between false diagnosis rates.For each dichotomous variable, a univariate analysis (chi-square) between the "success" and "failure" subgroups was performed to select variables with some predictive potential, using a liberal statistical criterion (P < 0.20). The corresponding positive likelihood ratio (LR+) was also considered so that a variable with LR+ ≥ 2 was also accepted, even if the Chi-square gave a P ≥ 0.20, which occurred in rare cases. In any case, only multivariate models that contained predictors that were all statistically significant were retained.Step 1: consideration of class-A variables, which are the variables that should be considered for model fitting , with genetics driving age and sex differences , as wellStep 2: in addition to class-A variables, consideration of variables that may influence outcomes through adherence to the home exercise program , 47, herStep 3: in addition to class-A and class-B variables, consideration of variables that may be associated with any exercise program (class-C variables—not treatment specific).A three-step hierarchical modeling was performed. In each of these steps, a backward stepwise approach was used. The three steps are described as follows:Various statistics to judge the performance of the selected multivariate models, including coefficients of determination (Nagelkerke’s R2), sensitivity (Se) and specificity (Sp) scores as well as positive and negative predictive values (PV+ and PV-) and likelihood ratios (LR+ and LR-) were calculated;Class-A, -B, and -C variables are described in Participants were recruited mainly through newspaper advertisements, except six from the clinics as these usually start an exercise program before the end of the acute phase. The flow diagram  describeParticipants’ demographic, anthropometric and clinical characteristics at baseline (T0) were equivalent between males (n = 50) and females (n = 60), with the exception of height and weight, as expected . Overalld = -1.24 and -1.70, respectively). Significant decreases of these outcomes were also observed at T34 (n = 100), also resulting in strong effect sizes .All the participants completed the 8-week exercise program and reached the third  phase of the program. Home-exercise adherence was high at T8 (ratio: 0.85 ± 0.21) and lower at T34 (ratio: 0.51 ± 0.40). The participants meeting the criteria for success, clinically significant improvement and failure at T8 were 54 , 11 (4 M + 7 F) and 45 (23 M + 22 F), respectively. At T34, they were 53 (25 M + 28 F), 11 (1 M + 10 F) and 36 (16 M + 20 F), respectively. Overall, the participants assessed at T8 (n = 110) showed a significant decrease (pre- to post-treatment) in the ODI and NPRS  resultinCandidate variables to multivariate logistic models are presented in As detailed in The selected CPR for success at T8  and oneThe selected CPR for success at each assessment time (T8 and T34) included only class-A variables , which aOne interpretation of positive likelihood ratios for evidence-based healthcare  suggest The CPRs of success at T8 and T34 comprised solely class-A variables. Their theoretical justification is discussed here. The reader interested in the possible role played by class-B and class-C variables in the prediction of the LSEP success (corresponding to other multiple regression models) can find a discussion in PPT-Reach was selected in the final CPRs, at both T8 and T34, with almost identical cutoffs . This test involves standing with a weighted bar  held at shoulder height and then extending the arms, parallel to the ground, are far as possible while maintaining an upright posture. The ratio represents the distance reached vs. arm length. This test assesses the role of the stabilizing muscles of the lumbar spine in a neutral posture, in which passive tissue stiffness plays a minimal role . RaisingThe same rationale underlies the inclusion of the prone instability test (ProneIT variable) in a previous derivation of a CPR for LSEP success . While tThe MCIP-HipE-Act-max variable  is derived from an MCI test and requires active unilateral hip extension while lying prone (until the thigh no longer touches the examination table). Limb movements, especially when only one limb is involved, usually cause asymmetric forces and moments at the lumbar level. It has been proposed that an inability to limit lumbar movement during limb movement would be indicative of lumbar instability, thus causing symptoms . Our datThe MCIS-HipAR-Pas-max variable  is derived from an MCI test in which the therapist passively moves the hip from a unilateral crook-lying position into abduction and external rotation. While the association between this variable and lumbar instability is not obvious, because the test is passive, a positive finding may indicate a relatively lower passive rotational stiffness in the lumbar spine, compared to the hip, inducing pain in the lumbar spine as it is pulled into rotation with the movement of the lower limb. Learning to actively stabilize (stiffen) the lumbar spine, with an LSEP, may benefit patients who experience pain with this test, allowing then to control and limit spine rotation during movements at the hip. It should be noted, however, that this pain provocation test may not be specific to patients who require an LSEP to eliminate these symptoms. It also cannot be ruled out that this test caused irritation of the sacroiliac joint (SI joint dysfunction was not an exclusion criterion), which is under tension during this test. Whether or not this test is specific to a lumbar instability disorder will be determined at the validation stage of the CPR.The presence of aberrant movements  was also retained in the CPR of Hicks, Fritz , as wellJoint hypermobility syndrome, as diagnosed with the Beighton scale, is thought to be caused by a decrease in collagen content in tendons, ligaments, joint capsules, and skin, which in turn reduces their stiffness and thus may have a relationship with joint instability and pain . A relatA low score for generalized ligament laxity (Beighton variable ˂ 5/9) was retained in the final CPR at T8. One speculative explanation is that individuals with a high Beighton score, presumably from birth, would have already learned to actively control the segmental movements of the spine, and would not derive added benefit from an 8-week LSEP. Another is that generalized tissue laxity would make a transient loss of inter-segmental motor control, leading to movement beyond a normal physiological range , less lBack muscle endurance (variable TME-Back > 225 s) was not retained in the final CPR at T8  would now proceed to stages 2  and 3 (impact study) of development . HoweverMost arguments support the choice of the CPR at T8. In terms of diagnostic performance indicators, when at least two variables are present, the CPR at T8 offers a better performance  than the CPR at T34 . In terms of usability by therapists, the CPR at T34 is also more burdensome, despite the CPR at T8 having four variables and the CPR at T34 having only three. This is because of the inclusion of a time consuming, and fatiguing, abdominal muscle endurance test  for the CPR at T34.In the 100 patients who completed the six-month follow-up, the effects of the LSEP were both positive at T8 and well maintained at T34, both for perceptions of disability  and for pain intensity . These results are in agreement with a meta-analysis  indicatiTwo CPRs of success for an LSEP were derived, one at the end of the program and one at six-month follow-up. Their diagnostic performance was good and usability acceptable as only three or four clinical tests were needed for the CPRs. Finally, the tests included in the CPRs measure concepts that have a clear relationship to spinal instability, providing a specific link to the treatment provided. These results support the further development of these CPRs by proceeding to the validation stage.S1 FileDescription of tools or procedures used to perform all measures, their corresponding interrater reliability, their variable abbreviations and whether they were considered as class A, B or C candidate predictors.(DOCX)Click here for additional data file.S2 FilePearson’s Chi-square P values, sensitivity, specificity as well as positive and negative likelihood ratios (LR+ and LR-) corresponding to each candidate predictor.(DOCX)Click here for additional data file.S3 FileLogistic regression multivariate models for success at the end of treatment (T8) and at the six-month follow-up (T34) and rational to select the final clinical prediction rule of success (best models) at each time point.(DOCX)Click here for additional data file.S4 FileRationale for the inclusion of class-B and class-C variables in the multivariate logistic models for success following a lumbar stabilization exercise program.(DOCX)Click here for additional data file.