How Do the Accrual Pattern and Follow‐Up Duration Affect the Hazard Ratio Estimate When the Proportional Hazards Assumption Is Violated?

Objective: Skeletal muscle dysfunction (sarcopenia) is an under-recognized complication of chronic kidney disease (CKD) that may have important clinical consequences. Gait speed is associated with sarcopenia and comorbid disease burden among older adults; however, little is known about the prognostic significance of gait speed in CKD. We determined the association of gait speed with all-cause mortality in a prospective cohort of non-dialysis CKD patients. Methods: We measured usual gait speed over 4-meters in 309 participants from a prospective study of non-dialysis CKD. Included subjects had an estimated glomerular filtration rate (eGFR ckdepi ) <90mL/min/1.73m 2 , were stroke-free and did not require a wheelchair for ambulation. Study coordinators assessed mortality during follow-up by phone contacts, medical record review, and the social security death index. We evaluated gait speed continuously, and using a cut point of 0.8 m/s, consistent with previous studies. We used Cox's proportional hazards to estimate the association of gait speed with mortality after adjustment for age, sex, race, smoking, diabetes, pre-existing CAD, BMI, eGFR and hemoglobin. Results: Median follow-up time was 2.7 years; range 27 days to 4.8 years. The mean age was 58.9 ± 13 years and mean eGFR by cystatin C (eGFR cysc ) was 48.5 ± 23mL/min/1.73m 2 . There were a total of 31 deaths (10.4%) during follow-up. Unadjusted mortality rates were 23 and 80 deaths per 1,000 person-years among participants who had a gait speed of >0.8m/s versus ≤0.8m/s, respectively. After full adjustment, gait speed ≤0.8m/s was associated with a 2.8-fold greater risk of death compared to a gait speed >0.8 m/s. Gait speed was also strongly associated with mortality when analyzed as a continuous variable ( Table ) and a stronger predictor of death than age, history of CAD, or diabetes. No. Deaths (%) Model 1 + Model 2 # Hazard Ratio 95% CI Hazard Ratio 95% CI Gait speed * 32(10) 0.74 (0.64-0.86) 0.75 (0.64-0.87) >0.8m/s 13 (6) Reference Reference ≤0.8m/s 19(19) 3.49 (1.54-7.95) 2.84 (1.25-6.48) * Gait speed analyzed continuously per 10cm/s increase in speed. +Model 1: Adjusted for age, sex, race, study site #Model 2: adds smoking, BMI, eGFR cysc , diabetes, prevalent coronary disease. Conclusion: Gait speed is strongly associated with death in a cohort of middle-aged CKD patients.

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Persistent emotional distress after a first-time myocardial infarction and its association to late cardiovascular and non-cardiovascular mortality

European Journal of Preventive Cardiology ◽

10.1177/2047487319841475 ◽

2019 ◽

Vol 26 (14) ◽

pp. 1510-1518 ◽

Cited By ~ 5

Author(s):

Claudia T Lissåker ◽

Fredrika Norlund ◽

John Wallert ◽

Claes Held ◽

Erik MG Olsson

Keyword(s):

Myocardial Infarction ◽

Confidence Interval ◽

Emotional Distress ◽

Cardiovascular Mortality ◽

Proportional Hazards ◽

Specific Treatment ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

First Time

Background Patients with symptoms of depression and/or anxiety – emotional distress – after a myocardial infarction (MI) have been shown to have worse prognosis and increased healthcare costs. However, whether specific subgroups of patients with emotional distress are more vulnerable is less well established. The purpose of this study was to identify the association between different patterns of emotional distress over time with late cardiovascular and non-cardiovascular mortality among first-MI patients aged <75 years in Sweden. Methods We utilized data on 57,602 consecutive patients with a first-time MI from the national SWEDEHEART registers. Emotional distress was assessed using the anxiety/depression dimension of the European Quality of Life Five Dimensions questionnaire two and 12 months after the MI, combined into persistent (emotional distress at both time-points), remittent (emotional distress at the first follow-up only), new (emotional distress at the second-follow up only) or no distress. Data on cardiovascular and non-cardiovascular mortality were obtained until the study end-time. We used multiple imputation to create complete datasets and adjusted Cox proportional hazards models to estimate hazard ratios. Results Patients with persistent emotional distress were more likely to die from cardiovascular (hazard ratio: 1.46, 95% confidence interval: 1.16, 1.84) and non-cardiovascular causes (hazard ratio: 1.54, 95% confidence interval: 1.30, 1.82) than those with no distress. Those with remittent emotional distress were not statistically significantly more likely to die from any cause than those without emotional distress. Discussion Among patients who survive 12 months, persistent, but not remittent, emotional distress was associated with increased cardiovascular and non-cardiovascular mortality. This indicates a need to identify subgroups of individuals with emotional distress who may benefit from further assessment and specific treatment.

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Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes

Neurology ◽

10.1212/wnl.0000000000004586 ◽

2017 ◽

Vol 89 (18) ◽

pp. 1877-1885 ◽

Cited By ~ 41

Author(s):

Ariela R. Orkaby ◽

Kelly Cho ◽

Jean Cormack ◽

David R. Gagnon ◽

Jane A. Driver

Keyword(s):

Lower Risk ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Confounding By Indication ◽

Cox Proportional Hazards Models ◽

Incident Dementia ◽

Us Veterans

Objective:To determine whether metformin is associated with a lower incidence of dementia than sulfonylureas.Methods:This was a retrospective cohort study of US veterans ≥65 years of age with type 2 diabetes who were new users of metformin or a sulfonylurea and had no dementia. Follow-up began after 2 years of therapy. To account for confounding by indication, we developed a propensity score (PS) and used inverse probability of treatment weighting (IPTW) methods. Cox proportional hazards models estimated the hazard ratio (HR) of incident dementia.Results:We identified 17,200 new users of metformin and 11,440 new users of sulfonylureas. Mean age was 73.5 years and mean HbA1c was 6.8%. Over an average follow-up of 5 years, 4,906 cases of dementia were diagnosed. Due to effect modification by age, all analyses were conducted using a piecewise model for age. Crude hazard ratio [HR] for any dementia in metformin vs sulfonylurea users was 0.67 (95% confidence interval [CI] 0.61–0.73) and 0.78 (95% CI 0.72–0.83) for those <75 years of age and ≥75 years of age, respectively. After PS IPTW adjustment, results remained significant in veterans <75 years of age (HR 0.89; 95% CI 0.79–0.99), but not for those ≥75 years of age (HR 0.96; 95% CI 0.87–1.05). A lower risk of dementia was also seen in the subset of younger veterans who had HbA1C values ≥7% (HR 0.76; 95% CI 0.63–0.91), had good renal function (HR 0.86; 95% CI 0.76–0.97), and were white (HR 0.87; 95% CI 0.77–0.99).Conclusions:After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans <75 years of age. Further work is needed to identify which patients may benefit from metformin for the prevention of dementia.

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Computerized histomorphometric features of glandular architecture predict risk of biochemical recurrence following radical prostatectomy: A multisite study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5060 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5060-5060 ◽

Cited By ~ 1

Author(s):

Patrick Leo ◽

Andrew Janowczyk ◽

Robin Elliott ◽

Nafiseh Janaki ◽

Rakesh Shiradkar ◽

...

Keyword(s):

High Risk ◽

Radical Prostatectomy ◽

Biochemical Recurrence ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Gleason Grade ◽

Training Set ◽

Validation Set

5060 Background: Following a radical prostatectomy (RP) for prostate cancer, a patient may experience biochemical recurrence (BCR), defined as two consecutive prostate specific antigen (PSA) readings > 0.2 ng/mL. BCR is correlated with metastasis and disease specific survival. Extant molecular based companion diagnostic tests for predicting risk of BCR and disease progression tend to be expensive and tissue destructive. We sought to evaluate whether computer extracted features of glandular architecture from routine digitized H&E slides could predict post-RP BCR risk. Methods: RP specimens from 683 patients (184 with BCR, 499 without) with post-surgical PSA follow-up information were gathered from six sites. Median non-BCR follow-up was 3.2 years. A representative tumor area was annotated on the diagnostic H&E slide of each patient. 324 (131 BCR) patients from two sites formed the training set. The other 359 (53 BCR) patients formed the validation set. Glands were segmented by a deep learning model. 216 features describing gland arrangement, shape, and disorder were then extracted. An elastic net Cox proportional hazards model was constructed from the training set using the top 10 stable features identified via feature selection. Risk score thresholds were chosen on the training set to stratify patients into low-, medium-, or high-risk. Validation set results were evaluated by the log-rank test and hazard ratio. For the 172 (37 BCR) patients for whom Gleason grade and preoperative PSA values were available, risk classifications were compared using Cox proportional hazards regression. Results: Nine of the top features were gland shape features and one was a gland arrangement feature. The hazard ratio between the low- and high-risk groups on the validation set was 3.04 (p < 0.05). The histomorphometric classifier was predictive of BCR (p < 0.05, hazard ratio = 1.63) independent of Gleason grade group and preoperative PSA in multivariate testing. Conclusions: Computer extracted features of gland morphology can stratify post-RP patients by BCR risk. Our computerized histomorphometric model could serve as a prognostic tool in the post-RP setting.[Table: see text]

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Hemorrhage From Arteriovenous Malformations During Pregnancy

Neurosurgery ◽

10.1227/neu.0b013e318256c34b ◽

2012 ◽

Vol 71 (2) ◽

pp. 349-356 ◽

Cited By ~ 59

Author(s):

Bradley A. Gross ◽

Rose Du

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Venous Drainage ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Cox Proportional Hazards Model ◽

Relative Paucity ◽

Increased Risk ◽

Risk Of Hemorrhage

Abstract BACKGROUND: Previous hemorrhage, deep venous drainage, and deep location are established risk factors for arteriovenous malformation (AVM) hemorrhage. Although pregnancy is an assumed risk factor, there is a relative paucity of data to support this neurosurgical tenet. OBJECTIVE: To elucidate the hemorrhage rate of AVMs during pregnancy. METHODS: We reviewed the records of 54 women with an angiographic diagnosis of an AVM at our institution. Annual hemorrhage rates were calculated as the ratio of the number of bleeds to total number of patient-years of follow-up. Patient-years of follow-up were tallied assuming lesion presence from birth until AVM obliteration. The Cox proportional hazards model for hemorrhage with pregnancy as the time-dependent variable was used to calculate the hazard ratio. RESULTS: Five hemorrhages in 4 patients occurred over 62 pregnancies, yielding a hemorrhage rate of 8.1% per pregnancy or 10.8% per year. Over the remaining 2461.3 patient-years of follow-up, only 28 hemorrhages occurred, yielding an annual hemorrhage rate of 1.1%. The hazard ratio for hemorrhage during pregnancy was 7.91 (P = 2.23 × 10−4), increasing to 18.12 (P = 7.31 × 10−5) when limiting the analysis to patient follow-up up to age 40. CONCLUSION: Because of the increased risk of hemorrhage from AVMs during pregnancy, we recommend intervention in women who desire to bear children, particularly if the AVM has bled. If the AVM is discovered during pregnancy, we recommend early intervention if it has ruptured; if it is unruptured, we recommend comprehensive counseling, weighing risks of intervention against continuation of pregnancy without intervention.

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Increased risk of stroke after trigeminal neuralgia – a population-based follow-up study

Cephalalgia ◽

10.1177/0333102411405225 ◽

2011 ◽

Vol 31 (8) ◽

pp. 937-942 ◽

Cited By ~ 8

Author(s):

Shin-Liang Pan ◽

Li-Sheng Chen ◽

Ming-Fang Yen ◽

Yueh-Hsia Chiu ◽

Hsiu-Hsi Chen

Keyword(s):

Trigeminal Neuralgia ◽

Proportional Hazards ◽

Underlying Mechanism ◽

Population Based ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Follow Up Study ◽

Medical Disorders ◽

Increased Risk

Background: There are no reports on the risk of stroke after trigeminal neuralgia (TN). The aim of this population-based follow-up study was to investigate whether the occurrence of TN is associated with a higher risk of developing stroke. Methods: A total of 1453 people with at least three ambulatory visits in 2001 with the principal diagnosis of TN were enrolled in the TN cohort. The non-TN cohort consisted of 5812 age- and sex-matched, randomly sampled subjects without TN. The 2-year stroke-free survival rate between the two groups was compared using the Kaplan-Meier method. The Cox proportional hazards regression model was used to estimate the hazard ratio of stroke after adjustment for demographic and clinical covariates. Results: In the TN cohort, 73 patients developed stroke during follow-up, while in the non-TN cohort, 157 subjects suffered a stroke. The crude hazard ratio of stroke for the subjects with TN was 1.86 (95% CI, 1.41–2.45; p < 0.0001). The adjusted hazard ratio was 1.76 (95% CI, 1.33–2.33; p < 0.0001) after adjusting for demographic characteristics and comorbid medical disorders. Conclusion: This study showed a significantly increased risk of developing stroke after TN. Further studies are needed to investigate the underlying mechanism of this association.

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The Relationship between Scabies and Stroke: A Population-Based Nationwide Study

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16183491 ◽

2019 ◽

Vol 16 (18) ◽

pp. 3491 ◽

Cited By ~ 1

Author(s):

Meng-Huan Wu ◽

Chien-Yu Li ◽

Huichin Pan ◽

Yu-Chieh Lin

Keyword(s):

Proportional Hazards ◽

Population Based ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Control Group ◽

Research Database ◽

Newly Diagnosed ◽

Nationwide Study ◽

The Relationship

Background: Scabies is a commonly occurring infectious skin infestation that substantially impacts the quality of life, while stroke, which consists of a neurological deficit resulting from a lack of blood flow to the brain, carries sizable economic costs. The pathophysiologic mechanisms underlying both diseases involve inflammatory processes that are mediated by the immune system; however, no prior research has been conducted to explore the relationship between the two conditions. Methods: This population-based nationwide study utilized data from the National Health Insurance Research Database (NHIRD) of Taiwan for a total of 6628 scabies patients, who comprised a scabies group, and a randomly selected cohort of 26,509 matching patients, who served as a control group. More specifically, the medical records for the patients in both groups were checked for seven years to identify any new cases of stroke within that seven-year follow-up period. The hazard ratio (HR) of stroke for the follow-up period was then calculated using Cox proportional hazards regressions, while comorbidities and demographic characteristics were likewise analyzed. Results: During the follow-up period, 2892 patients, or 8.7%, of the overall total of 33,137 patients included in the study were newly diagnosed with a stroke. Of those newly diagnosed stroke patients, 833 were from the scabies group, and 2059 were from the control group, accounting for 12.6% and 7.8%, respectively, of the individuals in each group. With a crude hazard ratio of 1.67, the patients in the scabies group had a significantly higher risk of subsequent stroke than those in the control group, although the adjusted hazard ratio (aHR) for the scabies patients, which was determined by adjusting for covariates, was only 1.32 (95% confidence interval (CI): 1.21–1.43). Conclusions: The results of the study indicated an elevated risk of stroke among scabies patients, an association that might be contributed to by immunopathological factors. This information could serve as a reminder to clinicians to remain alert to any indications of neurological impairment in patients previously infected with scabies.

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Effect of Ranitidine Intake on the Risk of Gastric Cancer Development

Healthcare ◽

10.3390/healthcare9081071 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1071

Author(s):

SunMoon Kim ◽

Suehyun Lee ◽

JeeYoung Hong ◽

Inseok Ko ◽

Jong-Yeup Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Proportional Hazards ◽

Sociodemographic Factors ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Cancer Development ◽

Rank Test ◽

Potential Association ◽

Korean National Health Insurance

Gastric cancer is one of the most prevalent cancers globally, with high mortality, particularly in East Asia. Certain ranitidine products contain potentially carcinogenic N-nitrosodimethylamine. We investigated the potential association between gastric cancer risk and ranitidine intake using a nationwide cohort, extracted from the Korean National Health Insurance Service. In this longitudinal study, we employed a 1:1 propensity score matching according to sociodemographic factors. A total of 40,887 subjects were enrolled, of which 906 developed gastric cancer during the follow-up period. We investigated gastric cancer events during the follow-up period using the survival analysis, log-rank test, and Cox proportional hazards regression models to estimate incidence, survival rate, and hazard ratio. The incidence of gastric cancer was 67,422; 67,470; and 67,444 person-years in the control, other histamine-2 blockers, and ranitidine groups, respectively. Because the adjusted hazard ratio of gastric cancer was 0.98 and 1.01 in the other histamine-2 blockers and ranitidine groups, respectively, we could not calculate the likelihood of gastric cancer development in the ranitidine group. Ranitidine intake did not significantly increase the incidence of gastric cancer. Therefore, the relative risk of gastric cancer may be low in patients taking ranitidine products in South Korea.

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Moving Beyond the Hazard Ratio in Quantifying the Between-Group Difference in Survival Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2014.55.2208 ◽

2014 ◽

Vol 32 (22) ◽

pp. 2380-2385 ◽

Cited By ~ 245

Author(s):

Hajime Uno ◽

Brian Claggett ◽

Lu Tian ◽

Eisuke Inoue ◽

Paul Gallo ◽

...

Keyword(s):

Proportional Hazards ◽

Hazard Ratio ◽

Health Science ◽

Design Stage ◽

Sufficient Information ◽

Ratio Estimator ◽

Ratio Estimate ◽

End Point ◽

Model Free ◽

Over Time

In a longitudinal clinical study to compare two groups, the primary end point is often the time to a specific event (eg, disease progression, death). The hazard ratio estimate is routinely used to empirically quantify the between-group difference under the assumption that the ratio of the two hazard functions is approximately constant over time. When this assumption is plausible, such a ratio estimate may capture the relative difference between two survival curves. However, the clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the underlying proportional hazards assumption is violated (ie, the hazard ratio is not constant over time). Although this issue has been studied extensively and various alternatives to the hazard ratio estimator have been discussed in the statistical literature, such crucial information does not seem to have reached the broader community of health science researchers. In this article, we summarize several critical concerns regarding this conventional practice and discuss various well-known alternatives for quantifying the underlying differences between groups with respect to a time-to-event end point. The data from three recent cancer clinical trials, which reflect a variety of scenarios, are used throughout to illustrate our discussions. When there is not sufficient information about the profile of the between-group difference at the design stage of the study, we encourage practitioners to consider a prespecified, clinically meaningful, model-free measure for quantifying the difference and to use robust estimation procedures to draw primary inferences.

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Markers of cognitive reserve and dementia incidence in the English Longitudinal Study of Ageing

The British Journal of Psychiatry ◽

10.1192/bjp.2020.54 ◽

2020 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Pamela Almeida-Meza ◽

Andrew Steptoe ◽

Dorina Cadar

Keyword(s):

Longitudinal Study ◽

Cognitive Reserve ◽

Proportional Hazards ◽

Leisure Activities ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Ageing Population ◽

Dementia Incidence ◽

English Longitudinal Study

Background In the current climate of an ageing population, it is imperative to identify preventive measures for dementia. Aims We implemented a multifaceted index of cognitive reserve markers and investigated dementia incidence over 15 years of follow-up in a representative sample of the English population. Method Data were 12 280 participants aged ≥50 years from the English Longitudinal Study of Ageing, free from dementia at their baseline assessments during wave 1 (2002–2003), 3 (2006–2007) or 4 (2008–2009), and followed up until wave 8 (2016–2017). The Cognitive Reserve Index was constructed as a composite measure of education, occupation and leisure activities, using a standardised questionnaire. Cox proportional hazards regression models were used to estimate the hazard ratios of dementia in relation to cognitive reserve levels (low, medium and high) and its components (education, occupation and leisure activities). Results During the follow-up period, 602 participants aged 56–99 years developed dementia. Higher levels of cognitive reserve (hazard ratio 0.65, 95% CI 0.48–0.89, P = 0.008) were associated with a lower risk of dementia. An individual analysis of its components showed that higher levels of education (hazard ratio 0.56, 95% CI 0.36–0.88, P = 0.012), occupation (hazard ratio 0.72, 95% CI 0.56–0.91, P = 0.008) and leisure activities (hazard ratio 0.74, 95% CI 0.56–0.99, P = 0.047) were predictive of a reduced dementia risk, with the first two components particularly protective in younger participants (<85 years). Conclusions This study showed a reduced risk of dementia for individuals with a higher level of cognitive reserve, represented by higher education, complex occupations and multifaceted level of leisure activities.

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