Hypothesis test for causal explanations in human pathology: evaluation of pulmonary edema in 181 autopsied patients with leukemia

Symbolic logic, as used in the formal theory of scientific explanation proposed by Hempel and Oppenheim, has been suggested as the basis for automated medical diagnosis. In human autopsy pathology the determination of cause-and-effect relationships is a major area subject to logical analysis. We propose a modification of the Hempel-Oppenheim schema in which the logical relationships must only be satisfied “much” of the time, as determined by binomial significance tests. The analysis employs “certainty levels” logic with a more limited consistency requirement than classical logic. The analysis is applied to a series of 181 autopsied patients with leukemia in an attempt to determine a possible role of chemotherapeutic agents in the etiology of pulmonary edema. Among 51 patients who had received cytosine arabinoside (Ara-C) within 30 days of death, there was significantly more unexplained moderate or massive pulmonary edema than among patients with no or remote therapy (p<0.001). The results suggest that a symbolic logical analysis combined with a binomial significance test can elucidate cause-and-effect relationships observed at autopsy, especially when there are multiple possible explanations for the same effect.     

Disruption of neurocognitive decision-making mechanisms in depression

To analyze the relationship of disruptions in neurocognitive decision-making mechanisms based on logic and reasoning, or in a situation of uncertainty based on emotional experience (emotional learning) with clinical indices of depression, a multidisciplinary clinical, psychological, and neurophysiological study was conducted in 28 patients suffering from depression (women aged 18–56) and 50 healthy volunteers (women aged 18–55). The intensity of depression was estimated quantitatively by the Hamilton’s Depression Rating Scale (HDRS-17) to qualitatively estimate cognitive functions, the “Ten Words” technique, the Wisconsin Card-Sorting Test (WCST), and the Iowa Gambling Task (IGT) were used; and to assess the functional brain state of all patients suffering from depression, a multichannel recording of the background electroencephalogram (EEG) was made. It was demonstrated that in depression, a neurocognitive deficiency was observed that correlates positively with the intensity of the depressive symptomatology. As well, a reduction occurs in the ability to make decisions based both on logic and reasoning (in the WCST), which is associated with EEG features of hypofrontality, and based on emotional learning (in the IGT test). Only in patients suffering from depression with a reduced ability to make rational decisions based on logic and reasoning was a “compensatory shift” observed toward decision making based on emotions, which leads to relatively higher indices of emotional learning. It is assumed that hypofrontality, which results in difficulties in making decisions requiring logical thought, leads to interruption of subcortical, including hippocampal, structures, an increase in the activation of which is related to better indices of emotional learning.     

Place de la TEP au FDG (18F) dans l’exploration des syndromes neurologiques paranéoplasiques

Paraneoplastic neurological syndromes (PNS) are rare non-metastatic manifestations of cancer. However, in this family of diseases, to recognize the underlying malignancy is an emergency. The ultimate aim is to treat the patient and try to stabilize or improve the neurological dysfunction, which is frequently the cause of the patient's death. The yield of FDG PET seems to be poor in unselected PNS. In the last decade, neurologists have attempted to provide more rigorous diagnostic criteria for PNS. Thus, “classical” PNS and a panel of “well-characterized” onconeural antibodies have been defined in order to facilitate triage of patients for whom FDG PET would be more sensitive. Currently, given the limited availability of PET cameras in France, this examination should be performed in the presence of either a “classical” PNS with or without onconeuralantibodies positivity or other PNS with onconeural antibodies positivity. The FDG PET should be triggered after a negative conventional imaging work up.     

Effects‐initiated assessments are not risk assessments

True risk assessments address the probability of a future risk occurring given a certain set of circumstances. However, “effects‐initiated assessments”; or “retrospective assessments”; often are improperly included under the broad appellation of “risk assessment”; and are conducted when an apparently adverse effect is seen in some environmental component and the question of cause (i.e., etiology) is raised. Base line risk assessments at Superfund sites or for Natural Resource Damage Assessments are examples of effects‐initiated assessments. We argue here that this type of study is not a risk assessment, either by strict definition of terminology or by logical approach taken in answering the posed question (s), and should more properly be called “diagnostic ecology.”; Diagnostic ecology starts from the premise that ecological effects have occurred and exposure to a Stressor has taken place. The problem then is to pose all possible etiologies and utilize deductive logic to systematically eliminate each agent except for one as the actual cause. A risk assessment, on the other hand, employs inductive reasoning. That is, hypotheses are generated about the possible sources of a stressor and the possible outcome if exposure occurs. Both exercises require an understanding of the ecological relationships of the various components in the ecosystem, both need an understanding of die cause‐and‐effect relationships of agents, and both require a proper framing of the questions being asked. However, risk assessors should not try to fit all environmental impact assessments into a single framework, but rather should recognize that biomedical techniques are better suited for solving diagnostic riddles than are prospective risk assessment approaches.     

Recent decline in the U.S. death rate from myeloproliferative neoplasms, 1999-2006

Background: Myeloproliferative neoplasms (MPNs) are classified as neoplasms of uncertain or unknown behavior in the International Classification of Diseases (ICD) Version 10 and can contribute to risk of death from complications (especially thrombosis). Methods: U.S age-standardized death rates using ICD-Version 10 codes relevant to classical MPN (i.e., polycythemia vera, essential thrombocythemia, and “chronic myeloproliferative disease”) were examined for 1999–2006. The underlying cause of death and also all causes (“multiple causes” or “mentions”) coded on death certificates were considered. Trends were assessed by using percentage change (PC) in rate between 1999 and 2006, and annual percentage change (APC) estimated from linear regression. Results: The decline in death rates was large for MPN, whether based only the underlying cause (PC = ?19.7%, APC = ?3.4%) or on the substantially higher rates based on any cause (PC = ?24.1%, APC = ?3.8%), and was consistent by gender and age group (<65 and 65+ years). For deaths with MPN coded as other than the underlying cause, cardiovascular diseases were the most common underlying cause and the ASR for these deaths declined substantially (PC = ?40.0%). Conclusions: Use of the underlying cause of death in surveillance will considerably underestimate MPN-related mortality rates in the population. Studies are needed on treatment in random samples of MPN patients from population-based cancer registries. Continued surveillance of MPN-related mortality rates in the population is needed in view of recent attempts (including the use of aspirin) to control cardiovascular complications of MPN.     

Dual Logic and Cerebral Coordinates for Reciprocal Interaction in Eye Contact

In order to scientifically study the human brain’s response to face-to-face social interaction, the scientific method itself needs to be reconsidered so that both quantitative observation and symbolic reasoning can be adapted to the situation where the observer is also observed. In light of the recent development of dyadic fMRI which can directly observe dyadic brain interacting in one MRI scanner, this paper aims to establish a new form of logic, dual logic, which provides a theoretical platform for deductive reasoning in a complementary dual system with emergence mechanism. Applying the dual logic in the dfMRI experimental design and data analysis, the exogenous and endogenous dual systems in the BOLD responses can be identified; the non-reciprocal responses in the dual system can be suppressed; a cerebral coordinate for reciprocal interaction can be generated. Elucidated by dual logic deductions, the cerebral coordinate for reciprocal interaction suggests: the exogenous and endogenous systems consist of the empathy network and the mentalization network respectively; the default-mode network emerges from the resting state to activation in the endogenous system during reciprocal interaction; the cingulate plays an essential role in the emergence from the exogenous system to the endogenous system. Overall, the dual logic deductions are supported by the dfMRI experimental results and are consistent with current literature. Both the theoretical framework and experimental method set the stage to formally apply the scientific method in studying complex social interaction.     

The impact of under and over-recording of cancer on death certificates in a competing risks analysis: A simulation study

Background: With linked register and cause of death data becoming more accessible than ever, competing risks methodology is being increasingly used as a way of obtaining “real world” probabilities of death broken down by specific causes. It is important, in terms of the validity of these studies, to have accurate cause of death information. However, it is well documented that cause of death information taken from death certificates is often lacking in accuracy and completeness. Methods: We assess through use of a simulation study the effect of under and over-recording of cancer on death certificates in a competing risks analysis consisting of three competing causes of death: cancer, heart disease and other causes. Using realistic levels of misclassification, we consider 24 scenarios and examine the bias in the cause-specific hazard ratios and the cumulative incidence function. Results: The bias in the cumulative incidence function was highest in the oldest age group reaching values as high as 2.6 percentage units for the “good” cancer prognosis scenario and 9.7 percentage units for the “poor” prognosis scenario. Conclusion: The bias resulting from the chosen levels of misclassification in this study accentuate concerns that unreliable cause of death information may be providing misleading results. The results of this simulation study convey an important message to applied epidemiological researchers.     

Espaces de représentation et psychopathologie

A subjective world can be conceptualized as a “representational space” — that is, as a universe displayed from memory, in which the subject “is sailing”. Recent cognitive theory provides some conceptual tools for describing such a space in a relevant way for clinical purposes. The construction of a representational space is based on mental representations: (a) analogical representations, which display a content in working memory; (b) symbolic representations, which code and link up analogical representations to form a represented world. The dynamics of representations and affects is ruled by a principle of unification of representational space. The topology of a representational space depends on objective and subjective constraints which cause some “folds” and limit the display of such a space. The interaction between an event and a subjective memory can be analyzed within this framework, so that the concepts of trauma and defence processes can be defined. Clinical syndromes are defensive configurations that tend to close the representational space.     

Certainty levels in the nullity method of symbolic logic: application to the pathogenesis of congenital heart malformations.

Investigating the pathogenesis of complex human congenital heart malformations involves special difficulties not usually encountered in studying human disease. Most malformations develop before clinical investigation is feasible, and reliable animal models are few. Virtually all advances in this field have come from thoughtful correlations of embryologic and patient observations. Symbolic logic is a natural medium for incorporating information of this nature into a mathematical and computer analysis, and has been recently employed in a study of the pathogenesis of the tetralogy of Fallot. The chief drawback of the symbolic logic approach, however, is its inability to handle uncertainty. This paper introduces an extension of the nullity method of symbolic logic which sorts patient observations and pathogenetic hypotheses into levels of certainty ranging from real data to reasonable preferences. A computer algorithm is presented which evaluates these levels of certainty, and the completeness and closure of this algorithm are proved mathematically. This computer algorithm identifies problem cases which are poorly explained by a given pathogenetic theory, and thus provides the initial step for refining the theory.     

Threads that Guide or Ties that Bind: William Kirby and the Essentialism Story

Nineteenth-century British entomologist William Kirby is best known for his generic division of bees based on tongues and his vigorous defence of natural theology. Focusing on these aspects of Kirby’s work has lead many current scholars to characterise Kirby as an “essentialist.” As a result of this characterisation, many important aspects of his work, Monographia Apum Angliæ (1802) have been over-looked or misunderstood. Kirby’s religious devotion, for example, have lead some scholars to assume Kirby used the term “type” for connecting an ontological assumption about essences with a creationist assumption about species fixity, which I argue conceals a variety of ways Kirby employed the term. Also, Kirby frequently cautioned against organising a classification system exclusively by what he called “analytic reasoning,” a style of reasoning 20th century scholars often associate with Aristotelian logic of division. I argue that Kirby’s critique of analytic reasoning brought the virtues of his own methodological agenda into sharp relief. Kirby used familiar metaphors in the natural history literature – Ariadne’s thread, the Eleusinian mysteries, and Bacon’s bee and spider metaphors – to emphasise the virtues of building tradition and cooperation in the goals and methodological practices of 19th century British naturalists.     

Weight-of-Evidence Issues and Frameworks for Sediment Quality (And Other) Assessments

Weight of evidence (WOE) frameworks for integrating and interpreting multiple lines of evidence are discussed, focusing on sediment quality assessments, and introducing a series of ten papers on WOE. Approaches to WOE include individual lines of evidence (LOE) as well as combined LOE (indices, statistical summarization, logic systems, scoring systems, and best professional judgment [BPJ]). The application of WOE, based on multiple LOE, is discussed relative to the published literature. Fully implementing WOE requires consideration of six main LOE in sediment (or other assessments); these LOE generally correspond to other causality considerations including Koch's Postulates. However, the issue of sediment stability is an additional consideration, and the use of tabular decision matrices is recommended in a logic system to address LOE described by others as “analogy”, “plausibility”, or “logical and scientific sense.” Three examples of logic system WOE determinations based on the Sediment Quality Triad and using tabular decision matrices are provided. Key lessons from these examples include the: generally limited utility of sediment quality value (SQV)-based LOE; need for BPJ; importance of ecological relevance; importance of assessing background conditions; and, need for appropriately customizing study designs to suit sitespecific circumstances (rather than application of “boiler-plate” assessments). Overall, more quantitative approaches are needed that better define certainty elements of WOE in an open framework process, i.e., statistical summarization culminating in a logic system incorporating BPJ.     

Short-term learning in conformational analysis

A method for learning short-term rules of conformational analysis is introduced. The technique works by discovering problems during the building of a conformation in Cartesian coordinate space, and builds an abstract critic suitable for reasoning in abstract symbolic space. The methods not only afford speed increases ranging from 1.0- to 2.3-fold in WIZARD (analysis completed in 100% to 43% of original run time), but can be modified to provide similar increases in other programs that use “template joining” and distance geometry. These methods also provide the basis for a longterm learning project.     

Computer simulation of medical reasoning in the assessment of kidney disease

A system for the simulation of clinical reasoning was applied to the evaluation of patient data in nephrological diseases. The system allows the physician to computerise the medical logic in his area of specialisation, to prepare suitable protocols for recording clinical observations, to analyse the patient data for assessing his present clinical status and to plan appropriate diagnostic and therapeutic interventions. The medical logic is expressed in modular form as a series of inferences to be confirmed or rejected on the basis of Boolean combinations of clinical findings and previous inferences. The acceptable Boolean combinations are formulated in terms of threshold logic. The computer programs produce alphabetical lists of the clinical findings appearing in the medical logic, which are organised by the physician into data acquisition protocols appropriate to each phase of clinical activity.The system was run on a series of 22 patients hospitalised in the Department of Nephrology. The patient status reports produced by the computer were in substantial agreement with the assessment of a senior nephrologist. The protocols assured a more complete and accurate recording of patient data than that appearing in the routine patient chart. The program was of value in standardising patient examinations and in the training of new medical staff.     

A Causal Analysis of Observed Declines in Managed Honey Bees (Apis mellifera)

The European honey bee (Apis mellifera) is a highly valuable, semi-free-ranging managed agricultural species. While the number of managed hives has been increasing, declines in overwinter survival, and the onset of colony collapse disorder in 2006, precipitated a large amount of research on bees’ health in an effort to isolate the causative factors. A workshop was convened during which bee experts were introduced to a formal causal analysis approach to compare 39 candidate causes against specified criteria to evaluate their relationship to the reduced overwinter survivability observed since 2006 of commercial bees used in the California almond industry. Candidate causes were categorized as probable, possible, or unlikely; several candidate causes were categorized as indeterminate due to lack of information. Due to time limitations, a full causal analysis was not completed at the workshop. In this article, examples are provided to illustrate the process and provide preliminary findings, using three candidate causes. Varroa mites plus viruses were judged to be a “probable cause” of the reduced survival, while nutrient deficiency was judged to be a “possible cause.” Neonicotinoid pesticides were judged to be “unlikely” as the sole cause of this reduced survival, although they could possibly be a contributing factor.     

Ecological theatre and the evolutionary game: how environmental and demographic factors determine payoffs in evolutionary games

In the standard approach to evolutionary games and replicator dynamics, differences in fitness can be interpreted as an excess from the mean Malthusian growth rate in the population. In the underlying reasoning, related to an analysis of “costs” and “benefits”, there is a silent assumption that fitness can be described in some type of units. However, in most cases these units of measure are not explicitly specified. Then the question arises: are these theories testable? How can we measure “benefit” or “cost”? A natural language, useful for describing and justifying comparisons of strategic “cost” versus “benefits”, is the terminology of demography, because the basic events that shape the outcome of natural selection are births and deaths. In this paper, we present the consequences of an explicit analysis of births and deaths in an evolutionary game theoretic framework. We will investigate different types of mortality pressures, their combinations and the possibility of trade-offs between mortality and fertility. We will show that within this new approach it is possible to model how strictly ecological factors such as density dependence and additive background fitness, which seem neutral in classical theory, can affect the outcomes of the game. We consider the example of the Hawk–Dove game, and show that when reformulated in terms of our new approach new details and new biological predictions are produced.     

A new conception of the shoot of higher plants

According to the classical model, the “shoot” consists only of the categories “caulome” (“stem” sensu lato) and “phyllome” (“leaf” sensu lato), (and “root” in cases of “adventitious” root formation). If lateral shoots are present, their position is axillary. Consequently, caulome as well as phyllome are inserted on the caulome and only on the caulome. This classical model of the shoot has two disadvantages of great consequence: (1) Intermediate organs cannot be accepted as such, but have to be interpreted (i.e. categorized) as either caulome or phyllome (or root) by distortion of the actual similarity. (2) Certain positional changes of organs cannot be accepted as such, but have to be “explained” by congenital fusion. The new conception of the shoot will have the advantages of the classical model but not its disadvantages. Hence, the shoot may consist of the following parts: (main and lateral) shoot, caulome, phyllome, root, emergence, and structures intermediate between (i.e. partially homologous to) any of the preceding. Thus, the five categories of the classical model, namely “shoot”, “caulome”, “phyllome”, “root” and “emergence” are no longer mutually exclusive; they may merge into each other due to an actual or potential continuum. Intermediate organs are therefore accepted as such; for example, an organ may be characterized as an intermediate form between a caulome and a phyllome. Besides intermediate forms, all changes in position are accepted as such. Hence, the following positional relations are possible: caulome and phyllome may be inserted on the caulome, caulome and phyllome may be inserted on the phyllome; roots may be inserted on caulome or phyllome; intermediate forms may be inserted on the caulome, phyllome, or other intermediate forms. Consequences of the new conception for morphological research are pointed out, especially for homologization, evolutionary considerations, and the direction in which research progresses.     

Evo-devo and the search for homology (“sameness”) in biological systems

Developmental biology and evolutionary studies have merged into evolutionary developmental biology (“evo-devo”). This synthesis already influenced and still continues to change the conceptual framework of structural biology. One of the cornerstones of structural biology is the concept of homology. But the search for homology (“sameness”) of biological structures depends on our favourite perspectives (axioms, paradigms). Five levels of homology (“sameness”) can be identified in the literature, although they overlap to some degree: (i) serial homology (homonomy) within modular organisms, (ii) historical homology (synapomorphy), which is taken as the only acceptable homology by many biologists, (iii) underlying homology (i.e., parallelism) in closely related taxa, (iv) deep evolutionary homology due to the “same” master genes in distantly related phyla, and (v) molecular homology exclusively at gene level. The following essay gives emphasis on the heuristic advantages of seemingly opposing perspectives in structural biology, with examples mainly from comparative plant morphology. The organization of the plant body in the majority of angiosperms led to the recognition of the classical root–shoot model. In some lineages bauplan rules were transcended during evolution and development. This resulted in morphological misfits such as the Podostemaceae, peculiar eudicots adapted to submerged river rocks. Their transformed “roots” and “shoots” fit only to a limited degree into the classical model which is based on either–or thinking. It has to be widened into a continuum model by taking over elements of fuzzy logic and fractal geometry to accommodate for lineages such as the Podostemaceae.     

Why Do Medical Professional Regulators Dismiss Most Complaints From Members of the Public? Regulatory Illiteracy,Epistemic Injustice,and Symbolic Power

Drawing on an analysis of complaint files that we conducted for the Irish Medical Council (Madden and O’Donovan 2015), this paper offers three possible explanations for the gap between the ubiquity of official commitments to taking patients’ complaints seriously and medical professional regulators’ dismissal—as not warranting an inquiry—of the vast majority of complaints submitted by members of the public. One explanation points to the “regulatory illiteracy” of many complainants, where the remit and threshold of seriousness of regulators is poorly understood by the general public. Another points to possible processes of “institutional epistemic injustice” (Fricker 2007; Anderson 2012) that unjustly undermine the credibility of certain complainants, such as those with low levels of formal education. A third explanation highlights the marginalization of the general public from “symbolic power” (Bourdieu 1989) to define what matters in medical professional regulation. The paper is offered in a spirit of ideas in progress and raising questions rather than definitive insights into the regulatory process.     

N‐(3‐Oxo‐acyl)‐homoserine lactone induces apoptosis primarily through a mitochondrial pathway in fibroblasts

N‐(3‐Oxododecanoyl)‐l ‐homoserine lactone (C12) is produced by Pseudomonas aeruginosa to function as a quorum‐sensing molecule for bacteria–bacteria communication. C12 is also known to influence many aspects of human host cell physiology, including induction of cell death. However, the signalling pathway(s) leading to C12‐triggered cell death is (are) still not completely known. To clarify cell death signalling induced by C12, we examined mouse embryonic fibroblasts deficient in “initiator” caspases or “effector” caspases. Our data indicate that C12 selectively induces the mitochondria‐dependent intrinsic apoptotic pathway by quickly triggering mitochondrial outer membrane permeabilisation. Importantly, the activities of C12 to permeabilise mitochondria are independent of activation of both “initiator” and “effector” caspases. Furthermore, C12 directly induces mitochondrial outer membrane permeabilisation in vitro. Overall, our study suggests a mitochondrial apoptotic signalling pathway triggered by C12, in which C12 or its metabolite(s) acts on mitochondria to permeabilise mitochondria, leading to activation of apoptosis.     

Improving Hierarchical Models Using Historical Data with Applications in High-Throughput Genomics Data Analysis

Modern high-throughput biotechnologies such as microarray and next-generation sequencing produce a massive amount of information for each sample assayed. However, in a typical high-throughput experiment, only limited amount of data are observed for each individual feature, thus the classical “large p, small n” problem. Bayesian hierarchical model, capable of borrowing strength across features within the same dataset, has been recognized as an effective tool in analyzing such data. However, the shrinkage effect, the most prominent feature of hierarchical features, can lead to undesirable over-correction for some features. In this work, we discuss possible causes of the over-correction problem and propose several alternative solutions. Our strategy is rooted in the fact that in the Big Data era, large amount of historical data are available which should be taken advantage of. Our strategy presents a new framework to enhance the Bayesian hierarchical model. Through simulation and real data analysis, we demonstrated superior performance of the proposed strategy. Our new strategy also enables borrowing information across different platforms which could be extremely useful with emergence of new technologies and accumulation of data from different platforms in the Big Data era. Our method has been implemented in R package “adaptiveHM,” which is freely available from https://github.com/benliemory/adaptiveHM.