Information and knowledge about cost of illness and labour productivity in patients with HER2-positive early-stage and metastatic breast cancer treated with trastuzumab is limited. The aim of this study was to estimate the direct and indirect costs associated with treatment of HER2-positive breast cancer among patients with early-stage and metastatic breast cancer, treated with trastuzumab, in a 10-year period after diagnosis.This study included all Danish HER2-positive breast cancer patients (≥ 18 years) treated with trastuzumab between 2005 and 2016 identified in The Danish Patient Register and the Danish Cancer Register. Furthermore, we identified patients experiencing metastatic or recurrent breast cancer. For the study populations, we estimated total direct costs and indirect costs for one year prior to the breast cancer diagnosis and up to 10 years after diagnosis compared with a group of matched controls free of breast cancer. In addition to The Danish Patient Register and Cancer Register, we applied patient level data from The Civil Registration System, The National Pathology Register, National Health Service Register for Primary Care, Register of Medicinal Product Statistics, Register of Municipal Services, The DREAM database, and Population’s Education Register.We identified 4,153 HER2-positive breast cancer patients, whereof 27% were identified with metastatic or recurrent breast cancer. During the follow-up period of 10 years, we estimated excess direct costs of EUR 115,000 among the total study population compared to controls; EUR 211,000 among patients with metastases or recurrence; and EUR 89,000 among patients without metastases or recurrence. Direct costs were found to be highest in the first year after diagnosis and also peaked in the year after recurrence. Labour productivity was significantly lower among patients with recurrence 10 years after breast cancer diagnosis compared with controls.In this study, we estimated the direct and indirect cost associated with HER2-positive breast cancer. The costs were significantly higher during the 10 years after diagnosis compared to the control group, specifically among patients experiencing metastases or recurrence of breast cancer.The online version contains supplementary material available at 10.1186/s12913-022-08143-7. Breast cancer is the most frequent type of cancer diagnosed among women in European countries, constituting 20–25% of all incident cancer diagnoses . In DenmAbout 10–15% of early-stage breast cancer patients have HER2-positive breast cancer . Before Although the various subtypes of breast cancer affect many thousands of women worldwide each year, information and knowledge about the cost of illness and labour productivity of patients with HER2-positive early-stage and metastatic breast cancer treated with trastuzumab is limited. Indirect costs are likely substantial, as a large proportion of HER2-positive cases exit the labour market after treatment . FurtherThe previous studies investigating cost of illness for HER2-positive patients have primarily been conducted as cohort studies or through trials. Denmark offers unique options for performing studies on real-world data via access to high-quality, exhaustive register data on the long-term outcomes of implementation of new targeted medicines. Therefore, we used the Danish national registers to investigate the association between HER2-positive breast cancer (with and without metastases or recurrence), extended direct and indirect costs.A retrospective population-based study was designed to analyse direct and indirect costs among Danish women diagnosed with HER2-positive breast cancer in the period 2005 to 2016 who were treated with trastuzumab. Our data included information starting from 2004, in order to observe the change from before diagnosis.Since 1968, all Danish citizens have been assigned a unique personal identification number, recorded in the Danish Civil Registration System (CRS) . For allInformation regarding highest obtained education was obtained from the Population’s Education Register  and was The study was conducted in Denmark. Denmark has a tax-financed universal healthcare system, where treatment is free at point of consumption. Hospitals are financed through a combination of block grant transfers and activity-based financing using a DRG-system. Primary care physicians fulfil a gatekeeper-function, where patients need a referral before receiving specialized or hospital care, unless emergency care is necessary. Private health insurance is available, but not widely used. Even if a patient is covered by private health insurance, cancer treatment is provided through the public sector. For prescription drugs, Danish citizens face an annual deductible fee of 2,0.650 Euro. After which, prescription drugs are financed 100% by the state.All treatment facilities and pharmacies are obligated to report administrative data to the Danish Health Data Authority. The activity data is routinely used for review of hospital activity and reimbursement in accordance with the Danish DRG-system. For cancer treatments, data quality was a stated aim of the Cancer Package II (Implemented 01 January 2006).The study population was defined as women ≥ 18 years diagnosed with incident HER2-positive breast cancer in the period between 2005 and 2016 who were treated with trastuzumab. All women with incident breast cancer were identified in the Danish Cancer Register using the ICD-10 code C50. In the Danish National Pathology Register, information on HER2 status was retrieved using SNOMED code T04 (breast) in combination with either SNOMED code F29603 (HER2 receptor overexpression) or SNOMED code FE13B5 (HER2 gene amplification). In the DNPR, treatment with trastuzumab was identified using treatment code BOHJ13. More than six treatments with trastuzumab in the year following diagnosis resulted in inclusion in the study population.Patients who experienced recurrence or metastatic breast cancer does not qualify as early-stage breast cancer. Metastatic cancer is considered the last stage cancer, while 80% of recurrent cancer cases is identified as metastatic . Hence sPatients with metastatic HER2-positive breast cancer were defined as patients who were registered with TNM-M code M1 at time of diagnosis or, patients who received more than 17 treatments of trastuzumab in the 13 months after diagnosis , 19. RecTo determine the cost of illness, we compare the cost of HER2-positive patients with controls from the Danish population. One control for each patient was randomly selected from the general population via the CRS, matched on age and highest obtained education as of the year of breast cancer diagnosis. All controls were female. The DNPR was used to ensure that all controls were unexposed to breast cancer in the study period. To reduce the risk of introducing bias, we limited the matching criteria to only birth year and highest obtained education. We had in total 91,964 potential controls and the controls were matched exact on a 1:1 ratio based on age and education. If education was obtained abroad or from a not-approved Danish institution, education will be missing in The Education Register. If a patient was observed with missing in this variable, it was matched with a control who also had missing in this variable. Each control was assigned the same index date as the matched case.Outcomes for this study included direct and indirect costs attributable to HER2-positive cancer. Direct costs consisted of costs generated from consumption primary care services, hospital care services and home care services. Indirect cost was estimated based on labour market productivity. Additionally, we included prescription medicine as a separate category.The direct costs were estimated based on services noted in the national registers. For each contact with the healthcare system an observation in the register data is made. This observation contains date and reason for visit, services provided to the patient  and the estimated cost of these services. The cost of all included services are determined by the national tariffs and fees .From the DREAM database yearly employment rates were estimated and subsequently labour productivity values were estimated by multiplying the yearly employment rate, with gross average yearly wages, adjusted for the number of effective weekly working hours among women. The labour productivity value estimations included only women considered to constitute the workforce, i.e. those between the ages of 18 and 65.Due to legal restrictions regarding access to detailed data on prescription medicines, it was not possible to merge this information on a patient level with other direct costs – hence, we report this in a separate category. However, an analysis of the overall costs of prescription medicines produced an estimate of any differences in costs between cases and controls.Prescription medication in this context include all reimbursed medications, not provided in a hospital setting. For example, anti-nausea medication is often provided in combination with chemotherapy. If that medication is provided in a hospital context, it will be registered in the DNPR. If the same prescription is re-filled at a pharmacy outside the hospital context later, that cost will be registered in this category. However, this category is not limited to cancer-related medications, but all prescription medication collected by the study participants in the study period..All costs were set to the 2016 price level, and tariffs in both the Danish National Health Service Register for Primary Care and the DNPR were inflated using the combined price and wage index for healthcare services, according to the Danish Regions [The study followed participants from one year prior to their index date, i.e. date of incident breast cancer diagnosis (1 January 2005 at the earliest), and until 10 years after index date, death, emigration, or end of follow-up (31 December 2016), whichever occurred first.Average individual direct and indirect costs were calculated on a yearly basis according to index date for cases and controls, respectively. Due to the large number of observations in all categories, a one-sample t-test was applied to determine significance in differences between direct costs among cases and controls.th treatment of trastuzumab if the patient was identified with more than 17 treatments of trastuzumab, or as the date of re-initiation of treatment with trastuzumab after a six-month break. Direct costs three years after recurrence were estimated. After three years, we do no longer attribute the costs to recurrence but consider it equal to the cost of HER2-positive cancer.A secondary analysis estimated the direct costs of metastatic and recurrent breast cancer. Thus, date of metastases or recurrence was defined as the date of breast cancer diagnosis if the patient was diagnosed with metastatic breast cancer (de novo breast cancer), as the date of the 18Finally, further analysis included an estimate of the individual average costs of prescription medicines among cases and controls.Data management and statistical analyses were carried out using SAS statistical software  on Statistics Denmark’s research computers via a remote server.Between 2005 and 2016, 7,156 incident HER2-positive breast cancer patients were identified in the Danish National Pathology Register. Among those, 4,153 (58%) were treated with trastuzumab within the first year after diagnosis ; however, the costs were only slightly higher among cases compared to the costs among controls (1.2 times).In the year before diagnosis (year -1), we found no statistically significant difference between metastatic or recurrence cases’ and controls’ average individual direct costs. The differences in total direct costs between cases in the total study population and controls, and between cases without metastatic or recurrence and controls, were statistically significant (p < 0.001) times higher among cases in the total study population compared to controls, 27.3 (p < 0.001) times higher among cases with metastases or recurrence compared to controls and 25.3 (p < 0.001) times higher among cases without metastases or recurrence compared to controls, corresponding to differences in actual costs of EUR 58,217, EUR 67,099 and EUR 54,910, respectively.In the year of diagnosis, the average direct costs were 25.9  times higher compared to controls in year 10, whereas the costs were 10.0 (p = 0.002) times higher among cases with metastases or recurrence and 1.2 (p = 0.402) times higher among cases without metastases or recurrence compared to controls.In subsequent years, the average direct costs remained statistically significantly higher among cases alive compared to controls alive in all study populations. In the 10p = 0.180 among the total study population, p = 0.99 among cases with metastases or recurrence and p = 0.103 among cases without metastases or recurrence. For all three study populations, labour productivity was slightly higher among cases compared to controls.Figure p < 0.001) times lower among cases compared to controls, whereas cases without metastases or recurrence showed labour productivity comparable to controls from year 9 and onwards (p = 0.114).Among the total study population, labour productivity decreased significantly in the year of diagnosis and remained statistically significantly lower during the entire follow-up period. Among the population of cases with metastases or recurrence, labour productivity was significantly lower throughout the study period; in year 10, labour productivity was 2.8  were identified with metastatic breast cancer at the time of diagnosis (i.e. de novo breast cancer), while the rest experienced a recurrence after a mean time of 1.5 years. Table The average individual costs of prescription medicines are presented in Table Using the Danish national registers, we carried out the first large-scale assessment of the association between HER2-positive breast cancer and direct costs related to metastases or recurrence and no metastases or non-recurrence. Our analyses showed higher direct costs in the 10 years after diagnosis among women with HER2-positive breast cancer who experience metastases or recurrence. During the 10-year follow-up period, patients in the total study population had excess direct costs of EUR 115,000 compared to controls, patients with metastatic or recurrence of breast cancer had excess direct costs of EUR 211,000 compared to controls, and patients without metastases or recurrence had excess direct costs of EUR 89,000 compared to controls. The average individual direct costs were higher in the years after diagnosis among breast cancer patients experiencing metastases or recurrence than among those not experiencing metastases or recurrence. This can partly be explained by the fact that approximately 5% of the study population was diagnosed with de novo breast cancer at incidence.Due to differences in methodology, study design and included costs – and thereby in the chosen perspective of the analyses – it is somewhat difficult to compare the results of the present study with cost estimates identified in the literature. Bermejo et al. (2020), from Spain, found total costs of HER2-positive/HR-positive to be EUR 290,243 in the five years following diagnosis, while for HER2-positive/HR-Negative it was EUR 249,152. They do not provide a control group to separate the attributable costs, and their cost estimates are based on expert opinion, and not observed costs .A recent study by Sussell et al.  investigOnly patients who received six or more treatments with trastuzumab was included in the patient group. This exclude HER2-positive patients who ceased treatment of trastuzumab before any effect of treatment can be expected . The resThe strengths of our study include its retrospective register-based design, which included all Danish women diagnosed with HER2-positive breast cancer treated with trastuzumab between 2005 and 2016 with complete information on direct costs up until 2016. By design, the risk of biases related to participation, outcome surveillance or follow-up in our analyses is therefore miniscule. Furthermore, we were able to adjust for age and highest obtained education (and gender by inclusion criteria for pool of controls) by matching the cases and controls on these factors, which limited confounding. While it could have been possible to expand on the matching criteria, it was set to only age and education to avoid selection bias. Direct costs were similar among cases and controls in the year prior to index date, which is essential in studies focused on cost of illness. The number of patients receiving trastuzumab in the study period is consistent with the sales figures of trastuzumab in Denmark, indicating a high validity of the procedure codes in the registers. All in all, the Danish registers are of high completeness, with few missing observations. As there are so few missing observations, we have not concerned ourselves with imputation.The estimation of indirect costs is based on the average income of women in Denmark, as opposed to the actual reported annual income for each individual. We chose this approach as we have detailed data on which weeks each individual worked. Hence, by using the average income, we can estimate the expected indirect costs which occurred after the cancer diagnosis were given to get a more accurate estimate of the production loss.However, this study also has a number of limitations that require consideration. Firstly, the phrase “recurrence of breast cancer” is not well defined. The Danish national registers do not include information on recurrence, so we defined “recurrence” by the use of trastuzumab. Therefore, we cannot rule out an element of mis-categorisation of patients as recurrent and non-recurrent, which might have influenced our results. Secondly, the incidence of HER2 breast cancer and the number of patients treated with trastuzumab varied and was particularly lower in the beginning of the study period. This could indicate an irregular use of the SNOMED code for HER2-positive and the procedure code for trastuzumab in the beginning of the study period, although the numbers stabilised in the last part of the study period.Thirdly, it was not possible to include the costs of prescription medicine in the total direct costs due to data access limitations. However, prescription medicine costs did not seem to vary much between cases and controls during the study period, which indicates that their absence may not have impacted the results significantly.And lastly, the findings are constrained to the comparison of HER2-positive patients who fit the inclusion criteria and cancer-free control group. Had the control group consisted of a different histologic breast cancer group, the excess costs would likely be lower.In conclusion, our study suggests that the direct costs for patients with HER2-positive breast cancer remains significantly higher than the direct costs for controls in the 10 years after diagnosis. Moreover, there is a need for future studies investigating how to identify patients with recurrence, since this information is not defined in the Danish national registers.Additional file 1: Table S1. Summary statistics of the matched and unmatched control population. Differences between group tested with t-test or chi2.Additional file 2: Table S2. Summary statistics of diagnosis of the study participants given as primary diagnosis in hospital setting in the two years prior to diagnosis date/index date.


N = 120), we show that eight-month-old infants punished antisocial others. Specifically, infants increased their selective looks at the aggressor after watching aggressive interactions. Additionally, three control experiments excluded alternative interpretations of their selective gaze, suggesting that punishment-related decision-making influenced looking behaviour. These findings indicate that a disposition for third-party punishment of antisocial others emerges in early infancy and emphasize the importance of third-party punishment for human cooperation. This behavioural tendency may be a human trait acquired over the course of evolution.Third-party punishment of antisocial others is unique to humans and seems to be universal across cultures. However, its emergence in ontogeny remains unknown. We developed a participatory cognitive paradigm using gaze-contingency techniques, in which infants can use their gaze to affect agents displayed on a monitor. In this paradigm, fixation on an agent triggers the event of a stone crushing the agent. Throughout five experiments (total  Using a participatory cognitive paradigm based on gaze contingency, Kanakogi et al. show that eight-month-olds increased their selective gaze to antisocial others to punish them, suggesting that preverbal infants engage in third-party punishment. The dominant explanation is that this disposition is a mechanism for maintaining cooperation6. Third-party punishment is unique to humans8 and has been well documented in adults3. However, debates about its evolved propensity9 and motivations10 are ongoing, and its point of emergence in ontogeny remains unknown.Third-party punishment is a disposition of individuals to punish transgressors or norm violators who have not harmed them directly, and it seems to be universal across cultures11. Young children are willing to incur a cost to avoid interacting with wrongdoers12, intervene against or tattle on moral transgressions13, and seem to expect antisocial actions to be punished14. Moreover, children not only punish wrongdoers but also prioritize helping the victim15. For example, they return a resource to the victim rather than remove a resource from a thief when they have options to punish or help. By age six, children engage in costly third-party punishment; they sacrifice their own resources to punish a transgressor who has acted unfairly17 and punish moral transgressors to satisfy both consequentialist and retributive motives18. However, to our knowledge, little to no work has investigated third-party punishment in preverbal infants, and thus its point of emergence in ontogeny remains unknown.Previous research asserts that even 19-month-old toddlers are willing to punish antisocial individuals in third-party contexts by taking treats away from them19 and hitting interactions between agents22. Infants can discriminate between caressing (positive) and hitting (negative) interactions involving two agents20, and the latter interactions are assumed to be negative from the infants’ viewpoint23. Moreover, not only do infants infer dominance hierarchies (the strong and the weak) from body size24, social interactions25 and relative height26, but they can also discriminate the aggressor from the victim in hitting interactions21. More importantly, infants show aversiveness to the aggressor21, affirm the agents who disturbed (doing negative action to) the aggressor and assume that the aggressor should be hit by other agents22. On the basis of current evidence, these types of actions might be functional as punitive behaviour, and the interaction might be worth interfering for infants.We focused on physical aggression, which is assumed to be salient to preverbal infants. It may therefore function as an intuitive form of punishment and be the most basic form of aggression that infants prefer to intervene against. We specifically focused on the hitting action29, in which infants can use their gaze to affect agents displayed on a monitor. In this paradigm, fixation on an agent triggers the event of a stone crushing the agent. Prior research that used the same hitting interaction employed in the current study has demonstrated that infants over six months old regard this interaction as negative23 and that eight-month-olds can act on objects on a monitor by their gaze29. We therefore chose eight-month-olds as participants in this study. We familiarized infants with a gaze-contingent association between looking at one of two objects or agents and a subsequent punitive event  or either of two objects presented side by side , the contingent event  occurred in the practical phase. Subsequently, the infants experienced ten identical gaze-contingent events, except that the target objects were two geometric agents with eyes  —namely, the relative evidence in favour of each model over the null model. We assumed that the prior model probability was uniform, and we evaluated the degree to which the data had changed the prior model odds for each model. We also computed the inclusion BF (ref. 30) (BFincl) for each effect to evaluate how probable the data were under models that included the effect compared with models that excluded the effect. To report BF10 and BFincl, we set the Cauchy distribution with location 0 and scale 1/√2 as a prior distribution for a coefficient parameter31. BFs are sensitive to the prior distribution for model parameters. It is therefore important to check whether the inferences from the data are robust to different prior specifications. We conducted a sensitivity analysis for BFincl, following recommendations made by previous studies regarding Bayesian analysis33.We conducted a generalized linear mixed model (GLMM) analysis with a binomial error structure and a logit link function to assess whether watching the aggressive interaction influenced selective looks in the posttest phase. The response variable was infant selective looks at the aggressor (= 1) or the victim (= 0) in the pretest or posttest. The explanatory variables included test type (pretest or posttest) and trial number. We compared models on the basis of the Bayes factor (BF). The model candidates were (1) the null model, (2) a model with the main effect of test type, (3) a model with the main effect of trial number, (4) a model with the main effects of test type and trial number, and (5) a model with the main effect of test type, the main effect of trial number and the interaction between test type and trial number. All models were compared with the null model, and we computed the BF  or the null hypothesis (model).According to Lee and WagenmakersP(M|data) = 0.590). The BF10 was 2.473, which indicated anecdotal evidence in favour of this model compared with the null model. Table incl for each effect. On average, the data anecdotally supported the model including the main effect of test type (BFincl = 1.748) and moderately supported the model excluding the main effect of trial (BFincl = 0.139) and the interaction term (BFincl = 0.161). The results of the sensitivity analysis  who experienced aggressive interactions identical to those in Experiment 1 but with less negative gaze-contingent events in the pretest and posttest phases. Specifically, materials fell onto an object or agent more softly than in Experiment 1  = 0.651). The BF10 was 1.000 since the null model was compared with itself. On average, the data moderately supported the model excluding the main effects of test type (BFincl = 0.190) and trial type (BFincl = 0.136), and very strongly supported the model excluding the interaction term (BFincl = 0.032) . To exclude this possibility, in Experiment 2, we tested another group of infants (2) Table . We ther35 as opposed to a sense that punitive action is the consequence of the infants’ intentions. To understand this, in Experiment 3, we decreased the strength of the gaze-contingent association. Specifically, we changed the reinforcement probability between looking at a specific agent and a subsequent punitive event from 100% (Experiment 1) to 50% (chance level)  = 0.705). The BF10 was 1.000 since the null model was being compared with itself. On average, the data moderately supported the model excluding the main effect of test type (BFincl = 0.167), strongly supported the model excluding the main effect of trial type (BFincl = 0.095) and very strongly supported the model excluding the interaction term (BFincl = 0.022) (Table A second possible explanation for the increase in infant selective looks at the aggressor in Experiment 1 is a mere expectation that the aggressor would be punished2) Table . We ther23. If this was the case in the present study, infants may have regarded geometric agents as the cause of a negative physical event rather than as aggressors. In Experiment 4, we tested this possibility by recruiting additional eight-month-old infants (N = 24) who were familiar with the same gaze-contingency events but modified the aggressive interactions used in Experiment 1. We tested infants using geometric figures with perceivable ‘animacy or agency’ removed by eliminating their eyes, ability to self-propel and distortion upon contact  = 0.544). The BF10 was 1.000 as the null model was being compared with itself. On average, the data anecdotally supported the model excluding the main effect of test type (BFincl = 0.404), moderately supported the model excluding the main effect of trial type (BFincl = 0.109) and strongly supported the model excluding the interaction term (BFincl = 0.062)  Table . We thus36. We therefore tested another infant group (N = 24) with identical procedures and the same sample size used in Experiment 1. The model comparison results demonstrated that the data were best represented by the model with the main effect of test type (Table P(M|data) = 0.795). The BF10 was 24.362, indicating strong evidence in favour of this model compared with the null model. On average, the data strongly supported the model including the main effect of test type (BFincl = 16.179) and moderately supported the model excluding the main effect of trial (BFincl = 0.139) and the interaction term (BFincl = 0.188). The sensitivity analysis results  and experiment  by using GLMM.The analyses reported above demonstrate that compared with the pretest phase, infants increased selective looking at an aggressor at the posttest phase in Experiment 1 and Experiment 5, but not in the other experiments. However, employing a contrast between the pretest and posttest phases for each experiment did not necessarily elucidate the differences in effect sizes of test type between the experimentsWe conducted comparisons of the effect size of test type for each experiment . Three control experiments excluded alternative parsimonious interpretations of these increases in selective looks at the aggressor: mere preferential looking at agents (Experiment 2), mere expectation that the agent would be punished (Experiment 3) and perceiving collisions as a negative physical event rather than aggression (Experiment 4). Finally, we replicated Experiment 1 to confirm that our findings indicated robust psychological phenomena (Experiment 5). Importantly, between-experiment differences were not attributable to variation in attention in the movie phase, as the Bayesian one-way analysis of variance results moderately supported the idea that there was no difference in looking time during the movie phase between the experiments 10. This outcome might provide crucial evidence for ongoing debates regarding the motivations and evolved propensity underlying third-party punishment. The tendency towards third-party punishment may be engrained in preverbal infants’ minds and may have evolved only in humans.Although many developmental studies have revealed that infants can evaluate the moral actions of others39. However, similarity in the underlying mechanism of gaze control between infants and these patients is not evident. Nonetheless, previous research using gaze-contingency techniques demonstrated that infants of the same age showed gaze behaviours for intentional control on the monitor29. Furthermore, the three control experiments implied that selective looking behaviour involves punishment-related decisions; infants increased their selective looks at the specific agent  only when their gaze was associated with a negative event  that consistently occurred  and when the event provided social information about the agents . In other words, infants changed their behaviour to accomplish their goal only when they perceived the means to punish, had a sense of self-agency for punitive behaviour and were in a situation that called for punishment. They did not change their behaviour if any of these three elements were lacking. Consequently, infant looking behaviours were probably decisions made with the intention to punish.One might doubt that the selective looks of infants reflect decision-making regarding punishment. Gaze-contingent techniques have been broadly used to investigate decision-making in patients with impaired limbs, such as those with amyotrophic lateral sclerosisA point to note is whether the gaze–action association learned during the pretest phase is preserved until the posttest phase even if the movie phase is inserted between the tests. During the movie phase, when infants gazed at the agent, the infants had no contingent events. It is thus possible that the gaze–action association is not preserved until the posttest phase. However, there are differences in the increase of selective looks after the movie phase between the experiments in which infants can learn the association (Experiments 1 and 5) and those where they cannot learn the same (Experiment 3). In addition, if infants were motivated to punish the aggressor, and if the association learning could not be maintained in the beginning of the posttest phase, the punishment rate would be at the chance level in the beginning of the posttest phase and would increase as the trials of the posttest phase elapsed. However, the observed data moderately supported the model excluding the interaction between test type and trial as well as the main effect of trial in Experiments 1 and 5, suggesting that the punishment rate for the aggressor in the posttest phase remained unchanged. We can therefore assume that the association between gaze and contingent event can be kept until the posttest phase.41. However, previous studies demonstrated that infants showed aversiveness to an agent who hit another agent21, affirmed an agent who disturbed the aggressor, and assumed that the aggressor should be hit by other agents22. It therefore seems plausible that infants regarded an agent who hit another agent as negative, thus expecting the aggressor to be punished, and consequently punishing the aggressor with their gaze. However, it may be slightly theory-laden to assert the psychological process of this punitive behaviour. Future studies are needed to identify associated underlying mechanisms. For example, because the aggressive interactions in this study involved multiple behaviours , explorations on what exactly infants pick up as the critical cue or whether they need to see multiple cues to view interactions between agents as truly aggressive would be valuable.There are some limitations worth noting. First, infants might think that the victim received a squeeze and thus the other actor should be squeezed as well; previous studies have indicated that infants expect equal treatment of others22, the objects seemed to move autonomously to some extent, and thus some infants might perceive the objects to be animates or agents. Finally, although infants showed intentional use of gaze for their decision-making in our study, we do not conclusively know whether the infants were aware that they punished the agent by their gaze. In other words, it is unclear whether the infants looked at the agent with a consciousness of punishment. A previous study proposed a multi-level framework that self-agency is based on complex mechanisms on several levels, ranging from implicit to explicit42. It is interesting to observe the levels of self-agency involved in the punishment behaviours in the current study.Second, although our data supported the idea that infants did not change their selective looks between the pretest and posttest in Experiment 4, the evidence for this was weak. This is consistent with the results comparing the effect size of test type between Experiment 4 and the main experiments. These results might be due to the individual differences in animacy perception for objects in Experiment 4. Although we removed the aspect of perceivable ‘animacy or agency’ in Experiment 4 on the basis of a previous study43 and social26 events. In contrast, recent research using the gaze-contingent technique has revealed active infant responses to contingent events29. We incorporated such techniques to investigate behaviour accompanying decision-making regarding others and determined that we can measure infants’ moral behaviour towards others. The application of this paradigm could reveal undiscovered cognitive abilities in preverbal infants.The presented paradigm in which infants can exhibit decision-making in a social context on a monitor might enable new infant cognitive research. Largely owing to limited methodologies as well as immature motor and verbal abilities in infants, most previous studies on infant cognition examined their perception and understanding of events from the viewpoint of a third party—that is, passive responses to physicalThis study was approved by Otsuma Women’s University’s Life Sciences Research Ethics Committee (no. 28-015) and the Behavioral Research Ethics Committee of the Osaka University School of Human Sciences (no. HB020-032).38. Eleven additional infants were tested but excluded owing to distress or fussiness (N = 4), or side-looking bias . The parents provided written informed consent before the experiment and were financially compensated for participation.The participants were 24 full-term eight-month-old infants . The sample size was determined on the basis of prior infant morality studies29. However, during the occurrence of contingent events, the red circle disappeared to allow for focus on said contingent events. The display background was aqua in colour.Infant gaze movements were measured using a Tobii TX300 near-infrared eye tracker (Tobii Technology), integrated with a 23-inch computer display . The sampling rate was 120 Hz. Task programming was completed in Visual Basic 2015 Express (Microsoft Corp.) and Tobii SDK (Tobii Technology). In all tasks, when an eye gaze was detected at a point on the display, a translucent red circle with a radius of 25 pixels appeared Fig.  to facilThe participants’ faces were monitored and recorded with a video camera (Panasonic HC-WX990M). Images on the PC screen (presented to the participants) and images of the participants were synthesized (Picture in Picture) using a video mixer device  and recorded on a laptop PC  with a monitor-capturing device .In the practical phase, the first six trials subjected the infants to gaze-contingent events in which fixation on a single object  for 500 ms resulted in a stone falling and crushing the object. This phase was set to reduce side-looking bias. In four subsequent trials, the infants were presented with two objects side by side (a red circle and a blue circle) instead of a single object. When the infants fixated on either of the two objects for 500 ms, a stone fell and crushed it. The presented position of each object or pair of objects was fixed among the participants.In the following pretest, the infants experienced gaze-contingent events identical to those in the practical phase except that the targets were two geometric agents with eyes  depicting one geometric figure hitting and crashing into another geometric figureThe infants were fastened in a baby carrier to prevent them from standing up and were placed on their mothers’ laps approximately 60 cm from the monitor. Nine-point calibration was used. The parents were instructed not to watch the monitor and not to talk or interact with their children during the experiment.The infants experienced ten gaze-contingent events in the practical phase. Then, the infants experienced ten gaze-contingent events in the pretest. In the movie phase, the infants were presented with animated movies of aggressive interactions three times. Finally, the infants experienced ten gaze-contingent events in the posttest. Attractive animated clips  with sound were inserted between trials if infants did not pay attention to the monitor.10 = 8.11, moderate evidence in favour of the alternative hypothesis; traditionally, the binomial test gives a P value below 0.05). To compare the proportion of infant selective looks at agents between pretest and posttest, we used GLMMs with a binomial error structure and a logit link function. The response variable was infant selective looks at the aggressor (= 1) or the victim (= 0) in the pretest or posttest. The explanatory variables (fixed effects) were test type (pretest or posttest) and trial number. We set participant identity as a random intercept. To keep the random effects structure “maximal”44, we also included all possible random slopes within participants and correlations.We excluded data from further analysis if infants showed a side-looking bias, which was defined as looking to one side in more than 12 of the 14 gaze-contingent events  , with the relative evidence in favour of each model over the null model (Table incl (ref. 30) for each effect to evaluate the level of likelihood that the data were under models that included the effect compared with models that excluded the effect  across all models. For reporting BF10 and BFincl, we set the Cauchy distribution with location 0 and scale 1/√2 as a prior distribution for a coefficient parameter31. We also set the default prior  of brms as the prior distribution of an intercept and the standard deviation of random effects. To check whether the main conclusions from the data were robust to different priors, we conducted a sensitivity analysis for BFincl  the null model, 2) a model with the main effect of test type, (3) a model with the main effect of trial number, (4) a model with the main effects of test type and trial number, and (5) a model with the main effect of test type, the main effect of trial number and the interaction between test type and trial number. All models were compared with the null model, and we computed the BF  of brms as a prior distribution of an intercept and the standard deviation of random effects. The posterior median and a 95% CI were calculated for each parameter.We estimated the posterior distributions of the model parameters and checked the posterior predictive distribution for an infant’s selective looks towards the aggressor for the best model in the model comparison results . The parameters were estimated with the Markov chain Monte Carlo (MCMC) method, and brms was used as an interface to Stan v.2.21.0 (ref. 48). As a general setting for MCMC sampling, iterations were set to 10,000, burn-in samples were set to 1,000 and the number of chains was set to four. The values of The computation of BFs and parameter estimation were implemented using the brms package.0 ref. 4. As a ge.3 ref. 4. The parN = 4), experimental error (N = 2) or side-looking bias . All other details were the same as in Experiment 1.The participants were an additional healthy 24 full-term eight-month-old infants . Eighteen additional infants were tested but excluded owing to distress or fussiness , machine trouble (N = 3) or side-looking bias . All other details were the same as in Experiment 1.The participants were an additional 24 full-term eight-month-old infants . Seven additional infants were tested but excluded owing to distress or fussiness  in all ten trials. This modification was to implement a 50% reinforcement probability. In the practical phase, pretest and posttest, when the infants fixated on one of two objects, half of the gaze-contingent events involved the object (or agent) that they looked at, while the other half involved the object (or agent) that they did not look at. The reinforcement order was randomized among infants; however, a given gaze-contingent event was repeated no more than three times , machine trouble (N = 1), parental intervention (N = 1) or side-looking bias . All other details were the same as in Experiment 1.The participants were an additional 24 healthy full-term eight-month-old infants . Seventeen additional infants were tested but excluded owing to distress or fussiness , machine trouble (N = 2) or side-looking bias . All other details were the same as in Experiment 1.The participants were an additional 24 full-term eight-month-old infants . Eleven additional infants were tested but excluded owing to distress or fussiness  were test type (pretest or posttest), experiment , trial number and the interaction between test type and experiment. Participant identity was set as a random intercept. We also included all possible random slopes within participants and correlations.The results indicating that infants selectively looked at the aggressor in the posttest rather than the pretest only in Experiments 1 and 5 are not sufficient to demonstrate that there were clear differences between the experiments in terms of changes in infants’ looking behaviour between the pretest and posttest phases46 and performed MCMC sampling in the same setting as in the analysis of each experiment. The values of The model parameters were estimated with the MCMC method. We used brmsmentclass2pt{minim49. We randomly generated 100 samples on the basis of the effect size while setting various values for the magnitude of individual difference. Thereafter, we treated the proportion of samples in which the 95% CI of the parameter for the effect of test type did not include zero as a simulated power, given the theoretically expected effect size. Unfortunately, we found that this sampling design was not sufficiently powerful for the range of individual differences estimated from our actual data and the theoretically expected effect sizes. If our sample had been generated from a theoretically expected effect size, our sampling design would have had sufficient power only when the individual difference in the test type effect was small. Although it was not possible to know the magnitude of individual difference in the test type effect a priori in this study, it is advisable to select a larger sample size to conduct a similar paradigm in the future  in Experiment 1 (and 5) . Permission to use the participant’s image was obtained by M.M.Supplementary Video 2Aggressive interaction  between two geometric-cube agents in Experiments 1, 2, 3 and 5.Supplementary Video 3Physical (inanimate) interaction  between two geometric cubes in Experiment 4.


Heart failure (HF) is a common chronic condition that affects over 26 million people worldwide. It is a progressive and debilitating disease with a broad symptom profile, intermittently marked by periods of acute decompensation. People with HF generally do not self-manage their condition well . A better understanding of self-care activities and what factors may indicate deterioration is warranted.The aim of this study was to determine the feasibility and acceptability of using wearable cameras to assess self-care activities in people with HF. The study objectives were to (1) explore whether changes in self-care activities could be identified prior to hospitalization and (2) determine the acceptability of wearable cameras to people with HF.A total of 30 people recently diagnosed with HF wore a camera for a maximum of 30 days; the camera took a photo every 30 seconds in the forward-facing direction. At the end of the study, all 30 participants were presented with 8 statements of acceptability, scored on a 5-point Likert scale. To determine whether camera images could identify changes in self-care activities and lifestyle risk factors before hospitalization, we analyzed images from participants (n=8) who were hospitalized during the 30-day study period. Images from the period immediately prior to hospitalization and a comparison were selected for each participant. Images were manually coded according to 9 different event categories relating to self-care and lifestyle risk factors, and events were compared between the 2 periods.P=.008) and were more sedentary (P=.02) prior to being hospitalized, compared to a period nonadjacent to hospitalization.The participants reported high acceptability for wearing the cameras, as most strongly agreed or agreed that they were comfortable to wear  and easy to use . The results of the camera image analysis showed that participants undertook fewer activities of daily living (Adults with HF were accepting of using a wearable camera for periods within a 30-day time frame. Wearable cameras were a feasible approach for providing data on selected self-care activities and lifestyle risk factors for HF and offer the potential to be a valuable tool for improving our understanding of self-care. Heart failure (HF) is a progressive and debilitating condition characterized by symptoms such as tachycardia, dyspnea, and fatigue caused by insufficient pumping of blood from the heart , which lSelf-care refers to the day-to-day management of chronic conditions by individuals to maintain wellness  and control symptoms and illness progression. It refers to a range of activities such as adhering to prescribed medications, undertaking daily care activities , managing body weight , and managing a healthy dietary intake  . DespiteThe EuroHeart Failure Survey  showed tIncreasingly, technologies have been harnessed to better understand and support self-care activities in people with a range of health conditions. One such technology is visual “life-logging,” which refers to the use of wearable cameras to digitally capture everyday life activities through first-person point-of-view images . WearablIn summary, wearable cameras may offer a potential tool to assist HF management. An enhanced picture of an individual’s self-care activities could augment existing health care services and provide new avenues for interventions. However, as no studies have used wearable cameras in people with HF for this purpose, the feasibility of detecting specific self-care activities using images from wearable cameras and acceptability in this population need to be determined.The aim of this study was to determine the feasibility and acceptability of using wearable cameras to assess self-care activities in people with HF. The study objectives were to (1) explore whether changes in self-care activities and lifestyle risk factors could be identified prior to hospitalization and (2) determine the acceptability of wearable cameras to people with HF.This study was part of a larger prospective observational pilot study that aimed to determine the feasibility and acceptability of using wearable cameras and point-of-care testing to assess self-care activities and identify periods of decompensation in people with HF. The study involved 30 people diagnosed with HF who wore a wearable camera for a maximum of 30 days and underwent point-of-care testing and self-assessed symptom scoring twice a week during the study period . In thisParticipants were recruited from a single-center HF outpatient clinic at a tertiary hospital in Melbourne, Australia. Inclusion criteria were newly diagnosed HF  outpatients, older than 18 years, able to read and understand English, and treated with medication. Participants were approached by a cardiologist or a trained researcher during outpatient clinics and asked to participate. Those who agreed were contacted by a researcher from Deakin University, who explained the study and undertook screening to determine eligibility. Eligible participants were scheduled for a baseline assessment, at which time a written consent was obtained.Participants were asked to wear the Narrative Clip camera  on theirAs this study aimed to determine the feasibility of using wearable cameras, the analysis was exploratory and descriptive in nature. As highlighted above, this analysis focused on only those (n=8) participants who were readmitted to hospital during the 30-day study period. Images from at least 2 days immediately prior to hospitalization (T1) were a requirement for inclusion in this analysis. The comparison period (T2) for each participant was at least 2 days the same days of the week as T1 and selected depending on when in the study the participant was hospitalized .Images from the selected days for each participant were sequentially reviewed and coded by 1 author (SA) who had received training from 2 authors (RM and RN) experienced with camera image review. Many images were similar; therefore, images were scanned until a unique event (an image capturing an event of interest) was observed.The research team developed categories for the events of interest after reviewing published literature on self-care and lifestyle risk factors . The folAll unique events were coded into these categories using an Excel worksheet (Microsoft Corporation), and the image reference was noted for ease of future reference. For example, the image in To assess acceptability, participants were presented with 8 statements to determine their perceptions of wearing the camera, including personal feelings, its utility, and technical issues. A 0-4 Likert-type scale  was used to measure to what extent the participants agreed with the statements.t tests were used for comparison; significance level was at .05.All data were exported from Excel to SPSS version 27 (IBM Corporation). The number of coded events from the 2 periods (T1 and T2) were tested for normal distribution using the Kolmogorov-Smirnov test. Thereafter, two-tailed paired sample Ethical approval was obtained from the Human Research Ethics Committee at Deakin University (HREC/16/MH/55) and the Western Health Human Research Ethics Committee (2016.071). The participants received information about the study through a patient information sheet and verbal explanation from the research team. They were informed that they could leave the study at any time . All participants had an opportunity to ask questions about the study before they gave written informed consent. During the study, participants were given the opportunity to delete images downloaded from their wearable camera. On completing the study, participants received a AU $40 (US $28) voucher.Of the 30 participants involved in the study, 10 (33%) were readmitted to hospital during the 30-day study period .Of the 10 participants readmitted to hospital with an exacerbation of HF, 2 (20%) did not wear the camera in the days prior to hospitalization and therefore did not meet the inclusion criteria for this analysis; thus, data from 8 participants were included. From these 8 participants, a total of 44 days of camera data were selected, and on average, 1000 images per day were available for each participant . For 6 participants, 6 days of camera data were analyzed, consisting of 3 days immediately prior to admission (T1) and 3 days from 2 weeks before hospitalization (T2). Moreover, 2 participants were hospitalized 2 days after the study commenced, and therefore only 4 days of camera data were analyzed for these participants—the 2 days immediately prior to admission (T1) and 2 days from 2 weeks after discharge (T2). All analyses included images from at least one weekday and a weekend day.Across all images selected for this analysis, 904 unique events were identified. Of these 904 events, 432 (48%) were sedentary behavior events, such as sitting or lying down, and 275 (30%) were activities of daily living, such as ironing or cooking. Physical activity events  that occurred in the home environment  were more common than those outside the home  and ADL events  were significantly different between T1 and T2  were in T1 and 540 (60%) in T2. In T1, participants had fewer unique events of sedentary behavior and ADLs compared to T2, indicating that they may have been sedentary for longer continuous periods of time prior to hospitalization. The number of medication events was lower in T1 (n=14) compared to T2 (n=25), and events relating to physical activities outside the home, shopping, and the presence of packaged foods were about the same across the 2 periods. Of the event categories, only sedentary behavior events  were presented with 8 statements of acceptability, scored on a 5-point Likert scale. Overall, participants reported high acceptability for wearing the cameras .This study sought to determine the feasibility and acceptability of wearable cameras to assess self-care activities and lifestyle risk factors in people with HF. Overall, the technology was considered feasible for better understanding self-care; however, technical issues warrant future attention. The technology was also acceptable to participants.We demonstrated the feasibility of using wearable cameras to collect data on self-care activities and lifestyle risk factors. Differences in the number of events were observed between the days immediately prior to hospitalization and 2 weeks before or after hospitalization. While we identified a range of self-care activities and lifestyle risk factors, one feasibility issue was the absence of images of people self-weighing—a common HF self-care practice. This absence could indicate that the study participants did not practice self-weighing or that the forward-facing direction of the camera did not capture the floor scale. Alternatively, as people with HF are typically advised to self-weigh in the morning after toileting, participants may not be wearing the camera during this activity.Some technical issues warrant discussion. Images were captured every 30 seconds throughout the day, which resulted in approximately 1000 images per participant per day. For this study, we manually reviewed images, which was extremely time-consuming. The quality of the images was mixed, with some images blurred or masked by clothing; thus, we could not code all images due to that lack of clarity. These issues will likely be resolved with technology improvements and participant training protocols. For example, technical solutions and machine learning techniques can review large quantities of data, detect patterns, and filter images into categories for easy recognition and analysis. We are currently applying these techniques to our entire image database.Acceptability for using wearable cameras was high for all participants, with most indicating the devices were comfortable to wear and easy to use. While participants self-reported that they thought wearable cameras were acceptable, it was evident from the data that not all participants wore the camera as instructed (during waking hours) every day. While we did not analyze our data to understand this, it could suggest that wearable cameras are only acceptable to participants at certain times of the day or during certain activities.The high level of acceptability observed in this study was consistent with findings from previous research on older adults older than 65 years with mild cognitive impairment . We alsoThe major strength of this study was the novelty of using wearable cameras to observe self-care activities in people with HF. To the best of our knowledge, this is the first study to apply this technology for this purpose. This study resulted in a rich data source, which provided an objective measure of self-care in people with HF. There were limitations to this study. Firstly, a small number of participants was used for analysis; however, as mentioned above, that number of participants yielded 44,000 images for review. Secondly, the time spent in some self-care activities, such as physical activity, is important to understand. In this study, we coded specific events but did not capture the time spent in each activity. Future studies could use automated image processing to analyze the time spent in each activity. Finally, another limitation is that only 1 researcher coded the images, and the intrarater reliability was not assessed; the results need to be considered with this in mind. Future studies should consider 2 or more coders or using automated techniques to code images.Wearable cameras offer the potential to help medical and allied health staff better tailor health education for people living with HF. To illustrate, newly diagnosed people with HF might wear a camera for 3-7 days. Automated processing could select or filter images to be rapidly reviewed by a health care professional. These insights into an individual’s self-care practices could then be used to facilitate conversations at outpatient clinics to improve behaviors. Images and conversations might capture misconceptions about self-care advice, such as continuing to add salt to food or purchasing packaged foods that contain added salt. Patient review of images might also increase awareness and motivation for participation in self-care behaviors by providing measures through which progress is tracked. Personalized support driven by the images could be delivered via a user’s smartphone . MoreoveAdults with HF were accepting of using a wearable camera for periods within a 30-day time frame. Wearable cameras were a feasible approach for providing data on selected self-care and lifestyle behaviors for HF. The use of wearable cameras offers the potential to augment clinical practice by tailoring future education for people living with HF; however, issues related to data collection and analysis need to be addressed to improve their utility for this purpose.