Design and modeling for drug combination experiments with order effects.

Combinations of drugs are now ubiquitous in treating complex diseases such as cancer and HIV due to their potential for enhanced efficacy and reduced side effects. The traditional combination experiments of drugs focus primarily on the dose effects of the constituent drugs. However, with the doses of drugs remaining unchanged, different sequences of drug administration may also affect the efficacy endpoint. Such drug effects shall be called as order effects. The common order-effect linear models are usually inadequate for analyzing combination experiments due to the nonlinear relationships and complex interactions among drugs. In this article, we propose a random field model for order-effect modeling. This model is flexible, allowing nonlinearities, and interaction effects to be incorporated with a small number of model parameters. Moreover, we propose a subtle experimental design that will collect good quality data for modeling the order effects of drugs with a reasonable run size. A real-data analysis and simulation studies are given to demonstrate that the proposed design and model are effective in predicting the optimal drug sequences in administration.

Impacts of the preceding cancer-specific health-related quality of life instruments on the responses to the subsequent EQ-5D-5L.

BACKGROUND: In clinical studies, the EQ-5D-5L is often employed with disease-specific health-related quality of life instruments. The questions in the former are more general than the latter; however, it is known that responses to general questions can be influenced by preceding specific questions. Thus, the responses to the EQ-5D-5L have the possibility of being influenced by the preceding disease-specific health-related quality of life instruments. This may lead to bias in the cost-effectiveness analysis results. Therefore, this study aimed to evaluate the impact of the preceding cancer-specific health-related quality of life instruments on the EQ-5D-5L responses. METHODS: We prepared questionnaire booklets containing the EQ-5D-5L, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and the Functional Assessment of Cancer Therapy General with different orders. Using a quasi-randomized design, they were distributed to the patients undergoing drug therapy for advanced cancer, who were classified into three groups: Groups 1, 2, and 3 (the EQ-5D-5L placed first, second, and last, respectively). We compared the EQ-5D-5L index and the missingness of EQ-5D-5L among the groups. RESULTS: The mean EQ-5D-5L index was 0.796, 0.760, and 0.789 for groups 1 (n = 300), 2 (n = 306), and 3 (n = 331), respectively. The difference between Groups 2 and 1 was - 0.036 (95% CI - 0.065 to - 0.007; p = 0.015). The proportion of patients with an incomplete EQ-5D-5L was 0.11, 0.11, and 0.05 for Groups 1, 2, and 3, respectively. The difference of the proportions between group 3 and 1 and between 3 and 2 was - 0.06 (95% CI - 0.10 to - 0.02; p = 0.003) and - 0.06 (95% CI - 0.10 to - 0.02; p = 0.003), respectively. CONCLUSIONS: Although the EQ-5D-5L index differed according to the instrument orders, the difference size would not be considerably larger than the minimally important difference. The patients tended to complete the EQ-5D-5L when they were placed at the end of the questionnaire.

Structuring healthcare advance directives: Evidence from Chinese end-of-life cancer patients' treatment preferences.

BACKGROUND: Patients' treatment decisions may be influenced by the ways in which treatment options are presented. There is little evidence on how patients with advanced cancer choose preferences for advance directives (ADs) in China. Informed by behavioural economics, we assess whether end-of-life (EOL) cancer patients held deep-seated preferences for their health care and whether default options and order effects influenced their decision-making. METHODS: We collected data on 179 advanced cancer patients who were randomly assigned to complete one of the four types of ADs: comfort-oriented care (CC) AD (comfort default AD); a life extension (LE)-oriented care option (LE default AD); CC (standard CC AD) and LE-oriented (standard LE AD). Analysis of variance test was used. RESULTS: In terms of the general goal of care, 32.6% of patients in the comfort default AD group retained the comfort-oriented choice, twice as many as in the standard CC group without default options. Order effect was significant in only two individual-specific palliative care choices. Most patients (65.9%) appointed their children to make EOL care decisions, but patients choosing the CC goal were twice as likely to ask their family members to adhere to their choices than patients who chose the LE goal. CONCLUSION: Patients with advanced cancer did not hold deep-seated preferences for EOL care. Default options shaped decisions between CC and LE-oriented care. Order effect only shaped decisions in some specific treatment targets. The structure of ADs matters and influence different treatment outcomes, including the role of palliative care. PATIENT OR PUBLIC CONTRIBUTION: Between August and November 2018, from 640 cancer hospital medical records fitting the selection criteria at a 3A level hospital in Shandong Province, we randomly selected 188 terminal EOL advanced cancer patients using a random generator programme to ensure all eligible patients had an equal chance of selection. Each respondent completes one of the four AD surveys. While respondents might require support in making their healthcare choices, they were informed about the purpose of our research study, and that their survey choices would not affect their actual treatment plan. Patients who did not agree to participate were not surveyed.

Testing the impact of overt and covert ordering interventions on sustainable consumption choices: A randomised controlled trial.

Food products have significant impacts on the environment over their life cycle. We investigated whether displaying products in ascending order of carbon footprint in an online supermarket environment can shift consumer choices towards more sustainable options. We examined whether the effect of the ordering intervention differs when the ordering is overt (information about the ordering is explicit), compared to when it is covert (participants not told about the ordering). We conducted a three-arm parallel-group randomised trial using 1842 online participants from England, Wales, and Northern Ireland. Participants shopped for a meal, choosing one product from each of six product categories in a simulated online supermarket. Six products were listed vertically on each product-category page. Products were randomly ordered for the control arm but ordered by carbon footprint in the covert and overt ordering arms. In the overt ordering arm, a statement was displayed at the top of each product page about the ordering of products. The primary outcome was whether one of the three most sustainable products was chosen in each product category. There was no effect of the covert ordering on the probability of choosing more sustainable products compared with the control arm (OR = 0.97, 95% CI 0.88-1.07, p = 0.533). Furthermore, we did not find evidence that the effects of the covert ordering and overt ordering differed (p = 0.594). Within the control condition, products in different positions were chosen with similar frequencies, suggesting that product positioning does not have an impact on choices. This may explain why re-ordering products had no effect. In the overt condition, only 19.5% of people correctly answered that the products were ordered according to sustainability in a follow-up question, suggesting that they didn't notice the statement. Results suggest that choices for grocery products might be too ingrained to be changed by subtle rearrangements of choice architecture like the ordering interventions, and highlight the difficulty of conveying information effectively to consumers in the online grocery shopping environment.

Preserved time but altered numerosity processing in epileptic patients with postoperative lesion in the inferior frontal gyrus.

Previous researches have shown that the inferior frontal gyrus (IFG) is involved in time and numerosity processing. This study aimed at examining (i) interval timing and (ii) interaction between duration and numerosity processing in four drug-resistant epileptic patients with postoperative lesions in the IFG in comparison with thirteen healthy controls. The duration reproduction and discrimination tasks performed in the sub- and supra-second ranges did not reveal any significant differences between patients and controls. The duration discrimination task of stimuli varying in numerosity (DurN) and the numerosity discrimination task of stimuli varying in duration (NumD) revealed that only numerosity judgment was altered in IFG patients. A time-order effect was notably observed in the NumD task but in opposite directions for the two groups: The second patch was perceived as more numerous than the first patch in controls and conversely as less numerous in patients. Finally in the DurN task, we observed a congruency effect which was dependent on numerical distance in patients but not in controls. These converging results suggest that the IFG would be more specifically involved in numerosity than in duration processing, possibly playing a role in numerical decision.

Order effects in the recall of autobiographical memories: evidence for an organisation along temporal and emotional features.

Investigating the recall process of autobiographical memories (AMs) and, particularly, the order in which AMs are recalled has the potential to shed light on the organisation of autobiographical memory. However, research on order effects in the recall of AMs is relatively rare. Moreover, to date, no study addressed the question of where emotion fits into the organisation. The present study aimed to close this gap by examining whether emotional valence serves as one organising principle. Data come from 117 older adults (M = 74.11; SD = 7.06) who reported up to 39 AMs. The use of a multivariate multilevel model with autoregressive effects allows us to analyse the order effect within one person, as well as how the order effect differs between persons. The results replicated a temporal first-order effect that has been shown in previous studies and moreover, demonstrated a temporal second-order effect. Furthermore, our results indicated an emotional first-order effect that was even stronger than the temporal first-order effect and an emotional second-order effect. In addition, both first-order effects differed reliably between persons. Thus, the present study emphasises the need for considering emotion in current theoretical formulations of autobiographical memory and also of considering individual differences in the order of AMs recalled.

A short review of biological research on the development of sexual orientation.

We review research supporting biological mechanisms in the development of sexual orientation. This research includes studies on neural correlates, prenatal hormones and related physical/behavioral correlates, genetics, and the fraternal birth order effect (FBOE). These studies, taken together, have provided substantial support for biological influences underlying the development of sexual orientation, but questions remain unanswered, including how biological mechanisms may differ in contributing to men's and women's sexual orientation development.

The Disjunction Effect in two-stage simulated gambles. An experimental study and comparison of a heuristic logistic, Markov and quantum-like model.

Savage's rational axiom of decision making under uncertainty, called the 'Sure Thing' principle, was purportedly falsified in a two-stage gamble paradigm by Tversky and Shafir (1992). This work revealed that participants would take a second-stage gamble for both possible outcomes of the initial-stage gamble, but would significantly depress this choice when no information was available on the outcome of the initial-stage gamble. Subsequent research has reported difficulty to replicate this Disjunction Effect in the two-stage gamble paradigm. We repeated this simulated two-stage gamble paradigm in an online study (N = 1119) but adapted the range of payoff amounts, and controlled the order of the blocks of two-stage gambles with, respectively without, information on the outcome of the first-stage gamble. The main empirical contributions of this study are that more risk averse participants produced (i) a reliable order effect in relation to the Disjunction Effect and the violation of the Law of Total Probability, and (ii) a novel inflation effect on gambling in the Unknown outcome condition analogous but opposite to the Disjunction Effect when Unknown outcome conditioned two-stage gambles precede the Known outcome conditioned ones. By contrast, we found that less risk averse participants produced neither of these effects. We discuss the underlying choice processes and compare the effectiveness of a logistic model, a Markov model and a quantum-like model. Our main theoretical findings are (i) a standard utility model and a Markov model using heuristic linear utility, contextual influence and carry-over effect cannot accommodate the present empirical results, and (ii) a model based on quantum dynamics, matched in form to the Markov model, can successfully describe all major aspects of our data.

On the Mathematics of the Fraternal Birth Order Effect and the Genetics of Homosexuality.

Mathematicians have always been attracted to the field of genetics. The mathematical aspects of research on homosexuality are especially interesting. Certain studies show that male homosexuality may have a genetic component that is correlated with female fertility. Other studies show the existence of the fraternal birth order effect, that is, the correlation of homosexuality with the number of older brothers. This article is devoted to the mathematical aspects of how these two phenomena are interconnected. In particular, we show that the fraternal birth order effect implies a correlation between homosexuality and maternal fecundity. Vice versa, we show that the correlation between homosexuality and female fecundity implies the increase in the probability of the younger brothers being homosexual.

Does Fraternal Birth Order Predict Male Homosexuality, Bisexuality, and Heterosexual Orientation with Same-Sex Attraction? Evidence from a Greek-Speaking Sample from Greece.

Studies have established that having older brothers is associated with an increased incidence of male homosexuality. This so-called fraternal birth order effect has been found in different times and cultural settings. The current study attempted to examine whether this effect was present in the Greek cultural context and whether it could also predict bisexuality or heterosexuality with occasional same-sex attractions. On the basis of an online sample of 1617 Greek-speaking participants, it was found that, for men, a higher number of older brothers were associated with an increased probability to be homosexual, but it had no effect on the probability to be bisexual or heterosexual with same-sex attractions. In women, the number of older brothers had not any effect on sexual orientation.

The relationship between fraternal birth order and childhood sex-atypical behavior among the Istmo Zapotec muxes.

Research on male androphilia (i.e., sexual attraction towards adult males) consistently finds that androphilic males tend to have more older biological brothers than males who are gynephilic (i.e., sexually attracted to adult females). This fraternal birth order effect (FBOE) has been well replicated among androphilic males who present publically in a male-typical (cisgender) and a female-typical (transgender) manner. There is some evidence that the FBOE is more pronounced among transgender androphilic males. However, no studies have directly compared both forms of male androphilia within the same culture. This study tested the FBOE, and its association with childhood sex-atypical behavior (CSAB), among the Istmo Zapotec of Oaxaca, Mexico, where both forms of male androphilia are referred to as a third gender, muxes. Our results indicated that both cisgender muxe nguiiu (n = 124) and transgender muxe gunaa (n = 120) were more likely to be later born among brothers than gynephilic men (n = 194). However, the number of older brothers did not differentiate between transgender and cisgender muxes, nor did it predict CSAB among muxes. These findings replicate the FBOE among both cisgender and transgender muxes but show no evidence that it is more pronounced among transgender androphilic males.

Interaction modifications lead to greater robustness than pairwise non-trophic effects in food webs.

Considerable emphasis has been placed recently on the importance of incorporating non-trophic effects into our understanding of ecological networks. Interaction modifications are well-established as generating strong non-trophic impacts by modulating the strength of interspecific interactions. For simplicity and comparison with direct interactions within a network context, the consequences of interaction modifications have often been described as direct pairwise interactions. The consequences of this assumption have not been examined in non-equilibrium settings where unexpected consequences of interaction modifications are most likely. To test the distinct dynamic nature of these "higher-order" effects, we directly compare, using dynamic simulations, the robustness to extinctions under perturbation of systems where interaction modifications are either explicitly modelled or represented by corresponding equivalent pairwise non-trophic interactions. Full, multi-species representations of interaction modifications resulted in a greater robustness to extinctions compared to equivalent pairwise effects. Explanations for this increased stability despite apparent greater dynamic complexity can be found in additional routes for dynamic feedbacks. Furthermore, interaction modifications changed the relative vulnerability of species to extinction from those trophically connected close to the perturbed species towards those receiving a large number of modifications. Future empirical and theoretical research into non-trophic effects should distinguish interaction modifications from direct pairwise effects in order to maximize information about the system dynamics. Interaction modifications have the potential to shift expectations of species vulnerability based exclusively on trophic networks.

Counterfactual thinking and age differences in judgments of regret and blame.

In the current study, we examined whether two different counterfactual thinking biases (i.e., action  bias and temporal order bias) influence children's and adults' judgments of regret and blame and whether the perspective that participants take (i.e., self vs. other) affects blame attributions. Little evidence was found for either bias in young children's judgments, and at older ages the temporal order bias had a stronger influence on judgments compared with the action bias. In addition, the results provide new evidence suggesting that there are developmental changes in the effects of self versus other perspectives on children's social judgments. The findings are discussed in the context of developmental change in counterfactual thinking.

Application of Theory of Quantum Instruments to Psychology: Combination of Question Order Effect with Response Replicability Effect.

Recently, quantum formalism started to be actively used outside of quantum physics: in psychology, decision-making, economics, finances, and social science. Human psychological behavior is characterized by a few basic effects; one of them is the question order effect (QOE). This effect was successfully modeled (Busemeyer-Wang) by representing questions A and B by Hermitian observables and mental-state transformations (back action of answering) by orthogonal projectors. However, then it was demonstrated that such representation cannot be combined with another psychological effect, known as the response replicability effect (RRE). Later, this no-go result was generalized to representation of questions and state transformations by quantum instruments of the atomic type. In light of these results, the possibility of using quantum formalism in psychology was questioned. In this paper, we show that, nevertheless, the combination of the QOE and RRE can be modeled within quantum formalism, in the framework of theory of non-atomic quantum instruments.

Moral Judgments Depend on Information Presentation: Evidence for Recency and Transfer Effects.

Moral judgements are crucial for social life and rely on the analysis of the agent's intention and the outcome of the agent's action. The current study examines to the influence of how the information is presented on moral judgement. The first experiment investigated the effects of the order in which intention and outcome information was presented. The results showed that participants relied more on the last presented information, suggesting a recency effect. The second experiment required participants to make two types of judgments (wrongness vs. punishment) and manipulated the order of the requested two types of judgments. Results showed an asymmetrical transfer effect whereby punishment judgements, but not wrongness judgements were affected by the order of presentation. This asymmetrical transfer effect was likely linked to the ambiguity of the punishment judgement. Altogether, the study showed that the order in which information was presented and the order in which one was asked to think about the wrongness of an action or the punishment that the action deserves were two factors that should be irrelevant, but actually influenced moral judgements. The influence of these factors was mostly observed during the most difficult judgements, precisely in situations where human decision is called upon, such as in court trials.

Birth order and recalled childhood gender nonconformity in Samoan men and fa'afafine.

Having a greater than average number of older biological brothers is a robust correlate of male androphilia (i.e., sexual attraction and arousal to adult males). Previous investigations have sought to understand whether this fraternal birth order (FBO) effect is also systematically related to recalled indicators of childhood gender nonconformity (CGN). However, these investigations have relied on data from low-fertility Western populations in which expressions of femininity in male children are routinely stigmatized and consequently, suppressed. The present study examined the FBO effect (among other sibship characteristics) and recalled indicators of CGN in Samoa, a high-fertility population, whose members are relatively tolerant of male femininity. Indeed, Samoans identify feminine androphilic males as belonging to an alternative gender category, known locally as fa'afafine. The present study compared the sibship characteristics of 231 fa'afafine and 231 opposite-sex attracted men from Samoa, as well as how these characteristics related to recalled CGN. Results replicated the well-established FBO effect for predicting male sexual orientation, with each older brother increasing the odds of being androphilic by 21%. However, no relationship was found between the number of older brothers (or other siblings) a participant had and their recalled CGN. Although fa'afafine reported significantly more CGN than Samoan men, CGN did not mediate the FBO effect, nor did the FBO effect and CGN interact to predict male sexual orientation. These findings are consistent with previous studies suggesting that the FBO effect is associated with male sexual orientation, but not childhood female-typical gender expression among androphilic males.

Attributions of Blame in Acquaintance Rape Scenarios: The Role of Blame Scale Presentation Order.

Three studies were conducted to examine the role of order effects in attributions of blame in cases of acquaintance rape. Participants were presented with a vignette describing an acquaintance rape and were then asked to respond to a victim blame scale and a perpetrator blame scale, the presentation order of which was manipulated. The results of Study 1 (n = 129) indicated that the participants who first responded to the perpetrator blame scale blamed the perpetrator less than the participants who first responded to the victim blame scale. This effect was replicated in Study 2 (n = 120) and Study 3 (n = 70), which was run 18 months after Study 2 and used a modified vignette. These findings suggest that order effects should be a methodological consideration in future studies on blame attribution.

Chou's pseudo amino acid composition improves sequence-based antifreeze protein prediction.

Antifreeze proteins (AFP) in living organisms play a key role in their tolerance to extremely cold temperatures and have a wide range of biotechnological applications. But on account of diversity, their identification has been challenging to biologists. Earlier work explored in this area has yet to cover introduction of sequence order information which is known to represent important properties of various proteins and protein systems for prediction purposes. In this study, the effect of Chou's pseudo amino acid composition that presents sequence order of proteins was systematically explored using support vector machines for AFP prediction. Our findings suggest that introduction of sequence order information helps identify AFPs with an accuracy of 84.75% on independent test dataset, outperforming approaches such as AFP-Pred and iAFP. The relative performance calculated using Youden's Index (Sensitivity+Specificity-1) was found to be 0.71 for our predictor (AFP-PseAAC), 0.48 for AFP-Pred and 0.05 for iAFP. We hope this novel prediction approach will aid in AFP based research for biotechnological applications.

The effect of repeated measurements and working memory on the most comfortable level in the ANL test.

OBJECTIVE: To study the effect of a large number of repetitions on the most comfortable level (MCL) when doing the acceptable noise level (ANL) test, and explore if MCL variability is related to central cognitive processes. DESIGN: Twelve MCL repetitions were measured within the ANL test using interleaved methodology during one session using a non-semantic version. Phonological (PWM) and visuospatial working memory (VSWM) was measured. STUDY SAMPLE: Thirty-two normal-hearing adults. RESULTS: Repeated measures ANOVA, intraclass correlations, and the coefficient of repeatability (CR) were used to assess the repeatability. Repeated measures ANOVA and CR indicated poor agreement between the two first repetitions. After excluding the first repetition, analyses showed that the MCL in the ANL test is reliable. A negative association was found between PWM and MCL variability indicating that subjects with higher PWM show less variability. CONCLUSIONS: The findings suggest that, after excluding the first repetition, the MCL in the ANL test is reliable. A single repetition of the MCL in the ANL test should be avoided. If an interleaved methodology is used, a single ANL repetition should be added prior to the actual testing. The findings also suggest that MCL variability is associated to PWM but not VSWM.

Attributions of Sexual Assault: Effects of Victim and Perpetrator Stereotypes, Presentation Order, and Participant Characteristics.

Research on sexual assault has shown that victim, perpetrator, and participant characteristics can influence evaluations of an assault. However, the studies have not examined a possible main effect or interactions from respectively introducing the victim or perpetrator first in an assault description, and previous studies have used participant samples with little diversity. We conducted two studies with factorial between-groups designs that varied presentation order in addition to victim and perpetrator stereotypicality and then assessed the impacts on participants' judgments of sexual assault scenarios. We used the online marketplace Prolific to collect large, diverse samples of participants, and in the second study, we collected roughly equal sample sizes of individuals who identified as Black females/males and White females/males. Our results indicate that multiple factors-including victim and perpetrator stereotypicality, presentation order, and participants' gender identities-significantly influenced judgments of the sexual assault, and there were numerous interactions. The results provide strongest support for a spreading activation model in which each factor can influence a participant's judgment of the other factors and the overall scenario. As such, the findings may bear on the legal handling of sexual assault cases as well as suggesting how different presentation formats and emphases in media coverage may sway the court of public opinion.