The Brain's Best Kept Secret Is Its Degenerate Structure.

Degeneracy is defined as multiple sets of solutions that can produce very similar system performance. Degeneracy is seen across phylogenetic scales, in all kinds of organisms. In neuroscience, degeneracy can be seen in the constellation of biophysical properties that produce a neuron's characteristic intrinsic properties and/or the constellation of mechanisms that determine circuit outputs or behavior. Here, we present examples of degeneracy at multiple levels of organization, from single-cell behavior, small circuits, large circuits, and, in cognition, drawing conclusions from work ranging from bacteria to human cognition. Degeneracy allows the individual-to-individual variability within a population that creates potential for evolution.

Causation and familial confounding as explanations for the associations of polygenic risk scores with breast cancer: Evidence from innovative ICE FALCON and ICE CRISTAL analyses.

A polygenic risk score (PRS) combines the associations of multiple genetic variants that could be due to direct causal effects, indirect genetic effects, or other sources of familial confounding. We have developed new approaches to assess evidence for and against causation by using family data for pairs of relatives (Inference about Causation from Examination of FAmiliaL CONfounding [ICE FALCON]) or measures of family history (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLyses [ICE CRISTAL]). Inference is made from the changes in regression coefficients of relatives' PRSs or PRS and family history before and after adjusting for each other. We applied these approaches to two breast cancer PRSs and multiple studies and found that (a) for breast cancer diagnosed at a young age, for example, <50 years, there was no evidence that the PRSs were causal, while (b) for breast cancer diagnosed at later ages, there was consistent evidence for causation explaining increasing amounts of the PRS-disease association. The genetic variants in the PRS might be in linkage disequilibrium with truly causal variants and not causal themselves. These PRSs cause minimal heritability of breast cancer at younger ages. There is also evidence for nongenetic factors shared by first-degree relatives that explain breast cancer familial aggregation. Familial associations are not necessarily due to genes, and genetic associations are not necessarily causal.

Breast and bowel cancers diagnosed in people 'too young to have cancer': A blueprint for research using family and twin studies.

Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.

Can Red Blood Cell and Platelet Transfusions Have a Pathogenic Role in Bronchopulmonary Dysplasia?

OBJECTIVE: To evaluate whether transfusions in infants born preterm contribute to the pathogenesis of bronchopulmonary dysplasia (BPD). STUDY DESIGN: We conducted a multihospital, retrospective study seeking associations between red blood cell or platelet transfusions and BPD. We tabulated all transfusions administered from January 2018 through December 2022 to infants born ≤29 weeks or <1000 g until 36 weeks postmenstrual age and compared those with BPD grade. We performed a sensitivity analysis to assess the possibility of a causal relationship. We then determined whether each transfusion was compliant with restrictive guidelines, and we estimated effects fewer transfusions might have on future BPD incidence. RESULTS: Eighty-four infants did not develop BPD and 595 did; 352 developed grade 1 (mild), 193 grade 2 (moderate), and 50 grade 3 (severe). Transfusions were given at <36 weeks to 7% of those who did not develop BPD, 46% who did, and 98% who developed severe BPD. For every transfusion the odds of developing BPD increased by a factor of 2.27 (95% CI, 1.59-3.68; P < .001). Sensitivity analyses suggested that transfusions might contribute to BPD. Fifty-seven percent of red blood cell transfusions and 68% of platelet transfusions were noncompliant with new restrictive guidelines. Modeling predicted that complying with restrictive guidelines could reduce the transfusion rate by 20%-30% and the moderate to severe BPD rate by ∼4%-6%. CONCLUSIONS: Transfusions were associated with BPD incidence and severity. Lowering transfusion rates to comply with current restrictive guidelines might result in a small but meaningful reduction in BPD rates.

A Note on Modelling Bidirectional Feedback Loops in Mendelian Randomization Studies.

Structural equation models (SEMs) involving feedback loops may offer advantages over standard instrumental variables estimators in terms of modelling causal effects in the presence of bidirectional relationships. In the following note, we show that in the case of a single "exposure" and "outcome" variable, modelling relationships using a SEM with a simple bidirectional linear feedback loop offers no advantage over traditional instrumental variables estimators in terms of consistency (i.e. both approaches yield consistent estimates of the causal effect, provided that causal estimates are obtained in both directions). In the case of finite samples, traditional IV estimators and SEM exhibited similar power across many of the conditions we examined, although which method performed best depended on the residual correlation between variables and the strength of the instruments. In particular, the power of SEM was insensitive to the residual correlation between variables, whereas the power of the Wald estimator/2SLS improved (deteriorated) relative to SEM as the magnitude of the residual correlation increased (decreased) assuming a positive causal effect of the exposure on the outcome. The power of SEM improved relative to the Wald estimator/2SLS as the instruments explained more residual variance in the "outcome" variable.

Interventional probability of causation (IPoC) with epidemiological and partial mechanistic evidence: benzene vs. formaldehyde and acute myeloid leukemia (AML).

INTRODUCTION: Causal epidemiology for regulatory risk analysis seeks to evaluate how removing or reducing exposures would change disease occurrence rates. We define interventional probability of causation (IPoC) as the change in probability of a disease (or other harm) occurring over a lifetime or other specified time interval that would be caused by a specified change in exposure, as predicted by a fully specified causal model. We define the closely related concept of causal assigned share (CAS) as the predicted fraction of disease risk that would be removed or prevented by a specified reduction in exposure, holding other variables fixed. Traditional approaches used to evaluate the preventable risk implications of epidemiological associations, including population attributable fraction (PAF) and the Bradford Hill considerations, cannot reveal whether removing a risk factor would reduce disease incidence. We argue that modern formal causal models coupled with causal artificial intelligence (CAI) and realistically partial and imperfect knowledge of underlying disease mechanisms, show great promise for determining and quantifying IPoC and CAS for exposures and diseases of practical interest. METHODS: We briefly review key CAI concepts and terms and then apply them to define IPoC and CAS. We present steps to quantify IPoC using a fully specified causal Bayesian network (BN) model. Useful bounds for quantitative IPoC and CAS calculations are derived for a two-stage clonal expansion (TSCE) model for carcinogenesis and illustrated by applying them to benzene and formaldehyde based on available epidemiological and partial mechanistic evidence. RESULTS: Causal BN models for benzene and risk of acute myeloid leukemia (AML) incorporating mechanistic, toxicological and epidemiological findings show that prolonged high-intensity exposure to benzene can increase risk of AML (IPoC of up to 7e-5, CAS of up to 54%). By contrast, no causal pathway leading from formaldehyde exposure to increased risk of AML was identified, consistent with much previous mechanistic, toxicological and epidemiological evidence; therefore, the IPoC and CAS for formaldehyde-induced AML are likely to be zero. CONCLUSION: We conclude that the IPoC approach can differentiate between likely and unlikely causal factors and can provide useful upper bounds for IPoC and CAS for some exposures and diseases of practical importance. For causal factors, IPoC can help to estimate the quantitative impacts on health risks of reducing exposures, even in situations where mechanistic evidence is realistically incomplete and individual-level exposure-response parameters are uncertain. This illustrates the strength that can be gained for causal inference by using causal models to generate testable hypotheses and then obtaining toxicological data to test the hypotheses implied by the models-and, where necessary, refine the models. This virtuous cycle provides additional insight into causal determinations that may not be available from weight-of-evidence considerations alone.

Copy number variation analysis in 138 families with steroid-resistant nephrotic syndrome identifies causal homozygous deletions in PLCE1 and NPHS2 in two families.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of kidney failure in children and adults under the age of 20 years. Previously, we were able to detect by exome sequencing (ES) a known monogenic cause of SRNS in 25-30% of affected families. However, ES falls short of detecting copy number variants (CNV). Therefore, we hypothesized that causal CNVs could be detected in a large SRNS cohort. METHODS: We performed genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on a cohort of 138 SRNS families, in whom we previously did not identify a genetic cause through ES. We evaluated ES and CNV data for variants in 60 known SRNS genes and in 13 genes in which variants are known to cause a phenocopy of SRNS. We applied previously published, predefined criteria for CNV evaluation. RESULTS: We detected a novel CNV in two genes in 2 out of 138 families (1.5%). The 9,673 bp homozygous deletion in PLCE1 and the 6,790 bp homozygous deletion in NPHS2 were confirmed across the breakpoints by PCR and Sanger sequencing. CONCLUSIONS: We confirmed that CNV analysis can identify the genetic cause in SRNS families that remained unsolved after ES. Though the rate of detected CNVs is minor, CNV analysis can be used when there are no other genetic causes identified. Causative CNVs are less common in SRNS than in other monogenic kidney diseases, such as congenital anomalies of the kidneys and urinary tract, where the detection rate was 5.3%. A higher resolution version of the Graphical abstract is available as Supplementary information.

Seaweeds as holobionts: Current state, challenges, and potential applications.

Seaweeds play a strong ecological and economical role along the world's coastlines, where they support industries (e.g., aquaculture, bioproducts) and essential ecosystem services (e.g., biodiversity, fisheries, carbon capture). Evidence from wild and cultured seaweeds suggests that microorganisms play crucial roles in their health and functioning, prompting the need for considering seaweeds and their microbiome as a coherent entity or "holobiont." Here we show that the number of studies investigating seaweed hosts and their microbiome have increased in the last two decades. This likely reflects the increase in the appreciation of the importance of microbiomes for eukaryotic hosts, improved molecular approaches used to characterize their interactions, and increasing interest in commercial use of seaweeds. However, although increasing, most studies of seaweed holobionts have focused on (i) a few seaweed species of ecological or commercial significance, (ii) interactions involving only bacteria, and (iii) descriptive rather than experimental approaches. The relatively few experimental studies have mostly focused on manipulating abiotic factors to examine responses of seaweeds and their microbiome. Of the few studies that directly manipulated microorganisms to investigate their effects on seaweeds, most were done in laboratory or aquaria. We emphasize the need to move beyond the descriptions of patterns to experimental approaches for understanding causation and mechanisms. We argue that such experimental approaches are necessary for a better understanding of seaweed holobionts, for management actions for wild and cultivated seaweeds, and to better integrate studies of seaweed holobionts with the broader fields of seaweed ecology and biology, which are strongly experimental.

The relationship between psoriasis and vitiligo: From a comprehensive study.

BACKGROUND: Both psoriasis and vitiligo are autoimmune skin diseases. Previous observational studies have indicated a relationship between the two conditions, and simultaneous onset of both diseases poses increased health risks to patients. However, limited research has explored the causal relationship between psoriasis and vitiligo. OBJECTIVES: To investigate whether a causal association exists between psoriasis and vitiligo. METHODS: A case of Chinese patients diagnosed with psoriasis and vitiligo has been reported. Transcriptome sequencing was performed on normal, psoriasis, vitiligo, and co-morbid skin tissues of the patients, and single-cell transcriptome sequencing was conducted on the co-morbid skin tissues. A comprehensive Mendelian randomization analysis of Genome-wide association studies (GWAS) was performed on a cohort of 261 018 European individuals with psoriasis from the IEU Open GWAS Project and vitiligo from the National Institutes of Health (NIH) Database of Genotypes and Phenotypes. RESULTS: Case report and transcriptome results showed that skin tissue with vitiligo combined with psoriasis exhibited both vitiligo and psoriasis. Single-cell transcriptome sequencing results showed that in comparison to normal skin and psoriatic skin, the proportions of CD8+ T cells, natural killer cells, naive T cells, T helper cells 17, regulatory T cells, conventional type 1 dendritic cells, Conventional type 2 dendritic cells, and plasmacytoid dendritic cells were all increased in skin tissue with vitiligo combined with psoriasis. Mendelian randomization analysis included 4510 patients with psoriasis and 4680 patients with vitiligo. The results showed no causal relationship between vitiligo and psoriasis in the forward direction (p = 0.192; odds ratio [OR], 1.059; 95% confidence interval [CI], 0.971-1.155) or in the reverse direction (p = 0.459; OR, 0.927; 95% CI, 0.757-1.134). CONCLUSIONS: This study suggests that the association between psoriasis and vitiligo may be closely related to immunity, however, Mendelian randomization studies do not support a causal relationship. These findings hold significant implications for clinicians aiming to enhance their understanding and treatment approaches for psoriasis and vitiligo.

Health and health behaviours in adolescence as predictors of education and socioeconomic status in adulthood - a longitudinal study.

BACKGROUND: The positive association of health with education level and socioeconomic status (SES) is well-established. Two theoretical frameworks have been delineated to understand main mechanisms leading to socioeconomic health inequalities: social causation and health selection but how these work in adolescence is poorly known. We studied if adolescent health and health behaviours predict higher education and higher SES in adulthood and if family background and school performance in adolescence explain these associations. METHODS: Surveys on health and health behaviours were sent to representative samples of 12-18-year-old Finns in 1981-1997 every second year (response rate 77.8%, N = 55,682). The survey data were linked with the respondents' and their parents' socioeconomic data from the Finnish national registries. Both latent variables, namely, health (perceived health, health complaints, chronic disease), health-compromising behaviours (smoking status, drunkenness frequency), and family background (parents' occupation-based SES, education, family type) and variables directly measuring health-enhancing behaviours (toothbrushing, physical activity) and school performance were used to predict higher education and higher occupation-based SES at age 34. Logistic regression analysis and structural equation models (SEM) were used. RESULTS: In logistic regression analyses, good health, health-enhancing behaviours, and lack of health-compromising behaviours were related to higher education and SES, also after controlling for family background and school performance. In the SEM analyses, good health, health-enhancing behaviours, and lack of health-compromising behaviours directly predicted higher SES and higher education, although the standardised coefficients were low (from 0.034 to 0.12). In all models, health, lack of health-compromising behaviours, and health-enhancing behaviours predicted school performance, which in turn, predicted the outcomes, suggesting indirect routes to these. Good socioeconomic prospects in terms of family background predicted good health, healthy behaviours, and good school performance in adolescence and higher SES and higher education in adulthood. CONCLUSION: Health and health behaviours in adolescence predicted education and SES in adulthood. Even though the relationships were modest, they support the health selection hypotheses and emphasise the importance of adolescence for health inequalities during the life-course. Health and health behaviours were strongly associated with school performance and family background which together modified the paths from health and health behaviours to the outcomes.

Bullying victimization and bullying perpetration, social anxiety, and social withdrawal in Portuguese adolescents: A reciprocal association model.

Further research is needed to clarify the association of the different forms of bullying with social anxiety and social withdrawal over time in adolescents. This two-wave panel study with a 1-year time lag (October 2021-October 2022) examined the cross-lagged relationships between bullying victimization and bullying perpetration, social anxiety (i.e., fear or distress in social situations), and social withdrawal (i.e., consistent, and deliberate social solitude). Participants were 485 middle school students (234 girls) attending the seventh or eighth grade at Time 1 (T1) (Mage = 12.67 years, SD = 1.14 years). Social anxiety and social withdrawal were assessed using subscales of the Social and Emotional Competencies Evaluation Questionnaire. Bullying perpetration and bullying victimization were assessed using the Bullying and Cyberbullying Behavior Questionnaire-Short Form. The within-wave associations between the study variables were similar at T1 and Time 2 (T2), with the exception that the association between bullying perpetration and social anxiety was much weaker at T1 than at T2. The results of the path analysis showed that T1 bullying perpetration predicted T2 social anxiety, and that T1 bullying victimization predicted T2 social withdrawal. We also found a reciprocal relationship between social anxiety and social withdrawal. These findings highlight the importance of preventive and remediation interventions to reduce social anxiety in adolescents who engage in and experience bullying behavior.

Interventionism and Intelligibility: Why Depression Is Not (Always) a Brain Disease.

Major depressive disorder (MDD) is a serious condition with a large disease burden. It is often claimed that MDD is a "brain disease." What would it mean for MDD to be a brain disease? I argue that the best interpretation of this claim is as offering a substantive empirical hypothesis about the causes of the syndrome of depression. This syndrome-causal conception of disease, combined with the idea that MDD is a disease of the brain, commits the brain disease conception of MDD to the claim that brain dysfunction causes the symptoms of MDD. I argue that this consequence of the brain disease conception of MDD is false. It incorrectly rules out genuine instances of content-sensitive causation between adverse conditions in the world and the characteristic symptoms of MDD. Empirical evidence shows that the major causes of depression are genuinely psychological causes of the symptoms of MDD. This rules out, in many cases, the "brute" causation required by the brain disease conception. The existence of cases of MDD with non-brute causes supports the reinstatement of the old nosological distinction between endogenous and exogenous depression.

A qualitative study of clinicians' perspectives on reasons for delays in clozapine initiation.

OBJECTIVES: To elicit mental health clinicians' views on the reasons for delayed initiation of clozapine treatment. METHOD: Thematic analysis of transcripts from a semi-structured interview of 15 mental health clinicians. RESULTS: Four major themes emerged from data analysis: Patient and Carer Factors, Medication factors, Protocol factors, and Prescriber factors. Patient and carer anxiety over side effects and experience of stigma, difficulties in implementing the monitoring protocol, problems with community managing of treatment, prescriber preferences and practices, and gaps in mental health services were some of the reasons identified. CONCLUSION: Education and support to patients and carers, a modified monitoring protocol, establishing clozapine clinics, improved early intervention services, and upskilling of clinicians can promote early clozapine initiation.

[Incapacity to work due to mental disorders-economic, individual, and treatment-specific aspects]. / Arbeitsunfähigkeit bei psychischen Störungen ­ ökonomische, individuelle und behandlungsspezifische Aspekte.

The changes in the modern work environment are accompanied by specific stressors that can have a negative impact on employees' mental health. In line with this, the proportion of sick-leave days due to mental disorders has recently risen to 17.7% compared to 10.9% in 2007, which in 2021 was associated with costs of 42.9 billion euros due to losses of gross value and productivity.Based on current health economic studies, this review provides an overview of the economic impact of incapacity to work and early retirement due to various mental disorders in Germany. In absolute figures, expenditure on incapacity to work is particularly high for common mental illnesses such as affective and anxiety disorders. Rarer mental disorders such as post-traumatic stress disorder and eating disorders cause high costs in relation to their low prevalence, particularly due to sickness benefit payments.In addition to these economic implications, the consequences of incapacity to work, early retirement, and unemployment are examined at an individual level and explanatory approaches for the specific psychosocial stresses are presented. The latter highlights the need for scientifically substantiated treatment methods. Certified treatments have proven to be efficient in reducing the number of sick-leave days, particularly for common mental disorders. This applies even more to workplace-related interventions, which appear to be superior to conventional methods in this respect. Workplace-based therapies incorporate work-related models and focus on the planning of reintegration into the workplace. Further naturalistic studies are needed to test the transferability of the effectiveness of these treatments to other disorders.

Irruption and Absorption: A 'Black-Box' Framework for How Mind and Matter Make a Difference to Each Other.

Cognitive science is confronted by several fundamental anomalies deriving from the mind-body problem. Most prominent is the problem of mental causation and the hard problem of consciousness, which can be generalized into the hard problem of agential efficacy and the hard problem of mental content. Here, it is proposed to accept these explanatory gaps at face value and to take them as positive indications of a complex relation: mind and matter are one, but they are not the same. They are related in an efficacious yet non-reducible, non-observable, and even non-intelligible manner. Natural science is well equipped to handle the effects of non-observables, and so the mind is treated as equivalent to a hidden 'black box' coupled to the body. Two concepts are introduced given that there are two directions of coupling influence: (1) irruption denotes the unobservable mind hiddenly making a difference to observable matter, and (2) absorption denotes observable matter hiddenly making a difference to the unobservable mind. The concepts of irruption and absorption are methodologically compatible with existing information-theoretic approaches to neuroscience, such as measuring cognitive activity and subjective qualia in terms of entropy and compression, respectively. By offering novel responses to otherwise intractable theoretical problems from first principles, and by doing so in a way that is closely connected with empirical advances, irruption theory is poised to set the agenda for the future of the mind sciences.

Mach's principle and Mach's hypotheses.

We argue that the fundamental assertion underlying Mach's critique of Newton's first law is that inertial motion is not motion in the absence of causes; rather, it is motion whose cause lies in some homogeneous aspect of the environment. We distinguish this formal requirement (Mach's principle) from two hypotheses which Mach considers concerning the origin of inertia: that the distant stars play (1) a merely "collateral" or (2) a "fundamental" role in the causal determination of inertial motion. In his later writings, Mach deliberately avoids referring to the concept of causation, and indeed, this has made the interpretation of Mach's principle a subject of widespread controversy. However, in his earlier writings, the substance of Mach's critique is less ambiguously expressed. Therefore, close attention is given to Mach's early writings and the evolution of his thought. Various accounts in the secondary literature on Mach's principle, in particular those of Norton and DiSalle, are assessed on this basis. We end with a defence of the Machian status and legitimacy of the early Einstein's research program.

The causal axioms of algebraic quantum field theory: A diagnostic.

Algebraic quantum field theory (AQFT) puts forward three "causal axioms" that aim to characterize the theory as one that implements relativistic causation: the spectrum condition, microcausality, and primitive causality. In this paper, I aim to show, in a minimally technical way, that none of them fully explains the notion of causation appropriate for AQFT because they only capture some of the desiderata for relativistic causation I state or because it is often unclear how each axiom implements its respective desideratum. After this diagnostic, I will show that a fourth condition, local primitive causality (LPC), fully characterizes relativistic causation in the sense of fulfilling all the relevant desiderata. However, it only encompasses the virtues of the other axioms because it is implied by them, as I will show from a construction by Haag and Schroer (1962). Since the conjunction of the three causal axioms implies LPC and other important results in QFT that LPC does not imply, and since LPC helps clarify some of the shortcomings of the three axioms, I advocate for a holistic interpretation of how the axioms characterize the causal structure of AQFT against the strategy in the literature to rivalize the axioms and privilege one among them.

Experimentation in cosmology: Intervening on the whole universe.

There are many arguments against the possibility of experimenting on the whole universe. This system seems to be too big to be manipulated, it exists in only one exemplar and its evolution is a non-repeatable process. In this paper, I claim that we can nonetheless talk about experimentation in cosmology if we use Woodward's non-anthropocentric notion of intervention. However, Woodward and other interventionists argued that an intervention was necessarily an exogenous causal process and thus that no intervention on a closed system such as the universe was possible. I discuss their argument and I determine the conditions under which a consistent notion of endogenous intervention on the universe can be defined. Then, I show that there is at least one cosmic phenomenon satisfying these conditions: the photon decoupling. Finally, I draw some conclusions from this analysis regarding a realist approach of cosmology.

R.A. Fisher, indeterminism, and the fundamental theorem of natural selection.

This paper is about the relationship between R.A. Fisher's fundamental theorem of natural selection (FTNS) and the two major pieces that Fisher wrote on indeterminism, "Indeterminism and Natural Selection" (1934) and Creative Aspects of Natural Law (1950). I argue that the FTNS presents a picture of natural selection that is interestingly different from what we find in these two indeterminism pieces, pace some recent work that advances the opposite conclusion. I also identify as the source of this difference both the mathematical form of the FTNS (i.e., a differential equation) and Fisher's meta-scientific commitment to advancing "general" claims about evolution.

Bodies of evidence: The 'Excited Delirium Syndrome' and the epistemology of cause-of-death inquiry.

"Excited Delirium Syndrome" (ExDS) is a controversial diagnosis. The supposed syndrome is sometimes considered to be a potential cause of death. However, it has been argued that its sole purpose is to cover up excessive police violence because it is mainly used to explain deaths of individuals in custody. In this paper, we examine the epistemic conditions giving rise to the controversial diagnosis by discussing the relation between causal hypotheses, evidence, and data in forensic medicine. We argue that the practitioners' social context affects causal inquiry through background assumptions that enter inquiry at multiple stages. This analysis serves to better understand the wide usage of the controversial diagnosis of ExDS.