The concept of frailty plays a major role in the statistical field of survival analysis. Frailty variation refers to differences in risk between individuals which go beyond known or measured risk factors. In other words, frailty variation is unobserved heterogeneity. Although understanding frailty is of interest in its own right, the literature on survival analysis has demonstrated that existence of frailty variation can lead to surprising artefacts in statistical estimation that are important to examine. We present literature that demonstrates the presence and significance of frailty variation between individuals. We discuss the practical content of frailty variation, and show the link between frailty and biological concepts like (epi)genetics and heterogeneity in disease risk. There are numerous suggestions in the literature that a good deal of this variation may be due to randomness, in addition to genetic and/or environmental factors. Heterogeneity often manifests itself as clustering of cases in families more than would be expected by chance. We emphasize that apparently moderate familial relative risks can only be explained by strong underlying variation in disease risk between families and individuals. Finally, we highlight the potential impact of frailty variation in the interpretation of standard epidemiological measures such as hazard and incidence rates.

Aufwerber and co-workers (2021) compared gait patterns between patients allowed to weight-bear immediately in an orthosis with patients deferring weight-bearing in a cast for two weeks followed by four weeks of weight-bearing in an orthosis. They found that immediate weight-bearing did not result in a more symmetrical gait pattern than deferring weight-bearing the first two weeks postoperatively 79 .

Abstract

Key Points Question Is the incidence rate of pediatric atopic dermatitis still increasing? Findings In this cohort study, all children resident in Norway younger than 6 years from January 1, 2009, through December 31, 2015, were included. The overall incidence rate of atopic dermatitis increased from 0.028 per person-year in 2009 to 0.034 per person-year in 2014, and for children younger than 1 year, the incidence rate increased from 0.052 per person-year in 2009 to 0.073 per person-year in 2014. Meaning This nationwide study suggests an increase in the incidence rate of pediatric atopic dermatitis, especially among children younger than 1 year.

Using a 2-level hierarchical frailty model, we analyzed population-wide data on testicular germ-cell tumor (TGCT) status in 1,135,320 two-generational Norwegian families to examine the risk of TGCT in family members of patients. Follow-up extended from 1954 (cases) or 1960 (unaffected persons) to 2008. The first-level frailty variable was compound Poisson-distributed. The underlying Poisson parameter was randomized to model the frailty variation between families and was decomposed additively to characterize the correlation structure within a family. The frailty relative risk (FRR) for a son, given a diseased father, was 4.03 (95% confidence interval (CI): 3.12, 5.19), with a borderline significantly higher FRR for nonseminoma than for seminoma (P = 0.06). Given 1 affected brother, the lifetime FRR was 5.88 (95% CI: 4.70, 7.36), with no difference between subtypes. Given 2 affected brothers, the FRR was 21.71 (95% CI: 8.93, 52.76). These estimates decreased with the number of additional healthy brothers. The estimated FRRs support previous findings. However, the present hierarchical frailty approach allows for a very precise definition of familial risk. These FRRs, estimated according to numbers of affected/nonaffected family members, provide new insight into familial TGCT. Furthermore, new light is shed on the different familial risks of seminoma and nonseminoma.

Heritability is often estimated by decomposing the variance of a trait into genetic and other factors. Interpreting such variance decompositions, however, is not straightforward. In particular, there is an ongoing debate on the importance of genetic factors in cancer development, even though heritability estimates exist. Here we show that heritability estimates contain information on the distribution of absolute risk due to genetic differences. The approach relies on the assumptions underlying the conventional heritability of liability model. We also suggest a model unrelated to heritability estimates. By applying these strategies, we describe the distribution of absolute genetic risk for 15 common cancers. We highlight the considerable inequality in genetic risk of cancer using different metrics, e.g., the Gini Index and quantile ratios which are frequently used in economics. For all these cancers, the estimated inequality in genetic risk is larger than the inequality in income in the USA.

Aims To measure and evaluate clinical response to nasal naloxone in opioid overdoses in the pre‐hospital environment. Design Randomised, controlled, double‐dummy, blinded, non‐inferiority trial, and conducted at two centres. Setting Participants were included by ambulance staff in Oslo and Trondheim, Norway, and treated at the place where the overdose occurred. Participants Men and women age above 18 years with miosis, rate of respiration ≤8/min, and Glasgow Coma Score <12/15 were included. Informed consent was obtained through a deferred‐consent procedure. Intervention and comparator A commercially available 1.4 mg/0.1 mL intranasal naloxone was compared with 0.8 mg/2 mL naloxone administered intramuscularly. Measurements The primary end‐point was restoration of spontaneous respiration of ≥10 breaths/min within 10 minutes. Secondary outcomes included time to restoration of spontaneous respiration, recurrence of overdose within 12 hours and adverse events. Findings In total, 201 participants were analysed in the per‐protocol population. Heroin was suspected in 196 cases. With 82% of the participants being men, 105 (97.2%) in the intramuscular group and 74 (79.6%) in the intranasal group returned to adequate spontaneous respiration within 10 minutes after one dose. The estimated risk difference was 17.5% (95% CI, 8.9%–26.1%) in favour of the intramuscular group. The risk of receiving additional naloxone was 19.4% (95% CI, 9.0%–29.7%) higher in the intranasal group. Adverse reactions were evenly distributed, except for drug withdrawal reactions, where the estimated risk difference was 6.8% (95% CI, 0.2%–13%) in favour of the intranasal group in a post hoc analysis. Conclusion Intranasal naloxone (1.4 mg/0.1 mL) was less efficient than 0.8 mg intramuscular naloxone for return to spontaneous breathing within 10 minutes in overdose patients in the pre‐hospital environment when compared head‐to‐head. Intranasal naloxone at 1.4 mg/0.1 mL restored breathing in 80% of participants after one dose and had few mild adverse reactions.

Counter-intuitive associations appear frequently in epidemiology, and these results are often debated. In particular, several scenarios are characterized by a general risk factor that appears protective in particular subpopulations, for example, individuals suffering from a specific disease. However, the associations are not necessarily representing causal effects. Selection bias due to conditioning on a collider may often be involved, and causal graphs are widely used to highlight such biases. These graphs, however, are qualitative, and they do not provide information on the real life relevance of a spurious association. Quantitative estimates of such associations can be obtained from simple statistical models. In this study, we present several paradoxical associations that occur in epidemiology, and we explore these associations in a causal, frailty framework. By using frailty models, we are able to put numbers on spurious effects that often are neglected in epidemiology. We discuss several counter-intuitive findings that have been reported in real life analyses, and we present calculations that may expand the understanding of these associations. In particular, we derive novel expressions to explain the magnitude of bias in index-event studies.