Niels Keiding

• Professor (Full) at University of Copenhagen

The paper traces the development of the use of martingale methods in survival analysis from the mid 1970s to the early 1990s. This development was initiated by Aalen’s Berkeley Ph.D.-thesis in 1975, progressed in the late 1970s and early 1980s through work on the estimation of Markov transition probabilities, non-parametric tests and Cox’s regressi...

Background The gut microbiota of children delivered by cesarean section differs from that of children delivered vaginally. In light of the gut-brain axis hypothesis, cesarean section may influence risk of affective disorders. Methods Population based prospective cohort study included Danish children born 1982 through 2001, with follow-up until 201...

Consider lifetimes originating at a series of calendar times \( t_{1} ,t_{2} , \ldots \). At a certain time \( t_{0} \) a cross-sectional sample is taken, generating a sample of current durations (backward recurrence times) of survivors until \( t_{0} \) and a prevalent cohort study consisting of survival times left-truncated at the current duratio...

Background: Hypotheses concerning adverse effects of changes in microbiota have received much recent attention, but unobserved confounding makes them difficult to test. We investigated whether surrogate markers for potential adverse microbiota changes in infancy affected autism risk, addressing unobserved confounding using a sibling study design....

Background Increasing attention deficit hyperactivity disorder (ADHD) incidence has been proposed to be caused by factors influencing microbiota in early life. We investigated the potential causality between ADHD and two surrogate markers for changes in children's microbiota: birth delivery mode and early childhood antibiotic use. Method This popu...

Background and purpose: Double-blind randomized studies on the effects of oral postmenopausal hormone therapies were stopped mainly because of increased risk of stroke. We aimed to assess the risk of all strokes and various subtypes associated with hormone therapy and explore the influence of regimens and routes of administration. Methods: A nat...

Background Studies link antibiotic treatment and delivery by cesarean section with increased risk of chronic diseases through changes of the gut-microbiota. We aimed to evaluate the association of broad-spectrum antibiotic treatment during the first two years of life with subsequent onset of childhood type 1 diabetes and the potential effect-modifi...

Specification of registers and codes used for defined variables. (DOCX)

Associations between redemption of broad-spectrum antibiotics within the first two years of life and subsequent onset of childhood type 1 diabetes (2 to 14 years, both included). Effects of birth weight and gestational age. (DOCX)

Classification of types of antibiotics into narrow- or broad-spectrum in accordance with the DANMAP definition. (DOCX)

Associations between redemption of broad-spectrum antibiotics within the first two years of life and subsequent onset of childhood type 1 diabetes (2 to 14 years, both included). Dose-response effects. (DOCX)

Associations between redemption of broad-spectrum antibiotics within the first two years of life and subsequent onset of childhood type 1 diabetes (2 to 14 years, both included). Effects of broad-spectrum antibiotics during pregnancy. (DOCX)

Exogenous sex hormones seem to play a role in colorectal carcinogenesis. Little is known about the influence of different types or durations of postmenopausal hormone therapy (HT) on colorectal cancer risk. A nationwide cohort of women 50-79 years old without previous cancer (n = 1,006,219) were followed 1995-2009. Information on HT exposures was f...

Background: Unfavorable conditions associated with cesarean section may influence the risk of type 1 diabetes in offspring, but results from studies are conflicting. We aimed to evaluate the association between prelabor cesarean section and risk of childhood type 1 diabetes. Methods: A Danish nationwide cohort study followed all singletons born...

To the Editor The large register study by Narod et al1 reported breast cancer–specific mortality after a ductal carcinoma in situ (DCIS) diagnosis with special focus on the influence of initial treatment received. There are 2 methodological problems with this article.First, by using the Kaplan-Meier approach to mortality curves (Figures 1 and 2, eF...

Low front-end cost and rapid accrual make Web-based surveys and enrolment in studies attractive, but participants are often self-selected with little reference to a well-defined study base. Of course, high quality studies must be internally valid (validity of inferences for the sample at hand), but Web-based enrolment reactivates discussion of exte...

Survival analysis is the study of the distribution of time-to-event data, that is, the times from an initiating event to some terminal event. A distinguishing feature of survival data is the occurrence of right censoring, where the terminal event for some individuals is not observed; instead, it is only known that this event is at least later than...

The influence of hormone therapy (HT) on risk for endometrial cancer is still casting which type of hormone therapy the clinicians recommend. It is unrevealed if HT has a differential influence on Type I versus Type II endometrial tumors, and little is known about the influence of e.g. different routes of administration and about the influence of t...

This paper was inspired by the studies of Niels Keiding and co-authors on estimating the waiting time-to-pregnancy (TTP) distribution, and in particular on using the current duration design in that context. In this design, a cross-sectional sample of women is collected from those who are currently attempting to become pregnant, and then by recordin...

Background: Studies of trends and tempo corrections of fertility have focused on female rather than male fertility; one reason being that the necessary detailed data are more widely available for mothers than for fathers. Objective: The objective is to present a demographic overview of the fertility trends of Danish men and women from 1980 to 2010....

Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of "high-risk" users is important for therapeutic reasons. We investigated int...

This issue of Lifetime Data Analysis (LIDA) is dedicated to John P. Klein, a long-time member of LIDA’s Editorial Board since 1994. John was born on December 30, 1950 and passed away on July 20, 2013 at the age of 62.John spent his career as a hard-working biostatistician, honoring solid old-fashioned virtues in his working discipline, complete hon...

Control for confounders in observational studies was generally handled through stratification and standardization until the 1960s. Standardization typically reweights the stratum-specific rates so that exposure categories become comparable. With the development first of loglinear models, soon also of nonlinear regression techniques (logistic regres...

The Social Inequality in Cancer (SIC) cohort study was established to determine pathways through which socioeconomic position affects morbidity and mortality, in particular common subtypes of cancer. Data from seven well-established cohort studies from Denmark were pooled. Combining these cohorts provided a unique opportunity to generate a large st...

Survival analysis is the generic name for analysis of time-to-event data. The distinguishing feature of such data is the presence of right-censored observations. Thus, for some subjects, instead of observing the real time to the event, only a lower limit for this time, the right-censoring time, is known. This kind of incomplete data calls for speci...

Event history analysis deals with data obtained by observing individuals over time, focusing on events occurring for the individuals unDer observation. Important applications are to life events of humans in demography, life insurance mathematics, epidemiology, and sociology. The basic data are the times of occurrence of the events and the types of...

To examine the long-term efficacy at the 36-month follow-up of an early psychosocial counselling and support programme lasting 8-12 months for community-dwelling patients with mild Alzheimer's disease and their caregivers. Multicentre, randomised, controlled, rater-blinded trial. Primary care and memory clinics in five Danish districts. 330 home-dw...

We develop nonparametric maximum likelihood estimation for the parameters of an irreversible Markov chain on states {0,1,2} from the observations with interval censored times of 0 → 1, 0 → 2 and 1 → 2 transitions. The distinguishing aspect of the data is that, in addition to all transition times being interval censored, the times of two events (0 →...

This study focuses on the causal effect of educational attainment on completed fertility for a cohort of Danish women born in 1963. The relationship between education and completed fertility (here defined as the number of children at age 41) is the result of a dynamic interplay between the two processes; in particular, educational attainment at a g...

Studying mechanisms underlying social inequality in postmenopausal breast cancer is important in order to develop prevention strategies. Standard methods for investigating indirect effects, by comparing crude models to adjusted, are often biased. We applied a new method enabling the decomposition of the effect of educational level on breast cancer...

To test whether the relatively unpredictable nature of labour onset can be described by the Poisson distribution. A descriptive retrospective study. From the Danish Birth Registry, we identified births from all seven obstetric clinics in the capital region of Denmark (n=211 290) between 2000 and the end of 2009. On each date, the number of births a...

We investigated trends in biological fertility in a comprehensive analysis of 5 major European data sets with data on time to pregnancy (TTP) and proportion of contraceptive failures. In particular, we distinguished a period effect from a birth cohort effect (lifelong tendency) in both sexes. Attempts at conception not resulting in birth were exclu...

Infertility is a couple-based fecundity impairment, although population level research is largely based upon information reported by female partners. Of the few studies focusing on male partners, most focus on the utilization of infertility services rather than efforts to estimate the prevalence and determinants of infertility as reported by male p...

What is the incidence of medical consultation for fecundity problems in the French population, taking into account pregnancy occurrence and resumption of contraceptive use?. Considering the occurrence of a pregnancy and resumption of use of contraception as competing risks, the cumulative incidence rate of medical consultation for fecundity problem...

BACKGROUND A new measure of the number of life years lost due to specific causes of death is introduced. METHODS This measure is based on the cumulative incidence of death, it does not require "independence" of causes, and it satisfies simple balance equations: "total number of life years lost = sum of cause-specific life years lost", and "total nu...

This article focuses on two aspects of event history analysis that have interested Jan Hoem since his early career: the effect on event history analysis methodology of non-standard sampling patterns, here illustrated by various types of sampling at a cross-section in calendar time; and the application of T. Schweder’s concept of local dependence, a...

The precautionary principle is a term used about a set of statements all expressing the general intention that, in environmental risk policy, it is prudent to not always wait for definitive proof of harm before taking regulatory action. We present the concept and outline its relation to scientific discovery and statistical uncertainty.

The antibiotic clarithromycin has been associated with fetal loss in animals and a study has found a doubling in the frequency of miscarriages among women using clarithromycin in pregnancy. The aim of the study was to investigate whether clarithromycin use in early pregnancy was associated with an increased risk for miscarriages and major malformat...

Several studies published in the past 10 years have evaluated the risk of venous thromboembolic complications with the use of newer hormonal contraceptives, but few have examined the risk of thrombotic stroke and myocardial infarction. Results of the few available studies have been conflicting. The aim of the Danish historical cohort study was to a...

SUMMARY The antibiotic trimethoprim acts as a folate antagonist. Since trophoblasts are very sensitive to drugs that interfere with the folic acid cycle and thereby inhibit DNA synthesis, use of trimethoprim during the first trimester could be associated with miscarriage. A nationwide cohort study including all women in Denmark with a registered pr...

Research into the peer review process has previously been conducted in English-language journals. This study deals with a Danish general medical journal with a relatively small pool of both reviewers and readers. The aim of the study was to compare the quality of reviews produced by identifiable and anonymous reviewers, and further to characterize...

To assess the efficacy at 12 months of an early psychosocial counselling and support programme for outpatients with mild Alzheimer's disease and their primary care givers. Multicentre, randomised, controlled, rater blinded trial. Primary care and memory clinics in five Danish districts. 330 outpatients with mild Alzheimer's disease and their 330 pr...

Although several studies have assessed the risk of venous thromboembolism with newer hormonal contraception, few have examined thrombotic stroke and myocardial infarction, and results have been conflicting. In this 15-year Danish historical cohort study, we followed nonpregnant women, 15 to 49 years old, with no history of cardiovascular disease or...

Time-to-pregnancy (TTP) is the duration from the time a couple starts trying to become pregnant until they succeed. It is considered one of the most direct methods to measure natural fecundity in humans. Statistical tools for designing and analysing time to pregnancy studies belong to survival analysis, but several features require special attentio...

Aim To assess the risk of myocardial infarction (MI) as a result of hormone therapy (HT), with focus on the influence of age, duration of HT, various regimens and routes, progestagen type, and oestrogen dose. Methods and results All healthy Danish women (n ¼ 698 098, aged 51 –69) were followed during 1995 –2001. On the basis of a central prescripti...

We aim to compare the life expectancy of a filling in a primary tooth between two types of treatments. We define the probabilities that a dental filling survives without complication until the permanent tooth erupts from beneath (exfoliation). We relate the time to exfoliation of the tooth to the age of the child and the time to failure of the fill...

The basic parameters in both survival analysis and more general multistate models, including the competing risks model and the illness-death model, are the transition hazards. It is often necessary to supplement the analysis of such models with other model parameters, which are all functionals of the transition hazards. Unfortunately, not all such...

Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting. We combined data from two case-cohort studies based in th...

Assessing couple fecundity on a nation-wide basis without excluding couples who eventually remain infertile is challenging. Our aim was to describe couple fecundity (in terms of frequency of involuntary infertility) among the general population living in France. We used a current-duration design. A random sample of 64 262 households was selected in...

Childhood acute lymphoblastic leukaemia is treated with long-term intensive chemotherapy. During the latter part of the treatment, the maintenance therapy, the patients receive oral doses of two cytostatics. The doses are tailored to blood counts measured on a weekly basis, and the treatment is therefore highly dynamic. In 1992–1996, the Nordic Soc...

The aim of the study is to compare differences in cancer stage at diagnosis between migrant women and native Danish women. The stage is used as a clinical indicator of access to healthcare until the point of diagnosis. Refugees and family reunited migrants who received residence permits in Denmark from 1 January 1993 to 31 December 1999 were includ...

The period 1868–1880 saw a dramatic development in analytical and graphical descriptions of mortality, varying with time and age; this took place almost entirely in the German language. This report attempts a survey of these developments with brief notes on other graphical representations and on how they evolved into the Lexis diagram and the McKen...

Backward recurrence times in stationary renewal processes and current durations in dynamic populations observed at a cross-section may yield estimates of underlying interarrival times or survival distributions under suitable stationarity assumptions. Regression models have been proposed for these situations, but accelerated failure time models have...

In this issue of the Journal, Snowden et al. (Am J Epidemiol. 2011;173(7):731–738) give a didactic explanation of G-computation as an approach for estimating the causal effect of a point exposure. The authors of the present commentary reinforce the idea that their use of G-computation is equivalent to a particular form of model-based standardizatio...

In a famous article, Simpson described a hypothetical data example that led to apparently paradoxical results. We make the causal structure of Simpson's example explicit. We show how the paradox disappears when the statistical analysis is appropriately guided by subject-matter knowledge. We also review previous explanations of Simpson's paradox tha...

There is a lack of appropriately designed trials investigating the efficacy of psychosocial interventions for patients with mild dementia and their family caregivers. This paper reports the rationale and design of the Danish Alzheimer Disease Intervention Study and baseline characteristics of the cohort. The study was a 1-year multicentre randomize...

We consider situations where data have been collected such that the sampling depends on the outcome of interest and possibly further covariates, as for instance in case-control studies. Graphical models represent assumptions about the conditional independencies among the variables. By including a node for the sampling indicator, assumptions about s...

Although family reunification migrants form a large proportion of migrants, their prevalence of mental disorders is unknown because research has focused on mixed groups of first generation immigrants and refugees. Our aim was to investigate the risk of mental disorders among family reunification migrants compared with that among native Danes. Famil...

Objectives Although family reunification migrants form a large proportion of migrants, their prevalence of mental disorders is unknown because research has focused on mixed groups of first generation immigrants and refugees. Our aim was to investigate the risk of mental disorders among family reunification migrants compared with that among native D...

Prescription databases are increasingly used in epidemiological studies concerning the use and the effects of drugs. However, this source of data does not provide direct observations of the time of initiation and discontinuation of drug treatment, and these time points therefore need to be estimated. The paper investigates the validity of methods t...

The most commonly used indicator of fertility, the period total fertility rate (TFR(p)), tends to underestimate actual fertility when women delay childbearing. The objective of this study was to examine to which extent fluctuations in Danish fertility rates result from changes in timing of births and, thus, whether the conventional TFR(p) is a dist...

Nonparametric estimation of the gap time distribution in a simple renewal process may be considered a problem in survival analysis under particular sampling frames corresponding to how the renewal process is observed. This note describes several such situations where simple product limit estimators, though inefficient, may still be useful.

Nonparametric estimation of the gap time distribution in a simple renewal process may be considered a problem in survival analysis under particular sampling frames corresponding to how the renewal process is observed. This note describes several such situations where simple product limit estimators, though inefficient, may still be useful.

For the estimation of the mutation frequency, m, of induced mutations in barley, the X2 mutant frequency has been proposed as an estimator of m E(F), where E(F) is the mean segregation frequency of a homozygous mutant from a heterozygous self-fertilized flower. Frydenberg (1963) has derived an approximation of the variance of this estimator. In the...

To investigate differences in risk of compulsory admission and other coercive measures in psychiatric emergencies among refugees and immigrants compared with that among native Danes. A register-based retrospective cohort design. All refugees (n = 29 174) and immigrants (n = 33 287) who received residence permission in Denmark from 1.1.1993 to 31.12...

Background: Whereas the effects of various socio-demographic determinants on a woman’s risk of having an abortion are relatively well-documented, less attention has been given to the effect of previous abortions and births. Objective: To study the effect of previous abortions and births on Danish women’s risk of an abortion, in addition to a number...

It is plausible that a couple's ability to achieve the desired number of children is limited by biological fertility, especially if childbearing is postponed. Family size has declined and semen quality may have deteriorated in much of Europe, although studies have found an increase rather than a decrease in couple fertility. Using four high-quality...

In this response, we will interpret ‘‘epidemiological’’ as ‘‘observational studies’’, and ‘‘clinical intervention’’ studies as ‘‘randomised studies’’. A prototype epidemiological study would be a cohort study, and a prototype clinical intervention study

Refugees are vulnerable to mental health disorders because of migration trauma. However, register-based prevalence studies are missing. To investigate the risk of mental disorders among refugees compared with that among native Danes. Refugees (n = 29,139), who received residence permission in Denmark from 1.1.1993 to 31.12.1999 were matched 1:4 on...

IntroductionStatistical conceptsEstimating event probabilitiesRegression modelsRemarksReferences

The paper traces the development of the use of martingale methods in survival analysis from the mid 1970's to the early 1990's. This development was initiated by Aalen's Berkeley PhD-thesis in 1975, progressed through the work on estimation of Markov transition probabilities, non-parametric tests and Cox's regression model in the late 1970's and ea...

Many studies which investigate the effect of drugs categorize the exposure variable into never, current, and previous use of the study drug. When prescription registries are used to make this categorization, the exposure variable possibly gets misclassified since the registries do not carry any information on the time of discontinuation of treatmen...

One method of assessing biologic fertility is to measure time to pregnancy (TTP). Accidental pregnancies do not generate a valid TTP value and lead to nonrandom missing data if couples experiencing accidental pregnancies are more fertile than the general population. If factors affecting the rate of accidental pregnancies, such as availability of ef...

The statistical properties of the two most widely used methods for setting environmental exposure standards are explored. The traditional NOAEL approach handles uncertainty in disagreement with the precautionary principle: a smaller and less sensitive study will tend to yield higher exposure limits. As an attractive alternative, the Benchmark dose...

Fecundability, the cycle-specific probability of pregnancy for couples with sexual intercourse and not using contraceptive methods is a central notion in reproductive health. From the point of view of the sampling method of the participants, there are three main approaches for fecundability studies: the retrospective approach, in which women are in...

The precautionary principle is a term used about a set of statements all expressing the general intention that, in environmental risk policy, it is prudent to not always wait for definitive proof of harm before taking regulatory action. We present the concept and outline its relation to scientific discovery and statistical uncertainty.

Longitudinal studies show higher mortality among abstainers and heavy drinkers than among light and moderate alcohol consumers. The influence on this association of missing information on alcohol intake due to attrition (dropout) has not been examined previously. The aims of this study were to characterize participants who dropped out and to evalua...

Several studies of the effect of education on second or third birth rates (e.g. Hoem et al. (2001)) have used the concept of relative age at previous birth (B.Hoem (1996)). B.Hoem's idea was to focus on the social meaning of age at previous birth. We broaden the discussion by considering other interpretations of the explanatory power of the age at...

The aim of the study is to compare differences in cancer stage at diagnosis between migrant women and native Danish women. The stage is used as a clinical indicator of access to healthcare until the point of diagnosis. Refugees and family reunited migrants who received residence permits in Denmark from 1 January 1993 to 31 December 1999 were includ...