People tend to associate abstract visual features with basic taste qualities.This narrative historical review critically evaluates the literature on theseassociations, often referred to as crossmodal correspondences, between basictastes and visual design features such as color hue and shape curvilinearity.The patterns, discrepancies, and evolution in the development of the researchare highlighted while the mappings that have been reported to date aresummarized. The review also reflects on issues of cross-cultural validity anddeviations in the matching patterns that are observed when correspondences areassessed with actual tastants versus with verbal stimuli. The various theoriesthat have been proposed to account for different classes of crossmodalcorrespondence are discussed, among which the statistical and affective  accounts currently appear most promising. Several criticalresearch questions for the future are presented to address the gaps that havebeen identified in the literature and help validate the popular theories on theorigin and operations of visual-taste correspondences. For insbasic taste qualities that will be discussed include bitter,sweet, salty, sour, and umami  and specific visual features. Where such information is available,the cross-cultural consensuality of the association patterns will also bediscussed. By building up the case with relevant evidence and highlighting someof the key gaps in the academic literature, this chapter provides an opportunityto systematically reflect on the progress that has been made in the field todate.Color  is one of the most widely-studied visual features inthe literature on crossmodal correspondences that has been published to date,offering arguably the most “natural” link to basic taste a. With cOne of the earliest studies to have documented color-taste correspondences wasconducted by the French chemical engineer N = 51) were tasked with picking one from a list of 12common color terms  “to describe” each of the four basic tastes.These tasks were carried out three times, separated by two-week intervals.Critically, unlike most of the later studies, the method used by O’Mahonyinvolved assessing within-participant consistency by determining the proportionof the participants who consistently picked the same color to match with a giventaste each time they were asked. This approach may well have excluded thosecases in which a participant considered a taste as matching with more than onecolor. Note also that such a closed responding design would have restricted thediscovery of color matches to the set of hues selected by the researcher.Among the pioneering attempts to document color-taste matches, a much morecomprehensive study was reported by N = 45) had to rate the intensity of every basic tastequality for each color with questions such as “how sweet is the color red?”Contrasting with Curious about how color appearance might affect taste perception, Even though the approach used by a posteriori analysis on the usage of verbal labels whenmatching crossmodal concepts, in which they speculated that the use oflinguistic stimuli may have exerted an unanticipated influence over mappingswhen compared to mappings between sensory stimuli.Some common limitations can be identified when looking back at the earlyvisual-taste crossmodal correspondences experiments, shared by the studiescovered thus far . Forexample, instead of using actual color stimuli, such as a palette or a swatchchart of colors, the researchers presented verbal descriptions of colors intheir association tasks. On the other side of the correspondence, the concept oftaste qualities was typically also represented by the words describing the basictastes . Using the results ofsuch research to support the existence of specific color-taste correspondenceswould require the assumption that lexical representations do indeed provide areasonable approximation of sensory stimuli. This question was also raised inWEIRD  ofdistinctively different cultural backgrounds, and ranged from 17 to 66 years ofage. The results revealed a similar pattern of color-taste correspondencesacross different cultural groups, with a high degree of consistency whencompared to the previous findings  from a range of non-Western backgrounds. They foundthe color associations of sweet, salty, and sour to show a high degree ofconsistency among participants from Japan (n = 136), Russia(n = 102), and Taiwan (n = 100), followingthe pattern established by the prior research  extended the study of such cultural similaritiesand differences in color-taste associations to individuals(arch see . Howevern = 59) and France (n = 60) regardingodor-color correspondences. Of the 16 odors that they tested, three were foundto be associated with different colors by the two populations. Here, though, itshould be noted that even among the odors matched differently between the twocultures, the disagreements were fairly subtle .This pattern of cultural universality with occasional minor discrepancies hasalso been documented in other areas of crossmodal correspondences research. Forinstance, Contrary to the paradigms used by Similar to the crossmodal correspondences that have been documented between colorand taste, a wealth of empirical research now demonstrates the existence ofcrossmodal correspondences between abstract shapes and basic tastes . What isThe idea of pairing sweet taste with rounded shapes and bitter taste with angularshapes has been floating around in the literature for more than half a centurynow c. Markssynesthesia of“tasting shapes”  have been observed consistently e.g., a. In genn = 15)and Colombia (n = 18) to identify any cross-culturaldifferences between these two countries. The symmetry and segment complexity ofshape was found to exert a considerable influence over participants’associations with taste. In both countries, symmetrical shapes and shapes withfewer elements were more consistently matched with a sweet taste. A significantinteraction was also observed between symmetry and fewer elements, which led tosweeter ratings in both countries, indicating synergy between the differentvisual attributes when conveying taste information.Up to this point, most studies on shape-taste correspondences have chosen tofocus on the contour angularity of shape, otherwise known as curvilinearity,while other geometric features have remained relatively untouched. Afteranalyzing several geometric features and their prospect of being associated withpositive emotion, N = 90) went on to investigate how specific types of shapesymmetry would influence the pattern of shape-taste associations. Theydemonstrated that shapes with both reflectional and rotational symmetry wererated as more pleasant and found to be most strongly associated with the tasteof sweetness, followed, in decreasing order, by shapes with only bilateralsymmetry and asymmetric shapes; Sour and bitter were associated with thesefeatures in precisely the opposite manner. Critically for the affective theory,Turoman et al.'s research has also contributed an evolutionary account to theexplanations of the underlying mechanisms of crossmodal correspondences , the observed patterns in their results weresomewhat different. In particular, Velasco et al. reported that thesweet-tasting solution was matched with rounded shapes, but no significantassociation was documented for the other basic tastes .While all basic taste words were found to have a robust match with either roundedor angular shapes e.g., , there aN = 19). This time, the researchers foundthat sour and sweet tastants were associated with angular and rounded shapes,respectively. The salty tastant was also associated with angular shapes whenadministered at the lower concentration, but there were no observabletaste-shape associations for either the bitter or umami tastants. In an attemptto determine what other factors might influence the shape matches, Velasco andhis colleagues also had their participants rate their liking for, and theperceived intensity of, each of the solutions they tasted. Their regressionmodel demonstrated that the concentration of the tastant and liking predictedmore than half of shape matches by accounting for approximately 59% of thevariance in curvilinearity ratings. These results suggested the three factors to be significant predictors of theshape curvilinearity that was found to be associated with the givenstimulus.Subsequently, Looking back over the studies that have been reviewed thus far, there exists aclear trend of taste correspondences for shape features in terms ofcurvilinearity and symmetry. While taste word associations with shape areconsistent for all basic tastes, this consistency does not fully translate whenmatching real tastants with shapes. Curvilinearity was less consistently matchedwith the non-sweet basic tastes when assessed with real tastants, especiallywith those solutions that were bitter a. One poAs discussed in the section on shape-taste correspondences, the consistency of tastemappings would appear to fluctuate somewhat between those experiments that haveincorporated real tastants and those that have used taste words instead. Grantedthat the difference by itself is not a contradiction, it can nevertheless be a causefor concern among researchers if taste words fail to offer a satisfactory measure ofthe shape-taste matching as the real tastants have been shown to do. Meanwhile, thestudies on color-taste correspondences that have been presented so far have alsoused taste words to assess associations; participants in these studies did not tasteany stimuli when making their color associations. Two issues can be raised here:First, associations established with verbal taste stimuli might differ from thoseassessed with sensory stimuli. Second, those patterns that have been established onthe basis of matching taste words might not work as expected when they are used todevise designs that wish to influence taste expectation or perception  hadto call out the name of the fruit shown on the screen as rapidly as possible afterhaving tasted a scoop of fruit slurry without having seen it. This task was carriedout while looking at an onscreen cue word. The participants completed the task inthree different conditions: The word on screen could be the name of the fruit thatthe participants were tasting (congruent condition), it could also be the name of adifferent fruit (incongruent condition), or it could be the name of an inedibleobject (control condition). Overall, the researchers documented shorter RTs andhigher accuracy rates for name identification when the screen text happened to becongruent with the tastant. The Stroop effect found here suggested that gustatoryexperience would compete with visual linguistic information for attentionalresources. Razumiejczyk et al. concluded that their findings provided evidence forthe crossmodal integration of taste (sensory experience) and taste words . It should, however, be noted that the integration of sensory andverbal stimuli does not guarantee the same crossmodal mapping patterns when matchedwith visual features.In a Stroop study carried out by N = 41) had to make speeded identification responsesto odorants while being presented with either congruent or incongruent visualstimuli. These visual stimuli either had a shape resembling the silhouette of afruit or the color of a fruit, which reflected the smell presented in the congruentcondition. As Demattè et al. expected, they found an interference effect caused bythe visual distractors in the incongruent condition. One explanation offered by theresearchers suggests that verbal representations were implicitly engaged in memoryduring the decision-making process of odor identification, the possibility of whichwould help to strengthen the feasibility of guiding perceptual expectations withverbal cues  picked a huefrom the color wheel to match with a basic taste after having tasted it in solution.Their mapping of color and taste was highly consistent with the prior literaturethat had used verbal stimuli. In other words, the color associations made with realtastants were comparable to those made with taste words. Combined with evidence fromWhile the use of verbal stimuli in crossmodal correspondences research has never beenseriously challenged, it remains a potential issue that could limit theeffectiveness of any attempts to modify sensory perception in real life. As such,Returning to the patterns of color-taste correspondences that were reported by N = 342) to taste chocolate and green tea ofvarying levels of bitterness, By asking participants  underpinning crossmodal correspondences. In recent years, progress hasundoubtedly been made in our attempts to understand what could have encouragedpeople to connect taste qualities and specific visual features. This section provides a summary of the various theories that have been put forward toaccount for the numerous different visual-taste associations reported to date, aswell as evidence that directly or indirectly supports those theories. Whereapplicable, speculations are made concerning how the various accounts would predictthe outcome of popular research questions yet to be addressed, and how novelparadigms can help verify the hypotheses of theoretical questions.When discussing the origins of color-taste crossmodal correspondences, theformation of these crossmodal associations can be compared to the associativelearning that results from accumulated observations, which saw the onset of onesensory feature predicting the likely presence of the other . Inthis regard, the robust association between sweet and red is perhaps based onthe adaptive behavior whereby colors are used to determine the ripeness offruit/leaves . InaddiBeyond the associative learning motivated by adaptive behaviors, people mayregister and internalize the associations between regularly co-occurring stimuliwhen interacting with, and learning from, concepts and objects in theenvironment . The proIf crossmodal associations are acquired from the environment, there should bechanges over years of development in the food and agricultural industries andperhaps some cultural variation too. The shift in the environment can besurprisingly rapid, for instance, linked to the introduction of artificialcoloring in food products and increasingly frequent cultural exchange . Spence Contextual cues exert a considerable influence over the associations betweencolor and taste ; other eHypothetically, learning how the inference is made from an ensemble of colorscould grant researchers an insight into the process underlying color-tasteassociations. This type of ensemble can be portrayed by a color profile thathappens to resemble a ubiquitous mediating source, such as, say, extractingdifferent shades of red and green in a ratio that is matching to the typicalimage of a strawberry see . If peopSome contextual cues can change how people perceive a visual feature'sconnotative meaning. For example, artificiality might turn a typicallyaversive hue  asround or angular due to the ambiguity. The discriminability anddistinctiveness of color hues would have assisted the generalization of thevisual experience as there is little ambiguity among competing cues independent of visualfeatures. The relationship between gustatory experience and emotion is notdefined solely by the taste quality but also by the intensity of tasteperception . A recenBetween the statistical and affective accounts, the evidence presented thus farwould appear to suggest that certain types of crossmodal correspondences arebetter explained by one account rather than the others. However, not much isknown about what might have driven one mediator to prevail over another. Infact, there is little knowledge concerning whether the underlying mechanism is acompetition or cooperation between the potential mediators. Worse still, theroute of mediation cannot be determined by the modality that happens to beassessed. The taste-color correspondences are likely mediated by statisticswhile the taste-shape correspondences are likely mediated by emotion. Likewise,the crossmodal correspondences involving color would appear to have exploitedinternalized statistics of the environment when matched with taste , but areprocessing fluency describes the positive effectassociated with processing easy and stress-free stimuli (or stimuluscombinations) (The term nations) . Some renations) . Theoretnations)  as when nations) . The ratnations) . This, iIn a dining environment, the appraisal of certain combinations of color andshape has shown signs that such arrangements are potentially being processedfluently. While on the topic of visual fluency, the century-old idea of the Kandinskycorrespondences has been suggesting the universal associations between colorand shape, based on the belief that visual features are fundamentallyinterconnected see . SupposeIt is also worth considering how typicality could induce a positive emotionthrough familiarity or by meeting expectations . A produIn summary, a wealth of literature on the crossmodal correspondences hasattempted to identify the underlying operations that have led to theassociations between taste qualities and different visual features . By now,dimensions of meaning by Osgood et al.) that are betterable of describing and conceptualizing the visual stimuli , such as activity  andpotency . For example, the effectof tastant concentration on shape-taste correspondences can be confirmed bycomparing the potency (taste intensity) and evaluation (emotion) factors insemantic differential analyses. Research has also revealed other dimensionsthat could be relevant when examining other potential mediators, such as thecluster of expectation, excitement, and typicality (relevant to thedimension of familiarity; complexity; Petrenko; While the research interest has primarily focused on the two discussedtheories as they hold the best prospect of explaining crossmodalassociations, there is no reason to exclude the mediation of other factors.Acknowledging the potential of these factors could lead to the discovery ofnew models that may help supplement the current ones. Relevant here, thereis likely a sizable reward if future interests can be directed to considerother factors in the vast semantic space a, thereli e.g., . This coAfter decades of research effort over the past decades, the literature documentingthe crossmodal correspondences between visual features and taste has accumulated acomprehensive understanding of these associations. Researchers have long arrived atthe consensus that color hue and a handful of geometric features are consistentlymatched with the basic taste qualities. In recent decades, it has also been shownthat the pattern of their associations can be used to create specific visual designsthat manipulate the appraisal and perception of taste under certain circumstances.With these fundamental understandings established, the subsequent studies grewdiverse and touched on various research questions ranging from cultural validity toreal-life applications. Overall, it is reassuring to observe a global consistency ofthe matching patterns across different cultures, although some weaker connectionshave also been identified. Notably, the association between shape curvilinearity andtaste qualities has not always appeared to be as robust as that recorded betweencolor hue and taste.When comparing the popular theoretical models accounting for the crossmodalcorrespondences, it is intriguing to note how the mediating process, or the causesleading people to draw taste matches, can be remarkably different for color andgeometric features. It would seem that an intuitive mediating route exists forcolor-taste associations, which can be attributed to the internalization of thecrossmodal statistics of the environment. However, when a mediating object isunavailable, such as when matching geometric features with taste, people appear tomatch unrelated stimuli on the basis of the emotion that is associated with thecomponent perceptual stimuli. Unfortunately, there has been little researchconcerning the interaction of these explanations, which would require novelparadigms to examine the competition of different mediating factors. It is believedthat further studies should consider mapping the relevant perceptual concepts to asemantic space, which will allow the crossmodal correspondences to be quantified andcompared on meaningful scales of emotion, potency, and activity. Doing so will alsoprovide a fair chance to reveal other factors responsible for mediating theassociations.


Clinical hypothyroidism is defined by the inadequate production of thyroid hormone from the thyroid gland to maintain normal organ system functions. For nearly all patients with clinical hypothyroidism, lifelong treatment with thyroid hormone replacement is required. The primary goal of treatment is to provide the appropriate daily dose of thyroid hormone to restore normal thyroid function for each individual patient. In current clinical practice, normalization of thyrotropin (TSH) level is the primary measure of effectiveness of treatment, however the use of a single biomarker to define adequate thyroid hormone replacement is being reevaluated. The assessment of clinical health outcomes and patient-reported outcomes (PROs), often within the context of intensity of treatment as defined by thyroid function tests , may play a role in evaluating the effectiveness of treatment. The purpose of this narrative review is to summarize the prominent health outcomes literature in patients with treated hypothyroidism. To date, overall mortality, cardiovascular morbidity and mortality, bone health and cognitive function have been evaluated as endpoints in clinical outcomes studies in patients with treated hypothyroidism. More recent investigations have sought to establish the relationships between these end results and thyroid function during the treatment course. In addition to clinical event outcomes, patient-reported quality of life (QoL) has also been considered in the assessment of adequacy of hypothyroidism treatment. From a health care quality perspective, treatment of hypothyroidism should be evaluated not just on its effectiveness for the individual patients but also to the extent to which patients of different sociodemographic groups are treated equally. Ultimately, more research is needed to explore differences in health outcomes between different sociodemographic groups with hypothyroidism. Future prospective studies of treated hypothyroidism that integrate biochemical testing, PROs, and end result clinical outcomes could provide a more complete picture into the effectiveness of treatment of hypothyroidism. Health outcomes research primarily aims to study the end results of health care practices and interventions. Within the scope of health care quality, health outcomes can serve as a form of measurement of the effectiveness of a specific treatment or group of treatments, in particular for chronic diseases in which the disease course is managed over time . HypothyThe literature included in this narrative review was identified from PubMed searches of English-language articles (1990 – present), articles previously identified by the authors from prior work, and the review of citations from the aforementioned articles. PubMed searches included the following key terms: “hypothyroidism,” “health outcomes,” “levothyroxine,” “mortality,” “cardiovascular,” “bone health,” “cognitive,” and “patient-reported outcomes.” Case series and case reports were not included. In the case when relevant review articles were identified, both the review article and the primary literature were cited. In keeping with the scope of this narrative review, literature was selected that examined end result clinical outcomes of hypothyroidism treatment that represent significant morbidity for the affected patient. Studies of clinical outcomes including all-cause mortality, cardiovascular morbidity and mortality, bone health, and neurocognitive outcomes are the focus of this review because they have been the most extensively studied and reflect end result outcomes, although studies of other clinical outcomes do exist. Additionally, only studies that directly compared treated hypothyroidism to healthy controls without thyroid disease or compared groups of treated patients with different TSH levels were included. Studies comparing patients with treated and untreated hypothyroidism  or comparing treated subclinical hypothyroidism alone with healthy controls were excluded.It is important to clarify that, given outcomes research often captures real-world data, a significant number of study participants treated with thyroid hormone likely presented with subclinical hypothyroidism . There are clear practice patterns that indicate that treatment with thyroid hormone is commonplace for subclinical hypothyroidism along with overt hypothyroidism , 6. SomePrior to the widespread clinical use of TSH and thyroid hormone radioimmunoassays, physicians relied on measurable bio-metabolic parameters to determine the appropriate dose of thyroid hormone replacement for patients with hypothyroidism. These included heart and respiratory rates, weight changes, basal metabolic rate, serum protein-bound iodine level, and symptoms of hypothyroidism (undertreatment) and hyperthyroidism (overtreatment) , 8. DuriIn today’s clinical practice, thyroid function tests have become the primary factors in the determination of euthyroidism in those taking thyroid hormone replacement. In hindsight, this practice shift was predictable in that it provided both physicians and patients with a clear “normal/abnormal” dichotomy regarding thyroid hormone replacement, which is desirable in a clinical environment that is burdened with growing medical complexity in the setting of clinic visit time constraints. However, there is evidence that the “normal/abnormal” dichotomy of thyroid function tests (and TSH in particular), while an essential feature of clinical practice, may not fully determine if euthyroidism has been achieved from a multi-organ system perspective for select patients . Data frcomplete picture of the thyroid status for a significant minority of patients treated with thyroid hormone, then the evaluation of the effectiveness of thyroid hormone therapy across a population of patients should include additional outcome measures. In conjunction with thyroid function tests, evaluation of health outcomes in treated patients would be informative. From this perspective, the goal of thyroid hormone replacement would be to normalize thyroid function tests and allow patients with hypothyroidism to achieve health outcomes that are indistinguishable from those without thyroid disease.If thyroid function testing alone does not provide a Several observational studies examining large patient populations have sought to determine the association between treated hypothyroidism and mortality. Relatively few published studies have compared all-cause mortality rates of those with treated hypothyroidism and those with normal thyroid function. In two earlier studies, all-cause mortality rates between treated hypothyroid patients and euthyroid controls were not significantly different , 28. Of More recently, several studies have examined mortality relative to overtreatment and undertreatment as defined by TSH levels in different clinical settings –33. TherThyroid function abnormalities are known to exert prominent effects on multiple organ systems, including the cardiovascular system . SimilarThyroid hormone also exerts prominent effects on bone, both during childhood during the growth phase, and during adulthood when thyroid hormone stimulates osteoclastic bone resorption . SeveralOvert (untreated) hypothyroidism has well established negative cognitive effects, including deficits in verbal memory, attention, language, psychomotor function, and executive function –51. TherNot all studies have identified cognitive deficits in treated individuals. A cross-sectional study of mostly older women with an average of 20 years on treatment with normal TSH levels  showed similar cognitive functioning results compared to euthyroid peers (mean age 73.6 years) . SeveralA potential rationale for the conflicting data on cognitive outcomes in treated hypothyroidism may be that each individual patient has a set “cognitive demand” that is determined by mental tasks that vary in intensity daily, and a “cognitive reserve” to compensate if thyroid hormone treatment does not fully restore normal neurocognitive function on a cellular and tissue basis within the brain Figure 1Studies that examine the association between degree of treatment of hypothyroidism (i.e. overtreatment and undertreatment) and health outcomes from real-world datasets provide a measure of the effectiveness of thyroid hormone replacement and also demonstrate the consequences of overtreatment and undertreatment. However, there are several important limitations that must be considered when interpreting these types of studies. First, there is a degree of selection bias built into these studies because patients without thyroid function tests are often not included. In a study of an adult German population with either a diagnosis of thyroid disease or a prescription for thyroid hormone, up to 40% of the population did not have an available TSH value over a 12 month period . It is lThird, it is likely that inconsistent use of thyroid hormone coincides with inconsistent use of other medications that modify cardiovascular risk. While isolating the specific effect of thyroid hormone on a clinical outcome remains a challenge in study design and statistical approach, TSH level remains an important marker of care for an individual patient. It can be reasonably assumed that patients with a strong pattern of adherence to thyroid hormone also regularly take other appropriate therapies, and vice versa. Fourth, there is no consistent definition of overtreatment and undertreatment of thyroid hormone in the existing literature with respect to which thyroid function tests should be included, what levels should be considered “abnormal,” and over what time period. The clinical use of individualized TSH reference ranges remains a point of heated debate . ComprehThe Centers of Medicare and Medicaid Services define a patient reported outcome (PRO) as any report of a patient’s health condition that is provided by the patient without interpretation of the response by a researcher or health care provider . Over a Since the development of the ThyPRO , 71 and How do QoL scores of treated subjects compare to controls without hypothyroidism? Numerous randomized and observational studies have included QoL measures as primary or secondary outcomes in patients with treated clinical and subclinical hypothyroidism , with maA reasonable definition of successful treatment of hypothyroidism should include the restoration of thyroid function  and resolution of symptoms . This aligns with prominent society guidelines on the treatment of hypothyroidism, which outline three primary goals of treatment: 1) normalization of TSH; 2) resolution of symptoms; 3) avoiding overtreatment , 86. HowMost outcomes studies have focused on key clinical outcomes  or PROs, but not both. Many studies consider thyroid function testing in the context of intensity of treatment . However, there may be a role for questionnaires such as ThyPRO to be used not as a study outcome but as a measurement of treatment, along with thyroid function testing. For example, such a study design could explore health outcomes in those with normal thyroid function but persistent symptoms or lower QoL scores. Of course, these types of studies must overcome limitations such as confounding factors and would require long-term survey follow up. However, examination of the relationship between hypothyroidism treatment and clinical health outcomes, in the context of both PROs and biochemical thyroid function Figure 2To date, there has been relatively few investigations into inequalities in the treatment of benign thyroid disease between sociodemographic groups, although more attention has been paid to the issue in recent years . When inOverall, there are several challenges that limit our ability to identify sociodemographic disparities in clinical outcomes in treated hypothyroidism. The interplay between age, sex, race/ethnicity, and thyroid function, and their relationship between clinical outcomes, is made more complex by potential differences in the “normal” ranges of thyroid function between different sociodemographic groups . FurtherAs mentioned previously, significant knowledge gaps remain in the study of health outcomes in treated hypothyroidism. In several of the large, retrospective studies, delineating between outcomes of treatment for overt versus subclinical hypothyroidism is not possible. Studies identifying patients at the time of diagnosis and initiation of treatment and measuring outcomes in a prospective manner would allow investigators to distinguish outcomes between these two groups. Furthermore, stratifying study populations not only by diagnosis, but also by age, sex, race/ethnicity, geographic location, or access to health care could further develop our limited knowledge of disparities in treatment . Our undThe study of health outcomes in treated hypothyroidism has yielded important findings that have expanded our understanding of the effectiveness of thyroid hormone replacement to restore normal thyroid function, improve QoL measures, and prevent adverse outcomes associated with hypothyroidism. Numerous studies have been conducted examining health outcomes or PROs in the context of TSH and thyroid hormone levels. Overall, these studies have demonstrated that there is room for improvement in the treatment of hypothyroidism with respect to health outcomes and QoL measures, and that maintaining thyroid function within the normal range for the duration of the treatment course is paramount to minimizing adverse health outcomes. Generally, restored thyroid function levels are associated with normalized cardiovascular health outcomes, but periods of overtreatment and undertreatment, if not rapidly corrected, increase the risk of adverse cardiovascular outcomes and overall mortality. Some deficits in cognitive function have been shown to persist even in the setting of normalized thyroid function. PROs in treated hypothyroidism have tended to follow a similar pattern in which lower QoL scores have persisted despite normalized thyroid function, particularly in populations with underlying autoimmune thyroid disease. While these thyroid function-outcome disparities warrant further investigation, there is no evidence to support titrating thyroid hormone treatment to resolve hypothyroid symptoms at the expense of normal thyroid function levels. Significant knowledge gaps also remain in the prevalence and underlying causes of sociodemographic disparities in health outcomes and PROs in hypothyroidism. Future prospective studies which integrate multiple health and patient-reported outcomes, along with biochemical thyroid testing, would provide a better understanding of the quality gaps—and how to improve them—for many patients with hypothyroidism.ME generated the initial outline, completed the literature review and authored the manuscript. MP reviewed the outline and authored the manuscript. All authors contributed to the article and approved the submitted version.The study was supported by the National Institute of Diabetes and Kidney Disease (NIDDK) of the National Institutes of Health (NIH) under award 5T32DK007011-46 ME. MP is supported by the National Institute on Aging (NIA) under award K08AG049684.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor JJ declared a past co-authorship with the author ME.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In this issue, Patel and Mihai describe their long-term outcomes in a large cohort of patients undergoing minimally invasive parathyroidectomy (MIP) for a single parathyroid adenoma, after concordant dual localisation with Sestamibi scintigraphy and ultrasound scan . They haEndocrine surgery is in a constant state of flux, with controversies regarding the optimal technique for thyroid surgery, the appropriate extent of thyroidectomy; hemi versus total thyroidectomy, with or without prophylactic central node dissection for papillary thyroid cancer, or the relative benefits of anterior versus posterior endoscopic approaches for minimally invasive adrenal surgery. The appropriate operative approach for primary hyperparathyroidism is the subject of similar controversy. In many centres around the world, the use of IOPTH is increasing. Although it may provide helpful guidance in a non-localised patient with equivocal intraoperative findings, or in patients undergoing reoperation after failure to cure, its routine use in well-localised patients undergoing MIP can be reasonably avoided. It is an inefficient and expensive exercise (unless undertaken in a dedicated high volume parathyroidectomy theatre), and based on the number needed to treat calculated with Patel and Mihai’s results, the cost–benefit equation for IOPTH use would be difficult to balance. However, it needs to be stressed that careful patient selection must be informed by reliable concordant functional and anatomical preoperative imaging.Patel and Mihai’s results mirror the Australian experience of the University of Sydney endocrine surgery unit and the Monash endocrine surgery unit , 3, who


Cancer therapy treatments produce extensive changes in the physiological and morphological properties of tissues, which are also individual dependent. Currently, a key challenge involves developing more tailored cancer therapy, and consequently, individual biological response measurement during therapy, such as tumor hypoxia, is of high interest. This is the first time human cerebral haemodynamics and cerebral tissue oxygenation index (TOI) changes were measured during the irradiation in clinical radiotherapy and functional near-infrared spectroscopy (fNIRS) technique was demonstrated as a feasible technique for clinical use in radiotherapy, based on 34 online patient measurements.Our aim is to develop predictive biomarkers and noninvasive real-time methods to establish the effect of radiotherapy during treatment as well as to optimize radiotherapy dose planning for individual patients. In particular, fNIRS-based technique could offer an effective and clinically feasible online technique for continuous monitoring of brain tissue hypoxia and responses to chemo- and radiotherapy, which involves modulating tumor oxygenation to increase or decrease tumor hypoxia. We aim to show that fNIRS is feasible for repeatability measuring in patient radiotherapy, the temporal alterations of tissue oxygenation induced by radiation.Fiber optics setup using multiwavelength fNIRS was built and combined with a medical linear accelerator to measure cerebral tissue oxygenation changes during the whole-brain radiotherapy treatment, where the radiation dose is given in whole brain area only preventing dosage to eyes. Correlation of temporal alterations in cerebral haemodynamics and TOI response to brain irradiation was quantified.Online fNIRS patient measurement of cerebral haemodynamics during clinical brain radiotherapy is feasible in clinical environment, and results based on 34 patient measurements show strong temporal alterations in cerebral haemodynamics and decrease in TOI during brain irradiation and confirmed the repeatability. Our proof-of-concept study shows evidently that irradiation causes characteristic immediate changes in brain tissue oxygenation.In particular, TOI seems to be a sensitive parameter to observe the tissue effects of radiotherapy. Monitoring the real-time interactions between the subjected radiation dose and corresponding haemodynamic effects may provide important tool for the researchers and clinicians in the field of radiotherapy. Eventually, presented fNIRS technique could be used for improving dose planning and safety control for individual patients. Typically, radiotherapy is delivered using a linear accelerator (LINAC) producing x-ray photons or electron beams. Radiotherapy is often administered with a curative intention, aiming to administer as high dose as possible to tumor tissue while sparing surrounding healthy tissue. Radiotherapy can be delivered by multiple techniques at variable radiation energy levels. Selection of technique and energy is based on tumor properties.in vivo dosimetry, which is used to some extend in external beam radiotherapy to detect major dose errors, to assess clinically relevant differences between planned and delivered doses, and to record doses received by individual patients. However, for a variety of reasons, it is not widely applied to verifying dose delivery to individual patients.,,Radiation doses and dose planning for different malignancies founded on historical evidence, clinical studies, and radiobiology. At present, the clinical efficacy of a treatment can only be determined on clinical or radiological responses observed after a significant period of time following radiotherapy. One significant consideration in dose calculation involves potential toxic effects on surrounding healthy tissue. Radiation treatment on brain tumours, in particular, may subacutely or chronically affect cognition and cause fatigue even at conventional doses. In the context of head and neck tumours and gastrointestinal carcinomas , mucositis is the most frequent dose-limiting factor. These acute and subacute adverse events often lead to severe and highly symptomatic long-term effects and impaired quality of life. There are currently no biological markers available to predict the development or later improvement of these symptoms. The only currently available method of tracing the number of dose errors is In recent years, tumor hypoxia has been studied particularly by using positron emission tomography.In this paper, we study immediate cerebral haemodynamic and tissue oxygenation changes during clinical brain radiotherapy. At present, more than 50 patients online fNIRS measurements have been performed in Oulu University Hospital, Finland, indicating that the NIRS technique is feasible for clinical patient monitoring in radiotherapy. Our first initial study was presented in 2020 by Myllylä et al.3,The fNIRS device built for this study utilizes frequency coding technique, which is based on modulating the illuminating light, each wavelength at a specific frequency and demodulating correspondingly after receiving. Sampling rate of raw fNIRS signals was 1 kHz. Ionizing radiation inside the radiotherapy treatment room poses high demands on the materials and devices and because of this fNIRS device was placed outside radiotherapy room and only the optical fibers for the illumination and detectors we brought to the radiotherapy chamber from the control room by a cable entry. All optical fibers and optodes must be free of ferromagnetic metals since these will be attached on the subject’s head in the area of ionizing radiation. Fibers were 10 m long having two light source inputs and one output tip to enable mixing of the LED light sources each modulated at a specific frequency.Measured raw NIRS time courses were converted into two-time courses representing temporal changes in HbO, HbR, and HbT concentrations using the modified Beer–Lambert lawIn the total 34 patients, radiotherapy measurements were analyzed from 10 patients  band (0.008 to 0.1 Hz).4In the following, we show in 5in vivo effect of radiation.The WBRT or whole brain radiotherapy is palliative treatment, which is given to patients with identifiable brain metastases and prophylaxis for microscopic disease. In WBRT, the radiation dose is given in whole brain area only preventing dosage to eyes. We measured immediate cerebral haemodynamic and TOI changes caused by the WBRT. Radiation itself is not choosing the tissues it affects, the radiolysis process generates several end-products , which cause reactions in chemical bonds of the tissue compounds, most notably DNA that itself can trigger responses in enzymes or immune systems. Consequently, we do not have physiological explanation of the response because there are no human or animal studies that we know of measuring these types of temporal real-time responses of irradiation. In addition, we cannot completely exclude involuntary physiological responses of patients to the external factors, as it would require “sham” treatments of the patients that our current ethical permission is not applicable. In this study, there were altogether 10 different patients, but the same subject went through several treatments that had the same treatment protocol. Altogether, 34 subject measurements were performed. However, it must be noted that these 34 measurements do not represent a set of independent observations. However, in order to ensure the creativeness of the measurement response, we conducted several verification fNIRS measurements by measuring radiation effects on water and blood samples inside vial. None of these caused changes in our fNIRS signals. Therefore, we can conclude that the presented fNIRS signal changes are visible only when measuring It seems the tendencies of tissue oxygenation are different for the first irradiation and the second irradiation. This effect could be due to multiple reasons. The main reason is being that the second irradiation is in much smaller scale in terms of absorbed dose compared to the first irradiation. Two irradiations in FIMRT technique with different absorbed doses in the WBRT are purely technical in order to provide more homogenous dose coverage in the whole brain. Furthermore, in the second irradiation, multileaf collimators move to the forehead (and sometimes back) of the patient giving dose only to the more central part of the brain, this means that the second irradiation is not only smaller dose but further away from our measuring range. Nevertheless, it seems that there could be some type of refractory period, which causes smaller or nonexistent response in back-to-back second irradiation. It remains to be elucidated whether this refractory period is due something physiological, originates from our measurement setup or is combination of both.,,Previous studies monitoring tissue oxygenation, HbT and blood flow in the course of radiotherapy, suggest changes in blood flow and oxygen supply to the tumor in the first few weeks of the therapy.Hypoxia plays a crucial role in the tumor response to radiotherapy. The possibility to detect tissue oxygenation changes during the treatment process can lead to different strategies in radiation dose planningOur results display instant cerebral haemodynamic response recorded by fNIRS during clinical radiotherapy. Furthermore, this study shows that TOI is an accurate parameter to observe in real time the immediate tissue oxygenation effects also in individual patient [see 6In this study, we show that fNIRS measurement of cerebral hemodynamics in clinical radiotherapy is feasible to perform in regular basis. The irradiation induces immediate temporal alterations in cerebral hemodynamics, particularly a strong decrease in cerebral TOI. Potentially, presented monitoring technique can be used in future for improving dose planning and safety control for individual patients.


Social withdrawal, or hikikomori, is one of Japan’s most serious psychosocial issues. The concept gained international attention around 2010 and widespread psychiatric epidemiological studies have since been conducted.With an understanding of the extensive range of hikikomori circumstances as a spectrum, we aimed to quantitatively measure the severity of hikikomori in adolescent subjects, an age group considered particularly susceptible to the condition, and to identify factors associated with its severity.We selected population demographics, socioeconomic data, and psycho-behavioral characteristics as factors related to hikikomori and explored their associations with hikikomori severity using cross-sectional analysis. Subjects were a patient group of middle school students examined as outpatients at a psychiatric clinic during adolescence for a chief complaint of hikikomori and a control group of middle school students matched for sex and age. Subjects’ parents completed a questionnaire pertaining to their child’s hikikomori symptoms and living environment along with the Child Behavior Checklist (CBCL). The data collected was then statistically analyzed.T-test results demonstrated that scores for all CBCL syndrome scales were significantly higher in the patient group, but no scores fell within the clinical range. Multiple regression analysis revealed that being anxious/depressed, somatic complaints, lack of communication between parents, and overuse of the Internet were statistical predictors of hikikomori severity.It may be possible to prevent hikikomori from becoming severe if the above predictors are used to identify high-risk individuals requiring active intervention while hikikomori is at an early stage.No significant relationships.


Where do our preferences come from? Traditional neurocognitive models of value-based choice view decision-making as a serial process in which stable preferences are the basis of subsequent choices  mechanism to deal with hard choices, as opposed to a post-decisional process for eliminating cognitive dissonance  value computation (2) conflict detection, (2) value updating, (3) value-based decision, (4) updated value representation .(1) Value computation: The first process involves the computation of value for both choice alternatives. This computation facilitates a comparative process, allowing the decision maker to identify and pursue the option with greatest expected value  Conflict detection: If the result of value computation is that the value differential between both items is not sufficient to distinguish between the choice items, and therefore, no motor preparations can be triggered, a moment of indecision or decision conflict occurs. If no decision conflict is detected, that is, the value differential is sufficient to discriminate among the options , then the system can compute a decision value and continues with the value-based choice (as described in the fourth step of this model). Behavioral evidence suggests that preference changes do not occur for easy choices, but only for hard decisions and individuals take significantly longer to solve hard over easy decisions  Value updating: Fixation duration plays a causal role in value-guided choice  Value-based decision: Based on the rapid fixation-guided computation of a new value signal, which might be subserved by a network subtending the precuneus and dlPFC, the decision system is now able to compute a decision variable as the value differential among the alternatives is now sufficient to distinguish between them. This means, the decision scenario now has transferred from a hard to a (relatively) easy one. The computation of decision value has been associated with dlPFC activity, which is connected to premotor areas conducting the actual motor choice  Updated value representation: Although preference changes were updated during hard choices, behavioral evidence indicates that only choice outcomes that are explicitly remembered were encoded as preference changes long-term ; choice outcomes that were forgotten or guessed did not trigger long-lasting preference changes (Salti et al., This opinion paper presented empirical findings that support the notion that our preferences evolve endogenously during the process of making decisions between equally preferred items. In those situations of indecision, the information gathered via fixation toward an item seems critical to reconstruct upcoming value-based decisions. This online mechanism of fixation-driven preference formation might be depended on the idiosyncrasy of an underlying prefrontal-parietal brain network. Such rapid changes in preferences prior to the initial undetermined decision, could constitute an adaptive mechanism enabling the individual to act. These in-decisional changes in preferences become behaviorally manifested when choice outcomes were explicitly remembered and encoded by episodic memory regions. Overall, these findings suggest a potential rethinking of the very notion of preferences and value-based choice. Further, they suggest a shift away from previous explanations of endogenous preference formation. Rather these findings suggest that seemingly self-determined, subjective cognitive concepts, such as our preferences, might be emergent consequences from the particulars of the decision scenario itself and brain networks underlying value-based decisions.The author confirms being the sole contributor of this work and has approved it for publication.This paper was funded by Dr. Rüdiger Seitz, via the Volkswagen Foundation, Siemens Healthineers, and the Betz Foundation.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Advances in neural networks have garnered growing interest in applications of machine vision in livestock management, but simpler landmark-based approaches suitable for small, early stage exploratory studies still represent a critical stepping stone towards these more sophisticated analyses. While such approaches are well-validated for calibrated images, the practical limitations of such imaging systems restrict their applicability in working farm environments. The aim of this study was to validate novel algorithmic approaches to improving the reliability of scale-free image biometrics acquired from uncalibrated images of minimally restrained livestock. Using a database of 551 facial images acquired from 108 dairy cows, we demonstrate that, using a simple geometric projection-based approach to metric extraction, a priori knowledge may be leveraged to produce more intuitive and reliable morphometric measurements than conventional informationally complete Euclidean distance matrix analysis. Where uncontrolled variations in image annotation, camera position, and animal pose could not be fully controlled through the design of morphometrics, we further demonstrate how modern unsupervised machine learning tools may be used to leverage the systematic error structures created by such lurking variables in order to generate bias correction terms that may subsequently be used to improve the reliability of downstream statistical analyses and dimension reduction.  Methodological advances in machine vision, namely the rapid evolution of neural network-based approaches to image segmentation and analysis, have garnered growing interest in the utility of imaging systems in livestock management . For somLandmark-based approaches to image analysis are a natural choice for such exploratory analyses. While not informationally complete, they can be easily implemented with manual annotation protocols in a range of programs without the extensive image preprocessing required by embedding techniques ,6. How tOne readily generalizable strategy that may be used to extract information about the shape of target features from coordinate vectors is to simply employ pre-defined geometric transforms that are intrinsically scale-free. Angle measures have been used extensively in definitions of subjective conformation scoring scales, and have subsequently been extended to analysis of livestock images. Previous work exploring the use of angle-based measures of leg conformation in breeding sows ,16 and sA more informationally complete strategy employed to produce scale-free biometrics is to align coordinate vectors across images via an affine transformation and then extract shape features using an unsupervised dimension reduction technique. Geometric morphometric (GM) analysis is a well-established method in anthropological studies that combines Procrustes alignment with gPCA feature extraction . In worknormalized length biometrics, an informationally complete approach to extracting coordinate-free descriptors of shape without preliminary affine alignment [projective biometrics, to produce locally normalized biometric values that could accommodate a wider range of complex morphological features than simple angle measures [The purpose of this study was to characterize the efficacy and reliability of two additional strategies to producing scale-free biometrics from uncalibrated 2D images of minimally restrained livestock that may offer an intermediate approach between these two existing analytical paradigms. The first was globally normalized Euclidean distance measures, here referred to as lignment . The secmeasures . DetaileIn this study, structural variations in the osseous and cartilaginous features of the bovine face were utilized as a model to contrast the performance of the normalized length and projective biometric approaches to scale-free measurement. The face was chosen as a model over more conventional type (conformation) traits for several reasons. From a theoretical standpoint, the face offered a diverse range of geometrically complex morphological features arranged densely over a compact anatomical region, which provided a comprehensive sampling of prospective geometric relationships from a manageable number of annotated points. Further, skull morphology could be subdivided into localized regions that facilitated functional comparisons between measurement systems, with some subregions featuring only fixed boney traits, and thus subject only to annotation and projection errors, and fleshier subregions, wherein annotation of underlying osseous and cartilaginous landmarks might also be influenced by changes in facial expressions . From a more pragmatic standpoint, the head is highly mobile with respect to all three axes of movement  even while the cow is otherwise stationary in a headlock, which facilitated location of a large number of individual animals in a working farm environment for repeated sampling. Finally, while comparisons between measurement systems are intended to be readily generalizable to a broader scope of prospective use cases, there are emerging utilitarian interests in assessment of livestock faces to extract measures of facial expression ,32,33,34Animal handling and imaging protocols implemented in this study were approved by the Colorado State University Institution of Animal Care and Use Committee (IACUC #16-6816A). This study followed all guidelines for the use and care of agricultural animals used in research outlined in the Colorado State University IACUC Composition and Responsibilities Policies and the Colorado State University Policy on the Use of Live Vertebrate Animals.Facial images of 108 mature Holstein dairy cows were collected over a two-week period on a commercial dairy in July 2017 using an Olympus TG-2 iHS 12MP Waterproof Camera. Cows were photographed while locked in the feed bunk of their home pen while standard herd checks were being performed (not longer than 90 min). The distance between the cow and camera person was allowed to vary from 1 to 3 standard bunk spaces, as determined by the unmanipulated arrangement of animals in the headlocks at roughly 50% stocking capacity. To better emulate a feasible experimental protocol, gross variations in out-of-plane facial angle were controlled by attempting to align as closely as possible the outlines of the proximal and distal eye orbitals.The procedural target was to photograph each cow from both side profiles on three separate days. Of the 108 cows recorded, complete image profiles were generated for 74 animals. The remaining cows were either not located for a third day of photographing or had an image discarded farther down the analysis pipeline due issues with image quality not identified on farm: poor image resolution, shadows, or feed and dirt obscuring facial landmarks. Missing values appeared randomly distributed across the herd, however, and not driven by any readily identifiable form of sampling bias. In total, 551 images were deemed suitable for analysis. Photos were analyzed using the image analysis toolbox in MatLab R2016a version 9.0.0.341360 . A total of 60 unique anatomical landmarks were defined across four distinct anatomical regions: eye, muzzle, topline, and forehead/jaw. Full details on the protocol used to identify these anatomical landmarks, and how they were partitioned between anatomical regions of the face, are provided in The first strategy employed here to extract scale free biometrics from these annotations was based on Euclidean Distance Matrix Analysis . In this2) with the number of anatomical landmarks selected, with many of the resulting distance measures being geometrically redundant. Dimension reduction techniques may be applied to reduce the overall problem size, but the resulting aggregate biometrics can be difficult to interpret [While Euclidean distances matrices are simple to compute, the number of normalized length biometrics produced grows polynomially O, Overall Facial Angle was calculated as the angle formed between the line passing between the rostral-most points of the eye and nose, and the horizontal plane of the image : left. N2 calculated using the piecewiseSEM package [p-value estimates are provided in In order to identify systematic correlations with changes in image quality, image attribute estimates were added as fixed effects as in Equation (3) to the mixed models used to estimate repeatability. The total proportion of variability in each observed biometric attributed to this fixed effect model was then estimated via the marginal R package ,41. The  package . For eacstatsby utility in the psych package was then used to decompose overall correlation between residual estimates into within- and between-photo correlations across each pairwise combination of biometrics within a given anatomical subregion of the face [p-values assessing the significance of the within- and between-group correlation values for each individual biometric are provided in To explore correlation structures present amongst error terms, mixed models were again independently fit to each biometric as in the repeatability analysis and residuals calculated at the level of side within cow . The stathe face . The addthe face . To avoiFactoMineR package [Dimension reduction techniques are frequently employed to concentrate information contained in scale-free biometrics down to a more tractable problem size for statistical analysis. If correlations between biometric measurements are not attributed exclusively to anatomical signal, however, dimension reduction tools may also consolidate information from extraneous within- and between-photo factors that impose systematic error structures between biometrics ,43. To a package ,45,46. TTo evaluate the repeatability of metrics produced by HMFA analysis, partial scores were extracted independently for each cow for the left and right side of the face, aggregating information across nested photo and annotation replicates. Random effects models were then fit independently to these partial scores for each factor dimension, with cow fit here as the only random effect. As the previous repeatability analyses revealed the proportion of variance attributed to side effect (fluctuating asymmetry) to be minimal , repeatability was then calculated at the cow level to approximate the overall repeatability of each HMFA score. For each anatomical subregion, scatter plots were then generated comparing these repeatability estimates to the total proportion of variance assigned to each corresponding basis (loading) dimension . To more directly evaluate the influence of systematic error structures on the results of the dimension reduction on the observed metric, HMFA analysis was also carried out on the residual values generated to evaluate error structure. Any dimensions that explained at least 5% of the residual variability were retained for the error basis. If no bases met this criterion, the error basis consisted of only the first principal axis generated by the HMFA analyses. Canonical correlation analyses were then conducted to compare the resulting error basis space to each of the individual basis dimensions estimated from the observed data . The resSystematic error structures created between biometrics by lurking variables have the potential to lead downstream statistical analyses astray. Where repeated measures are available to provide, through repetition, a reasonable estimate of the true value of a morphometric feature, we hypothesized that these same residual correlation structures between biometrics might be leveraged by unsupervised machine learning tools to empirically recover an approximation of the link function between lurking variables and observed measurements . This miLIT package) in R [To create encodings of the systematic error structures found in both morphometric system, we here utilized clustering utilities that we have introduced in previously work that are available in the Livestock Informatics Toolkit (ge) in R . First, ge) in R ,51. Clusge) in R . Heatmapge) in R . From thTo create an optimal encoding of systematic error attributed to image level attributes , the hierarchical nature of error structures within this nested image data set was leveraged by recursively applying the proposed algorithmic pipeline for creating an bias correctio term for errors in image annotation. This was conducted by recalculating residual estimates between observed biometrics measurements and BLUP estimates calculated at the level of side of the face nested within cow, here using a fully nested fixed effects model that also contained the bias correction term for errors in image attributes. Data Mechanics clustering was again applied to the resulting scaled residual matrix, with the coarsest encoding capable of capturing all heterogeneity in error values again used to create a discretely encoded variable that would serve as a bias correction term for image attributes.piecewiseSEM package was again used to calculate the marginal R2, in order to estimate the total proportion of variance in each observed biometric that was attributed to bias correction terms and subsequently and thus excluded from the final BLUP estimates [ggplot2 package was used to plot the overall repeatability values for each biometrics before and after bias correction for each anatomical subregion of the face, wherein the color of each data point was used to reflect the proportion of total variance attributed to systematic bias in the observed estimate [Fully nested mixed effects models were then refit to each individual biometric using both bias correction terms. From these regression results, the overall repeatability of each biometric was recalculated, as in the previous methods section. Additionally, the stimates . Resultsestimate . Perhaps the most striking result of the repeatability analyses was the range of values that individual biometrics assumed across both measurement systems see . The majContrasting the distribution of overall repeatability estimates against the density curves for within-photo repeatability revealed clear and consistent loss in measurement precision with the inclusion of variables that could not be held constant between photos. As a result, “single shot” repeatability for biometrics produced from both measurement systems generally ranged from moderate to poor. The fleshier muzzle and eye subregions were perhaps the most severely impacted, with relatively few biometrics demonstrating overall repeatability estimates above 0.5 with either measurement strategy. The muzzle subregion proved particularly susceptible to the impact of between-photo error, given its comparably strong within-photo repeatability values. As muzzle biometrics largely measured fleshier cartilaginous features—nostrils, lips, chin—this result could indicate that these biometrics were influenced by between-day changes in facial expression . Alternatively, as the muzzle is relatively far away from both the poll (the axis of movement of the skull) and the boney eye orbital  this result could also be attributed to out-of-plane changes in facial angle. The bonier forehead and topline subregions fared somewhat better, with the impact of between-day error somewhat attenuated in comparison and some biometrics even achieving good overall repeatability estimates exceeding 0.75. For these subregions, projective biometrics demonstrated a slight upward shift in density relative to normalized length metrics, especially amongst the topline subregion.When biometrics suffering from readily identifiable shortcomings in annotation protocols were excluded from consideration, both measurement systems produced repeatability estimates comparable to previous work on scale free measurements in livestock. Kristjansson et al. (2013) and Gmel et al. 2018) reported within-photo repeatability ranging from roughly 0.5–0.98 in their image-based measurements of leg angles in horses ,18. Whil reportedOverall, the results of the repeatability analysis reveal that both measurement systems were capable of producing morphometrics with adequate or even good repeatabilities from one annotation of a single photo, but that such biometrics were ultimately in the minority of candidate metrics underscore the importance of preliminary measurement validation. For metrics where variations in the underlying static morphology was partially obscured by fleshier features, multiple images would be necessary to produce reasonably precise measurements. In this use case featuring morphological traits that were quite small in scale, the repeatability of all measurements could have been improved through replication of the landmark annotations—a strategy that could also be employed to bolster measurement precision in use cases of non-replicable transient features, such as facial expression.Addition of image attribute variables related to image scale and orientation to the mixed modeling equations provided additional insights into the potential sources of between-day error. Overall, the proportion of variance attributed to these image attribute values were negligible for the overwhelming majority of biometrics for both measurement systems see . AmongstFor normalized length biometrics the majority of marginal R values were again trivial, with some notable exceptions. A subset of metrics in the forehead and jaw anatomical subregion produced marginal R values in excess of 0.1. Closer inspection revealed that annotations of the cranial-most point along the jaw (point ‘M’) were influenced by abduction of the head towards the chest, with contraction of musculature at attachments along the jaw altering how far back from the chin the jaw bone could be visualized, thus leading to a significant association with Overall Facial Angle. This issue appears to have been attenuated amongst projective biometrics, as the position and angle the line of the jaw itself, onto which interpolated points were projected, was not affected by these head movements. This result underscores that, where it can be anticipated a priori, the impacts of uncontrolled variations in animal pose can be at least partially avoided through careful design of projective biometrics.Of perhaps greater concern, however, were the magnitude of correlations between image attributes and a notable proportion of normalized length metrics for the eye. Again, coefficient estimates revealed that Overall Facial Angle and not Frame:Face Ratio drove these association, and so the efficacy of the global scaling strategy employed by normalized length measures was not called into question. While it is possible that in-plane variations in facial angle (pitch) could be correlated to out-of-plane changes in head position (roll and yaw), it seems unlikely that the subsequent projection errors would have been seen only in the eye and for no other anatomical subregions. Closer inspection revealed the highest magnitudes of correlation were generally found between landmark annotations along the outer eyelid, and that annotations along the line of boney eye orbital generally produced the lowest marginal R estimates. This suggests that movement of the fleshy features of the eye between photos may account for these associations. It is possible that reactions to the photographer might have elicited synonymous changes in head position and facial expression. Changes in the eyelid could also have simply been compensatory, allowing the cow to maintain visual focus on the camera person with changes in head position. Visual inspection of the raw images did not ultimately provide clear evidence for one explanation over the other, underscoring the difficulty in interpreting normalized length metrics. That such changes were not also captured in the projective length biometrics is likely attributable to their informationally incomplete nature. For landmark points of the eye annotated between each pair of adjacent latitudinal and longitudinal corners, projective biometrics only included information on the displacement from this anatomical reference line, whereas informationally complete normalized length measures would have been affected by both displacement and the position of these points along the length of their corresponding reference lines. Overall, this result emphasizes that, while the normalization schemes employed by both scale-free morphometrics systems appear resilient to variation in distance between animal and camera, imaging protocols should still consider that the animals themselves may still be influenced by camera position.Correlation analyses revealed strong associations amongst residual estimates for both measurement systems see . BetweenIn comparing the performance of normalized length and projective biometrics with respect to within-photo error correlations, little advantage is seen for any anatomical subregion save for the eye, where normalized length measures again appear to generate proportionately higher magnitude correlations. This result is perhaps partially attributable to differences in how roundness, the most pervasive anatomical feature for the eye, is geometrically encoded by these two measurement systems. For projective biometrics, the displacement of a curve from a baseline (roundness proportion) and the relative position of that maxima point along that baseline (roundness point proportion) form the arms of a right triangle, and thus are geometrically orthogonal quantities, which in turn aids in orthogonalizing errors in landmark annotations. Normalized length metrics, on the other hand, can be visualized as the hypotenuses of the same triangles, the lengths of which are simultaneously influenced by errors in point annotation in both the x- and y-directions relative the base, resulting in more diffuse error correlation structures among within-photo errors see . That thDifferences in the resilience to between-photo error correlation demonstrated by these two measurement systems were less consistent. Thicker tails are observed on the distribution of additive between-photo correlation for normalized length biometrics in the forehead and muzzle subregions, but projective biometrics demonstrate slightly thicker tails with eye and topline biometrics. Multiple sources of error may be contributing to such error structures. For anatomical subregions with fleshier traits, namely the eye and muzzle metrics, changes in facial expression between photos may partially account for correlations amongst error terms. As contractions of facial muscles cause some length measures to shorten, others must grow longer in compensation, creating systematic error structures that would be consistent across cows by virtue of their shared muscular anatomy . That chNontrivial between-photo correlations were also found amongst topline metrics, however, which consisted exclusively of boney traits, and so changes in expression cannot be the only source of such error correlation. Changes in out-of-plane angles of the face (head posture) here become suspect. With any changes in roll and yaw of the head along the axis of the poll between images, projection of the anatomical points on the 3D dimensional surface of the skull onto the 2D plane of the image will be warped. Indeed, because these points all lie on the same rigid surface of the skull that is similar in overall configuration across animals, such movements will induce systematic transformations in their relative coordinate locations, and thus in turn the coordinate-free distance measures computed from them ,53. A viiid error assumption would not necessarily be met for all potential sets of biometrics [Regardless of their ultimate cause, high magnitudes of correlations between biometric error terms are cause for statistical concern. When biometrics are added to the right-hand side of the model equation as predictor variables, high magnitude error correlations could enhance overall correlations between covariates, which could in turn cause variance inflation and model instability. Of perhaps greater concern, however, would be scenarios where multiple biometrics are added to the left-hand side of the equation as a multivariate response. This might occur if such biometrics were incorporated into genetic analyses or simply in multivariate analyses attempting to utilize correlations between biometrics to improve measurement precision and thus carry out more robust tests of model hypotheses. Here, the standard ometrics . Indeed,ometrics . If the Results of dimension reduction analysis revealed that HMFA did succeed in producing aggregate scores of facial morphology with good repeatability estimates for both measurement systems see . In compOne noteworthy pattern observed in both measurement systems across all anatomical subregions is that, while the first few basis dimensions produced by the HMFA analysis yielded scores with both good repeatability and little correlation to the subspace estimated for the error structure, there are many dimensions with intermediate repeatability values that are quite close to the error subspace. This may suggest that, while the first few bases are successfully isolating the underlying anatomical signal from the measurement noise, these intermediate values may also be concentrating systematic error structures alongside these more moderate anatomical inter-relationships. This raises methodological concerns, as most of these intermediate dimensions with acceptable repeatability estimates would be retained for further statistical analysis when basis dimension is determined by visual inspection of the corresponding scree plots  variance attributed to encodings of systematic error structures here occupied a much wider range of estimates, being as high as 0.85 for some biometrics. This result is not surprising, given that previous analyses of error structures recovered higher magnitude correlations for both these anatomical subregions, but it does confirm that these biometrics may be significantly biased by lurking variables related to annotation and imaging protocols. Addition of bias correction terms improved repeatability estimates of a notable proportion of biometrics within these anatomical subregions—some more than 20%—so that a greater proportion of biometrics in either measurement system could be said to exhibit acceptable (>0.50) or even good (>0.75) repeatability values. These improvements were not, however, as uniform as in the topline and muzzle subregions, which warranted further examination.Improvements in the repeatability estimates for eye biometrics were notably higher for projective biometrics than for normalized length metrics. Comparison of the encoding granularities used to create annotation and image error bias correction terms, which are presented in 2 values. That the observed values of these biometrics are so heavily influenced by systematic error induced by lurking variables suggests that, for applications where imaging cannot be replicated, these metrics might even be directly employed as bias correction terms using a similar encoding pipeline to allow for nonlinearity in the latent link function. For example, in applications with transient facial expression, repeated images of the target features of analysis might not be easily obtained, but if multiple images are acquired from each animals, structural morphometrics sensitive to variation in camera position might be extracted and this UML pipeline applied to create bias correction terms for projection error, allowing researcher to apply minimally invasive imaging protocols while still minimizing the risk of measurement bias. Responses to bias correction also differed between the two measurement systems for forehead biometrics. While coarser encodings were here recovered for projective biometrics by clustering analyses when compared with the results for normalized length see , improveWhile differences in the performance of bias correction terms between anatomical subregions here seems most easily explained by the efficacy of the UML pipeline to recover latent error structures, this information must also be passed to the mixed effect model through the fixed effects terms in order to influence the final estimation of the underlying morphometrics. By utilizing a clustering-based approach, nonlinearity in the latent link function connecting the observed measurements with the one or more sources of systematic error in this system could be accommodated without stating a specific model. Such coarsening of the data, however, may place practical limitations on the acuity of the bias correction model. In these analyses, clustering granularity was selected subjectively to capture all systematic heterogeneity that was visually distinguishable by heatmap. Finer encodings might be used to further minimize loss of information, with any over-fitting of the bias correction terms ultimately only translating to more conservative estimates of random effects. Future work, however, might also consider applications of nonlinear manifold embedding approaches in this bias correction pipeline to create continuous linearized estimates of latent lurking variables . While sThe results of these analyses show that both normalized length and projective biometrics are resilient to fluctuations in image scale and are capable of extracting morphometric measurements from uncalibrated 2D images with moderate to good repeatability. For applications that require high accuracy measurements of finer scale features, replication of image annotations may be needed, particularly for landmarks identified by their relative displacement from anatomical reference lines. Both measurement systems, however, were susceptible to systematic bias induced by variations in lurking variables that cannot be held constant between images. We have shown that such systematic error can lead astray standard multivariate approaches to dimension reduction, which could in turn increase the risk that statistical inferences gleaned from such datasets could become confounded with lurking variables. To avoid risk of spurious inference, without increasing the complexity or invasiveness imaging protocol, additional care must be taken not only in the design of the biometrics but also the downstream analyses. We have demonstrated that simple and readily generalizable unsupervised learning tools are capable of working with, not against, the systematic error structures created in scale free biometrics to infer information about lurking variables. Encoded variables extracted from these clustering results can subsequently be incorporated into downstream analyses to control statistically for variables that cannot be controlled on farm, thereby helping to ensure that the insights and intuitions gleaned from these emerging PLF data streams can provide a reliable foundation for future work. While these new algorithmic techniques have been shown to improve the overall reliability of scale free morphometrics from unstructured data sets, future work should consider how structured systematic sampling techniques might be incorporated into image acquisition protocols to further improve the efficacy of these measurement systems. In particular, subsequent work might consider how this algorithmic pipeline might be expanded to incorporate targeted application of more costly and invasive 3D imaging techniques, in order to better overcome systematic biases from variations in camera position in applications with minimally restrained livestock that require less invasive 2D imaging tools.


Psychopathy is associated with severe deviations in social behavior and cognition. While previous research described such cognitive and neural alterations in the processing of rather specific social information from human expressions, some open questions remain concerning central and differential neurocognitive deficits underlying psychopathic behavior. Here we investigated three rather unexplored factors to explain these deficits, first, by assessing psychopathy subtypes in social cognition, second, by investigating the discrimination of social communication sounds  from other non-social sounds, and third, by determining the neural overlap in social cognition impairments with autistic traits, given potential common deficits in the processing of communicative voice signals. The study was exploratory with a focus on how psychopathic and autistic traits differentially influence the function of social cognitive and affective brain networks in response to social voice stimuli. We used a parametric data analysis approach from a sample of 113 participants  with ages ranging between 18 and 40 years . Our data revealed four important findings. First, we found a phenotypical overlap between secondary but not primary psychopathy with autistic traits. Second, primary psychopathy showed various neural deficits in neural voice processing nodes  and in brain systems for social cognition . Primary psychopathy also showed deficits in the basal ganglia (BG) system that seems specific to the social decoding of communicative voice signals. Third, neural deviations in secondary psychopathy were restricted to social mirroring and mentalizing impairments, but with additional and so far undescribed deficits at the level of auditory sensory processing, potentially concerning deficits in ventral auditory stream mechanisms (auditory object identification). Fourth, high autistic traits also revealed neural deviations in sensory cortices, but rather in the dorsal auditory processing streams (communicative context encoding). Taken together, social cognition of voice signals shows considerable deviations in psychopathy, with differential and newly described deficits in the BG system in primary psychopathy and at the neural level of sensory processing in secondary psychopathy. These deficits seem especially triggered during the social cognition from vocal communication signals. Psychiatric disorders and psychiatric-affine personality dimensions can severely affect the recognition of social signals –4. This Individuals with psychopathic traits show dysfunctional brain activity mainly in cognitive social brain nodes and their connections , 14. DatA second factor concerns the focus on visual material that carries specific feature information as the target focus of social recognition tasks for participants. First, visual material and especially face recognition setups are often limited to receptive social cognition tasks that only have a restricted interactive and communicative component. Unlike human faces, the human voice seems more strongly related to communication contexts, as it is the carrier for nonverbal (non-speech) and speech communications , 33. VoiA third factor concerns the psychopathological and neurofunctional overlap with other psychiatric disorders and traits. Investigations tried to identify such commonalities and differences of psychopathy with cluster-B personality disorders , 42, adoBesides marked socio-affective deficits, about 90% of those with ASD are also affected by sensory processing symptoms . The neuWe here took a parametric neuroimaging approach to test several of the outlined open research questions about the neurofunctional mechanisms that underlie social perception abilities and deficits in psychopathy as a dimensional trait measure. We hypothesized that in response to social voice stimuli, psychopathic and autistic traits would differentially correlate with neurofunctional diversity in regions of the social cognitive and affective brain networks . The study was mostly exploratory, but with a specific focus on these networks.N = 113 human participants with an age range 18–40 y  and including 41.6% male (n = 47) and 58.4% female participants (n = 66). We recruited as many participants as possible for the data set and did not include a stopping rule. We also did not perform an a priori for the sample size due to the exploratory nature of the design. The sample size allows for parametric regression analysis of a varied distribution and is at least equal or higher in comparison to the sample sizes of similar studies  corrected) above the percentage of false alarms  and miss trials . In terms of reaction times, we found that individuals took more time to respond in false alarms trials than in hit trials .All participants were very accurate in indicating the actual repetition of sounds , and this was significantly  between the LSRPtotal  and the LSRPprim score  with the individual hit rate level. This indicates that individuals with high levels of psychopathic traits and especially individuals scoring high on primary psychopathy have more difficulties in detecting sound repetitions.We furthermore determined whether the accuracy of hit rates for repeated sounds would depend on the four major personality traits investigated here. We accordingly found a negative correlation  and right amygdala (CMA subnucleus).This neural activation pattern for processing voice signals was largely repeated when we determined the neural effects specifically for processing speech and non-speech voice signals Fig. . The neutotal  and LSRPprim  were positively correlated with activity in right PTe and LSRPprim showed an additional positive association  with an area in the mid-section of right STC (mST) as part of higher-order AC. No associations were found between the overall activation level in these ROIs and the AQ score. We also assessed whether personality traits showed an association with activation levels for voice processing as a social sound signal . Left and right ioFC showed lower signals with higher LSRPtotal scores , where left ioFC activity was negatively associated with LSRPsec  and right ioFC was negatively associated with LSRPprim . Furthermore, right CMA activity was negatively associated with LSRPtotal  and LSRPprim , with LSRPprim also showing a negative association with ACC activity . This pattern of brain-personality associations was largely repeated for the neural effects of speech processing , with only the ACC-LSRPprim association missing. For the neural effects of non-speech sounds, we only found negative relationships with the right MC .In the next step, we determined whether personality traits showed an association with the neural activation levels across all five sound categories as a general measure of sound sensitivity Fig. . For thinal Fig. –5. When trait, PANASab, BDI) and the demographic variables  as regressor-of-no-interest to account for the potential influence of these variables. Using the LSRPtotal score as a predictor for neural signal difference between voice and non-voice sounds  participants met the screening cutoff point of ≥26 of the AQ score, which may indicate the possibility of psychopathological problems in the range of an ASD diagnosis, and 4 (3.5%) participants even met the clinical threshold of ≥32 indicating severe autistic complications . The LSRAfter establishing the distribution of psychopathic and autistic trait scores in our sample, we performed correlation analyses to assess the relationship of these specific traits with more general personality traits Fig. e. First,Psychopathic and autistic traits thus seem to be associated with certain impairments along socio-affective personality traits. We next tested if this would also apply to brain mechanisms for the processing of socially relevant voice and speech communicative signals. First, we determined the general fronto-temporal-limbic neural network for processing such communicative signals independent of variations on the trait dimension. This network comprised low- and higher-order AC, (pre-)motor regions, and infero-orbital frontal regions as previously described –40, withThere were further observations of neural hypoactivity associated with primary psychopathy. Primary psychopathy revealed hypoactivity in right MC for the processing of non-speech voices and in right amygdala for speech sounds. Hypoactivity in the MC was in an area that innervates the lips  and mighWhile the former analysis was restricted to ROIs of the neural voice processing network, we performed additional and unrestricted whole-brain analyses to reveal the broader influence of psychopathic and autistic traits in the neural processing of social communication signals. We found that increasing levels of psychopathic traits were related to widespread hypoactivity across socio-affective processing networks Fig.  that areThese results overall point to broad social processing deficits from voice communication signals in psychopathy, but there were also differential neural deficits for primary and secondary psychopathy. Primary psychopathy seems to show neural deficits in almost all social processing subnetworks and the additional BG subnetwork. This confirms the lack of affective empathy , a lack On the personality phenotype level, we described some similarities between secondary psychopathy and autistic traits above. Increasing autistic traits led to hypoactivity in left vPM, ACC, and in bilateral AC Fig. . While tTaken together, our data show behavioral and especially neural processing deficits for social voice and speech signals that correlate with psychopathic and autistic traits in a community sample. Individuals scoring high on primary psychopathy showed considerable behavioral and neural processing deficits, pointing to social processing deficits at various cognitive and affective levels. Extending previous findings, our data highlight neural dysfunctions in the BG system, which might be especially relevant for decoding social information from auditory communication signals. Secondary psychopathy showed differential neural deficits, with specific and so far, unreported deficits found at the level of sensory integrative processing. This sensory deficit could be specific to voice communication signal processing, given the specific complexity of auditory signals and the neural effort to decode social information from sounds. This sensory processing deficit could be a common factor with autistic traits, for which we also found a large overlap in terms of the personality phenotype with secondary psychopathy.Supplemental Material