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Comparison of methods for survival analysis of dependent data.

Analysis of dependent survival data by conventional partial likelihood methods produces unbiased estimates of the regression coefficients but incorrectly estimates their variance. Here we compared the conventional partial likelihood methods with two alternative methods for analyzing dependent survival data. The first alternative method estimated the regression coefficient by the partial likelihood approach but adjusted the variance to account for clustering. The second alternative method used marginal likelihoods to estimate both the regression coefficient and its variance. We evaluated the performance of the three methods using simulated and actual data. Simulated data were used to examine bias, efficiency, type I errors, and power. An Old Order Amish genealogy was analyzed under these models to illustrate their performance on real data. The simulation study showed that all three methods provided unbiased estimates of the regression coefficient, but the efficiency of the estimated regression coefficient varied according to the simulation conditions. The standard partial likelihood method showed increasing type I error as the dependence increased within clusters. Both alternative methods had acceptable levels of type I errors at all dependence levels. In the analysis of genealogic data, the regression coefficient was similar in the three methods showing stable estimates of the regression coefficients. The variance estimates from the alternative methods were slightly different from the conventional method, suggesting a flow level of dependence. This study displays the effect of violating the independence assumption and provides guidelines for using alternative statistical methods.

Analysis of Variance↗

Genetic evaluation of mastitis in dairy cattle using linear models, threshold models, and survival analysis: a simulation study.

The objective was to study, by simulation, whether survival analysis results in a more precise genetic evaluation for mastitis in dairy cattle than cross-sectional linear models and threshold models by using observation periods for mastitis of 2 lengths (the first 150 d of lactation, and the full lactation, respectively). True breeding values for mastitis liability on the underlying scale were simulated for daughters of 400 sires (average daughter group size, 60 or 150), and the possible event of a mastitis case within lactation for each cow was created. For the linear models and the threshold models, mastitis was defined as a binary trait within either the first 150 d of lactation or the full lactation. For the survival analysis, mastitis was defined as the number of days from calving to either the first case of mastitis (uncensored record) or to the day of censoring (i.e., day of culling, lactation d 150 or day of next calving; censored record). Cows could be culled early in lactation (within 10 d after calving) for calving-related reasons or later on because of infertility. The correlation between sire true breeding values for mastitis liability and sire predicted breeding values was greater when using the full lactation data (0.76) than when using data from the first 150 d (0.70) with an average of 150 daughters per sire. The corresponding results were 0.60 and 0.53, respectively, with an average of 60 daughters per sire. Under these simulated conditions, the method used had no effect on accuracy. The higher accuracy of sire breeding values can be translated into a greater genetic gain, unless counteracted by a longer generation interval.

Animals↗

Survival analysis of suicide risk after attempted suicide.

Survival analysis of suicide risk by sex and age after attempted suicide was studied in a cohort of 1573 suicide attempters referred to the psychiatric emergency room at the Karolinska Hospital from 1981 to 1988. The time course of suicide risk and the overall prognosis after attempted suicide and, in particular, the possible usefulness of sex and age as risk factors for the prediction of suicide risk after attempted suicide was analyzed. Nearly two thirds of the sample were women and most of the suicide attempters were young (in their twenties and thirties), and the median age was 35 years. The overall mortality after a 5-year mean observation period after attempted suicide was 11%, and the suicide mortality was 6%. The suicide risk after attempted suicide among men (8.3%) was nearly twice the female suicide risk (4.3%). Age as a possible suicide risk factor was analyzed for each sex separately by median split subgrouping. It was concluded that both older and younger male suicide attempters are at high risk of suicide (7% and 10% respectively), and older women are at higher risk than younger (6% vs 2%). The suicide risk is particularly high during the first year after the suicide attempt. The high suicide risk group of young adult male suicide attempters is one of the main feasible targets of psychiatric intervention research programs on suicidal behavior. Suicide among young men is a major cause of years of life lost.

Adolescent↗

An empirical evaluation of period survival analysis using data from the Canadian Cancer Registry.

OBJECTIVE: To provide an empirical evaluation of the performance of period analysis in comparison to traditional methods of survival analysis for predicting future 5-year cancer survival using data from the Canadian Cancer Registry. METHODS: 5-year relative survival estimates were derived by period and traditional methods of analysis using data available at the conclusion of 1997. The extent to which these estimates agreed with survival later observed for cancer cases diagnosed in 1997 was quantified by calculating the squared difference of the estimate to the corresponding relative survival ratio actually observed. RESULTS: Period analysis was observed to be superior to, or comparable with, cohort analysis in predicting the average 5-year relative survival observed later for virtually all individual cancer sites studied. The improvement in survival estimation was most pronounced for prostate cancer. Where period estimates did not match the eventually observed value, they were predominantly on the lower side. Complete analysis estimates were generally observed to be in between the cohort and period values. CONCLUSIONS: The period method of survival analysis provides more up-to-date estimates of 5-year survival than do traditional cohort-based methods.

Adolescent↗

Relative survival analysis in R.

Relative survival techniques are used to compare the survival experience in a study cohort with the one expected should they follow the background population mortality rates. The techniques are especially useful when the cause-specific death information is not accurate or not available since they provide a measure of excess mortality in a group of patients with a certain disease. There are several approaches to modeling relative survival, but there is no widely used statistical package that would incorporate the relevant techniques. The existing software was mostly written by the authors of different methods, in different computer languages and with different requirements for the data input, which makes it almost impossible for a user to choose between available models. We describe our R package relsurv that provides functions for easy and flexible fitting of several relative survival regression models.

Cohort Studies↗

Multilevel survival analysis of amalgam restorations amongst RAF personnel.

OBJECTIVE: To introduce the concepts of multilevel survival analysis through an investigation into the longevity of amalgam restorations. BASIC RESEARCH DESIGN: The multilevel Cox proportional hazard model is illustrated using amalgam restoration data comprising three levels: repeated restorations at level-1, teeth at level-2, and subjects at level-3. The outcome was duration of amalgam restoration survival. Single-level and multilevel Cox methods are contrasted. PARTICIPANTS: The data were from a survey of amalgam restorations (reported elsewhere), involving 200 RAF personnel aged between 16 and 37 years at enlistment between 1947 and 1979, having served continuously for a minimum of 16 years prior to 1994. RESULTS: Differences existed between single-level and multilevel methods; the latter being the method of choice. Initial caries experience was a good predictor of longevity. Molar teeth fared worse than pre-molars and MOD & B, MOD & L, and MOD & BL restorations experienced considerably greater risk of failure than did MOD, MO, DO and MO/DO ext types, which in turn fared worse than occlusal restorations. Root-treated and pinned teeth also experienced an elevated risk of premature failure. There was a moderate but significant increase in restoration failure amongst subjects who were seen by more dentists throughout their service. CONCLUSIONS: The application of multilevel modelling to survival analysis provides an appropriate and powerful solution to the problem of lack of independence amongst dental restorations. It is beneficial that studies undertake a multilevel analysis in preference to ignoring hierarchy or omitting swathes of information in order to perform a single-level analysis.

Adolescent↗

Improving Cox survival analysis with a neural-Bayesian approach.

In this article we show that traditional Cox survival analysis can be improved upon when supplemented with sensible priors and analysed within a neural Bayesian framework. We demonstrate that the Bayesian method gives more reliable predictions, in particular for relatively small data sets. The obtained posterior (the probability distribution of network parameters given the data) which in itself is intractable, can be made accessible by several approximations. We review approximations by Hybrid Markov Chain Monte Carlo sampling, a variational method and the Laplace approximation. We argue that although each Bayesian approach circumvents the shortcomings of the original Cox analysis, and therefore yields better predictive results, in practice the use of variational methods or Laplace is preferable. Since Cox survival analysis is infamous for its poor results with (too) many inputs, we use the Bayesian posterior to estimate p-values on the inputs and to formulate an algorithm for backward elimination. We show that after removal of irrelevant inputs Bayesian methods still achieve significantly better results than classical Cox.

Antineoplastic Agents↗

Population-based survival analysis of colorectal cancer patients in Singapore, 1968-1992.

Since the 1980s, colorectal cancer incidence in Singapore has ranked second to lung in males and females. We describe a population-based analysis of survival of colorectal cancer patients diagnosed from 1968 to 1992 in Singapore. Data of colorectal cancer patients diagnosed during 1968-1992 were retrieved from the Singapore Cancer Registry. Patients were passively followed up for death to the end of 1997. The final dataset consisted of 10,114 subjects. Observed and relative survival rates were calculated by stage (localized, regional metastases and distant metastases), age, ethnicity and calendar period for both genders. Over the study period, a significant progress in survival of colorectal cancer patients was observed. For localized cancer of the colon, the 5-year age-standardized relative survival (ASRS) increased from 36% in 1968-1972 to 66% in 1988-1992 for males and from 32 to 71% for females. For localized rectal cancer, the 5-year ASRS improved from 25 to 66% for males and from 23 to 66% in females. Similarly, improvement was observed in colorectal cancer patients with regional metastases, but not in those with distant metastases. Calendar year period and clinical stage of disease were identified as major significant prognostic factors of survival for colorectal cancer. The substantially improved colorectal cancer survival rates reflected the interplay of cancer control activities in various areas, such as health promotion, early diagnosis and treatment. Our study shows a unique changing pattern of survival experience for colorectal patients from a country undergoing rapid economic development.

Aged↗

Descriptive epidemiology and survival analysis of nasopharyngeal carcinoma in the United States.

Population-based incidence data on nasopharyngeal carcinomas (NPC) from the Surveillance, Epidemiology and End Results program in the United States were examined for the years 1973-1986. The 1,645 cases showed incidence rates varying according to ethnic origin, with chinese having the highest, followed by Filipinos, Blacks and Whites. In females the incidence was about half of that seen in males, in each of these groups. There was no evidence of changes in incidence rates during the study period. An analysis of survival with NPC was undertaken using hazard function regression models to allow for control of multiple variables. Survival was found to be independently influenced by age and stage at diagnosis, histologic type, grade and sex. Significant ethnic differences in survival remained after adjustment for these factors, with Chinese surviving longest followed by Filipinos, Whites and Blacks. These difference in survival remained after control for the variation in population-wide mortality rates associated with age, ethnicity, sex and calendar year. We present evidence that survival has improved for this disease over time.

Adolescent↗

Death and relapse in anorexia nervosa: survival analysis of 151 cases.

The traditional historic-prospective follow-up study of anorexia nervosa patients may be well served by recent methods of statistical analysis, the so-called models for the analysis of survival data. These models are particularly suited to the sort of incomplete observations usually produced a longitudinal studies. They include methods for estimating the probability of death and relapse as a function of time. This makes possible powerful comparisons among studies and among subsamples in single studies. In the present study, 151 patients were followed-up after 4-22 yrs. The hazard of death was on average 0.5% per year, the hazard of relapse 3% per year. With both measures, the risk declined steadily after therapeutic contact.

Adolescent↗

Do the results of semen analysis predict future fertility? A survival analysis study.

The authors examined the results of the initial semen analysis from 1089 couples in an infertility clinic. The distributions of the values for various semen variables among couples who remained infertile were very similar to those among couples who later conceived. A cutoff point was selected in each pair of distributions to compare the cumulative probability of conception for couples with higher and lower results. The authors took into account the varying times to conception or loss to follow-up by using life table analysis. No statistically significant differences were found at the P = 0.05 level of significance. Cox's univariate and multiple regression models were then used to investigate the relationship between various semen characteristics and future fertility. Finding no significant influence of any semen characteristic on the cumulative probability of conception, the authors believe that using specific values of the semen analysis to estimate the potential for fertility of infertile couples is not useful.

Actuarial Analysis↗

Numerical and structural aberrations in advanced neuroblastoma tumours by CGH analysis; survival correlates with chromosome 17 status.

Rapid tumour progression in neuroblastoma is associated with MYCN amplification, deletion of the short arm of chromosome 1 and gain of 17q. However, patients with advanced disease without MYCN amplification and/or 1p deletion have a very poor outcome too, which suggests other genetic defects may predict an unfavourable prognosis. We employed CGH to study 22 tumours of patients at stages 3 and 4 over one year of age (6 and 16 cases respectively). Patients were divided in groups (A) long-term survivors and (B) short-term survivors. CGH showed a total of 226 chromosome imbalances (110 in group A and 116 in group B). The neuroblastoma cells of long-term survivors showed a preponderance of numerical aberrations (54%vs 43%); particularly gains of entire chromosomes 1 (P< 0.03), 7 (P< 0.04) and 19 (P< 0.05). An extra copy of 17 was detected in 6/8 (75%) samples of group A and only 1/14 (7%) samples of group B (P< 0.002). Conversely, tumours of patients who died from disease progression displayed a higher frequency of structural abnormalities (43%vs 35%), including loss of 1p, 9p, 11q, 15q and 18q and gain of 12q, although the difference was not significant (P = 0.24). Unbalanced gain of 17q was detected in 8/14 (57%) tumours of group B and only 1/8 (13%) tumours of group A (P< 0.05). The peculiar genetic difference observed in the tumours of long and short-term survivors may have prognostic relevance.

Child↗

Botulinum toxin injections for achalasia symptoms can approximate the short term efficacy of a single pneumatic dilation: a survival analysis approach.

OBJECTIVE: Botulinum toxin injection can induce a temporary symptomatic remission in some patients with achalasia, but the comparative utility of the approach is not fully known. This study used survival analysis methods to better understand the ability of single or repeated botulinum toxin injections to postpone the need for other treatments. METHODS: The response to botulinum toxin in 42 patients with idiopathic achalasia who had not received prior treatment was compared with the outcome in 26 consecutive patients who underwent initial treatment with pneumatic dilation. Survival analysis methods were employed using time to retreatment as the principal outcome measure. RESULTS: Retreatment (any type) was required in 50% of subjects at 265 days (0.73 yr) after the first botulinum toxin injection. In contrast, retreatment after initial pneumatic dilation was required in <40% of patients after 2 and 5 yr of follow-up. The curves became significantly separated (p < 0.05) within 1 yr after initial treatment. Of those treated solely with botulinum toxin injections, repeated as needed, only 46% required pneumatic dilation or surgery by 2 yr. Survival analysis curves for repeated injections and initial pneumatic dilation did not differ statistically at 1 or 2 yr (p = 0.5 and p = 0.4, respectively). Correlational analyses indicated that, of the clinical parameters tested, only the degree of dysphagia for liquids was useful in selecting the better responders to botulinum toxin injections, with lesser symptoms predicting longer time to retreatment. CONCLUSIONS: Botulinum toxin injections, repeated as needed, can approximate the benefits of a single pneumatic dilation for < or = 2 yr from the standpoint of usual factors that drive further management.

Botulinum Toxins, Type A↗

Survival analysis in family research.

Within the field of family psychology, questions regarding the risk of event occurrence may be common. Such questions, about whether and when events occur and what predicts these occurrences, pose particular methodological challenges and are often best addressed via a statistical method known as survival analysis. This article provides a brief overview of that method, explicating through a data example the major components of a discrete-time survival analysis. Readers not familiar with this method are encouraged to use this article as an introduction to survival analysis and recognize its potential usefulness within the field of family psychology.

Epidemiologic Methods↗

Survival analysis of lamb mortality in a terminal sire composite population.

Records of mortality during the first year of life of 8,642 lambs from a composite population at the U.S. Meat Animal Research Center were studied using survival and logistic analyses. The traditional logistic approach analyzes the binary response of whether or not a lamb survived until a particular time point, thus disregarding information on the actual age at death. Survival analysis offers an alternative way to study mortality, wherein the response variable studied is the precise age at death while accounting for possible record censoring. Lamb mortality was studied across five periods based on management practices: birth to weaning, birth to 120 d of age, birth to 365 d of age, weaning to 365 d of age, and 120 to 365 d of age. Explanatory variables included in the models were sex, type of birth, age of dam, and whether or not a lamb was raised in a nursery. The survival analysis was implemented using Weibull and Cox proportional hazards models with sire as random effect. The logistic approach evaluated sire, animal, and maternal effects models. Lambs culled during any period were treated as censored in the survival analyses and were assumed alive in the logistic analyses. Similar estimates of the explanatory variables were obtained from the survival and logistic analyses, but the survival analyses had lower standard errors than the logistic analyses, suggesting a slight superiority of the former approach. Heritability estimates were generally consistent across all periods ranging from 0.15 to 0.21 in the Weibull model, 0.12 to 0.20 in the Cox model, 0.08 to 0.11 in the logistic sire model, 0.04 to 0.05 in the logistic animal model, and 0.03 to 0.07 in the maternal effects logistic model. Maternal effects were important in the early stages of lamb life, but the maternal heritability was less than 0.07 in all the stages studied with a negative correlation (-0.86 to -0.61) between direct and maternal effects. The estimates of additive genetic variance indicate that the use of survival analysis estimates in breeding schemes could allow for effective selection against mortality, thereby improving sheep productivity, welfare, and profitability.

Age Factors↗

Prognosis of chronic lymphocytic leukemia: a multivariate survival analysis of 150 cases.

A multivariate survival analysis by means of Cox's multiple regression model was performed on a series of 150 consecutive patients with chronic lymphocytic leukemia (CLL) from a single institution. In addition to the well established prognostic factors, such as anemia and thrombocytopenia, a marked prognostic value of the degree of absolute peripheral lymphocytosis emerged from this analysis. This was evident in the whole population as well as in low and intermediate risk groups of patients (Rai's stages 0, I, and II and International Workshop on CLL stages A and B), pointing out that different subsets of patients can be isolated within these groups.

Female↗

A note on competing risks in survival data analysis.

Survival analysis encompasses investigation of time to event data. In most clinical studies, estimating the cumulative incidence function (or the probability of experiencing an event by a given time) is of primary interest. When the data consist of patients who experience an event and censored individuals, a nonparametric estimate of the cumulative incidence can be obtained using the Kaplan-Meier method. Under this approach, the censoring mechanism is assumed to be noninformative. In other words, the survival time of an individual (or the time at which a subject experiences an event) is assumed to be independent of a mechanism that would cause the patient to be censored. Often times, a patient may experience an event other than the one of interest which alters the probability of experiencing the event of interest. Such events are known as competing risk events. In this setting, it would often be of interest to calculate the cumulative incidence of a specific event of interest. Any subject who does not experience the event of interest can be treated as censored. However, a patient experiencing a competing risk event is censored in an informative manner. Hence, the Kaplan-Meier estimation procedure may not be directly applicable. The cumulative incidence function for an event of interest must be calculated by appropriately accounting for the presence of competing risk events. In this paper, we illustrate nonparametric estimation of the cumulative incidence function for an event of interest in the presence of competing risk events using two published data sets. We compare the resulting estimates with those obtained using the Kaplan-Meier approach to demonstrate the importance of appropriately estimating the cumulative incidence of an event of interest in the presence of competing risk events.

Humans↗

Non-linear survival analysis using neural networks.

We describe models for survival analysis which are based on a multi-layer perceptron, a type of neural network. These relax the assumptions of the traditional regression models, while including them as particular cases. They allow non-linear predictors to be fitted implicitly and the effect of the covariates to vary over time. The flexibility is included in the model only when it is beneficial, as judged by cross-validation. Such models can be used to guide a search for extra regressors, by comparing their predictive accuracy with that of linear models. Most also allow the estimation of the hazard function, of which a great variety can be modelled. In this paper we describe seven different neural network survival models and illustrate their use by comparing their performance in predicting the time to relapse for breast cancer patients.

Breast Neoplasms↗