The ontology of craniofacial development and malformation for translational craniofacial research.

We introduce the Ontology of Craniofacial Development and Malformation (OCDM) as a mechanism for representing knowledge about craniofacial development and malformation, and for using that knowledge to facilitate integrating craniofacial data obtained via multiple techniques from multiple labs and at multiple levels of granularity. The OCDM is a project of the NIDCR-sponsored FaceBase Consortium, whose goal is to promote and enable research into the genetic and epigenetic causes of specific craniofacial abnormalities through the provision of publicly accessible, integrated craniofacial data. However, the OCDM should be usable for integrating any web-accessible craniofacial data, not just those data available through FaceBase. The OCDM is based on the Foundational Model of Anatomy (FMA), our comprehensive ontology of canonical human adult anatomy, and includes modules to represent adult and developmental craniofacial anatomy in both human and mouse, mappings between homologous structures in human and mouse, and associated malformations. We describe these modules, as well as prototype uses of the OCDM for integrating craniofacial data. By using the terms from the OCDM to annotate data, and by combining queries over the ontology with those over annotated data, it becomes possible to create "intelligent" queries that can, for example, find gene expression data obtained from mouse structures that are precursors to homologous human structures involved in malformations such as cleft lip. We suggest that the OCDM can be useful not only for integrating craniofacial data, but also for expressing new knowledge gained from analyzing the integrated data.

Commentaries on "Informatics and medicine: from molecules to populations".

OBJECTIVE: To discuss interdisciplinary research and education in the context of informatics and medicine by commenting on the paper of Kuhn et al. "Informatics and Medicine: From Molecules to Populations". METHOD: Inviting an international group of experts in biomedical and health informatics and related disciplines to comment on this paper. RESULTS AND CONCLUSIONS: The commentaries include a wide range of reasoned arguments and original position statements which, while strongly endorsing the educational needs identified by Kuhn et al., also point out fundamental challenges that are very specific to the unusual combination of scientific, technological, personal and social problems characterizing biomedical informatics. They point to the ultimate objectives of managing difficult human health problems, which are unlikely to yield to technological solutions alone. The psychological, societal, and environmental components of health and disease are emphasized by several of the commentators, setting the stage for further debate and constructive suggestions.

Low-dose neuroleptic regimens in the treatment of borderline patients.

The use of pharmacologic agents in treating patients described as borderline generally has been accorded an insignificant, or at best, minor, role. We discuss this observation and review the literature that has dealt with this aspect of treatment. Diagnostic criteria are presented that appear to define a specific population of borderline patients who have been observed to be responsive to low doses of neuroleptic drugs. Five case histories of patients with conditions diagnosed and treated in this manner are presented, followed by a discussion of the implications of this approach in terms of clarifying the nosologic issues that have arisen around the "borderline" concept.

The Digital Anatomist distributed framework and its applications to knowledge-based medical imaging.

The domain of medical imaging is anatomy. Therefore, anatomic knowledge should be a rational basis for organizing and analyzing images. The goals of the Digital Anatomist Program at the University of Washington include the development of an anatomically based software framework for organizing, analyzing, visualizing and utilizing biomedical information. The framework is based on representations for both spatial and symbolic anatomic knowledge, and is being implemented in a distributed architecture in which multiple client programs on the Internet are used to update and access an expanding set of anatomical information resources. The development of this framework is driven by several practical applications, including symbolic anatomic reasoning, knowledge based image segmentation, anatomy information retrieval, and functional brain mapping. Since each of these areas involves many difficult image processing issues, our research strategy is an evolutionary one, in which applications are developed somewhat independently, and partial solutions are integrated in a piecemeal fashion, using the network as the substrate. This approach assumes that networks of interacting components can synergistically work together to solve problems larger than either could solve on its own. Each of the individual projects is described, along with evaluations that show that the individual components are solving the problems they were designed for, and are beginning to interact with each other in a synergistic manner. We argue that this synergy will increase, not only within our own group, but also among groups as the Internet matures, and that an anatomic knowledge base will be a useful means for fostering these interactions.

Motivation and organizational principles for anatomical knowledge representation: the digital anatomist symbolic knowledge base.

OBJECTIVE: Conceptualization of the physical objects and spaces that constitute the human body at the macroscopic level of organization, specified as a machine-parseable ontology that, in its human-readable form, is comprehensible to both expert and novice users of anatomical information. DESIGN: Conceived as an anatomical enhancement of the UMLS Semantic Network and Metathesaurus, the anatomical ontology was formulated by specifying defining attributes and differentia for classes and subclasses of physical anatomical entities based on their partitive and spatial relationships. The validity of the classification was assessed by instantiating the ontology for the thorax. Several transitive relationships were used for symbolically modeling aspects of the physical organization of the thorax. RESULTS: By declaring Organ as the macroscopic organizational unit of the body, and defining the entities that constitute organs and higher level entities constituted by organs, all anatomical entities could be assigned to one of three top level classes (Anatomical structure, Anatomical spatial entity and Body substance). The ontology accommodates both the systemic and regional (topographical) views of anatomy, as well as diverse clinical naming conventions of anatomical entities. CONCLUSIONS: The ontology formulated for the thorax is extendible to microscopic and cellular levels, as well as to other body parts, in that its classes subsume essentially all anatomical entities that constitute the body. Explicit definitions of these entities and their relationships provide the first requirement for standards in anatomical concept representation. Conceived from an anatomical viewpoint, the ontology can be generalized and mapped to other biomedical domains and problem solving tasks that require anatomical knowledge.

Vascular hypotension and bradycardia following intraocular injection of acetylcholine during cataract surgery.

Two patients, an 80-year-old woman and a 70-year-old man, experienced profound systemic hypotension and bradycardia following intraocular acetylcholine administration during cataract surgery. When we compared these two cases with three previously published reports of similar occurrences, we found no common factors other than age that might have predisposed these patients to such complications. All five patients were in relatively good health and each received different combinations of premedication. This reaction occurred in two patients given local anesthesia, two given local anesthesia with intravenous sedation, and one given general anesthesia. Although a cause-and-effect relationship has not been proven, the suggestive temporal sequence of events indicated that all patients undergoing cataract surgery in which the use of intraocular acetylcholine is contemplated should be monitored by an anesthesiologist.

Long-term course of chloroquine retinopathy after cessation of medication.

Seven patients with chloroquine retinopathy were examined ten years after their therapy with chloroquine or hydroxychloroquine, or both, had been discontinued and an additional five patients with chloroquine retinopathy were similarly examined from two to eight years after their therapy had been discontinued. Visual acuity, visual fields, and ophthalmoscopic examinations were compared to those performed at the time therapy was discontinued. These long-term observations confirmed the previously published observations based on short-term studies that chloroquine retinopathy tends to remain stable after therapy is discontinued, although a few patients in the early stages of retinopathy may show regression and occasionally a patient with a more advanced stage of the disease may show progression.

Pharmacotherapy of borderline states.

Our current state of knowledge regarding the pharmacologic management of BDs is at an early point in its evolution, exceeded only marginally by our ability to define the nosologic boundaries of these disorders. As the boundaries become better defined, especially those shared with the AD spectrum, and concurrently there is an effort to define nosologic subgroups based on differential drug treatment response, we gradually will be able to prospectively make better prescribing decisions and thereby reduce the trial-and-error aspect, with its potential for further sensitizing this population who already deal poorly with inconstancy.

A psychiatrist-rated battery of measures for assessing the clinical status of psychiatric inpatients.

Despite the increasing demand for outcome assessment measures, no published reports have provided a standardized way to assess psychiatric inpatients that includes diagnosis and observer ratings of psychopathology. This paper reviews general principles for selecting outcome assessment measures, proposes a battery of instruments based on already available measures to assess clinical status in psychiatric inpatients, reviews methods of implementing the battery in an academic inpatient psychiatric setting, and presents preliminary data on its interrater reliability, construct validity, and range of response to acute hospitalization. Preliminary results suggest that the battery may be useful for resident and medical student education and for enhancing quality assurance and continuous quality improvement.

Knowledge-driven ultrasonic three-dimensional organ modeling.

A representation is described for nonstructured biologic objects which are single-valued distortions of a sphere. The representation is implemented in a model-driven system for extracting three-dimensional (3-D) organ reconstructions from a series of arbitrarily oriented ultrasound slices. A training set of ultrasonic reconstructions of similarly shaped objects is used to give the computer generic knowledge of a given shape class. This knowledge is in the form of local slope constraints defined on an object coordinate system. The combination of constraints, interacting together via a relaxation process on continuous label sets, attempts to capture the essential shape and range of variation for an organ class. An initial tolerance region and ``bestguess'' organ surface are established by the interaction of the learned shape knowledge with manually input organ landmarks. A hypothesize-verify paradigm is employed to alternately request new data and to update the tolerance region and bestguess surface. Examples from runs on two balloon classes are presented. These examples show: 1) the local constraints interact to produce a reasonable global depiction of the essential shape and range of variation, 2) the use of shape knowledge permits accurate results from only one third of the available data, and 3) the 3-D shape knowledge provides a two-dimensional (2-D) tolerance region for plan-guided edge detection.

Imaging and the Human Brain Project: a review.

OBJECTIVES: Survey current work primarily funded by the US Human Brain Project (HBP) that involves substantial use of images. Organize this work around a framework based on the physical organization of the body. METHODS: Pointers to individual research efforts were obtained through the HBP home page as well as personal contracts from HBP annual meetings. References from these sources were followed to find closely related work. The individual research efforts were then studied and characterized. RESULTS: The subject of the review is the intersection of neuroinformatics (information about the brain), imaging informatics (information about images), and structural informatics (information about the physical structure of the body). Of the 30 funded projects currently listed on the HBP web site, at least 22 make heavy use of images. These projects are described in terms of broad categories of structural imaging, functional imaging, and image-based brain information systems. CONCLUSIONS: Understanding the most complex entity known (the brain) gives rise to many interesting and difficult problems in informatics and computer science. Although much progress has been made by HBP and other neuroinformatics researchers, a great many problems remain that will require substantial informatics research efforts. Thus, the HPB can and should be seen as an excellent driving application area for biomedical informatics research.

Knowledge-based client-server approach to structural information retrieval: the Digital Anatomist Browser.

Structural information can be defined as data and knowledge about biological objects ranging in size from molecules to the whole body. A framework is described for organizing structural information around a well-defined set of terminology and semantic relationships, and for disseminating multimedia structural information by means of a wide-area information server that is accessible over the internet. A Macintosh-based client of this server, called the Digital Anatomist Browser, has been used to teach neuroanatomy for the last 2 years. The client-server approach provides each student unlimited access to a rapidly growing knowledge base of structural biology that, while immediately useful for anatomy teaching, has the potential to be an organizing framework for other kinds of medical knowledge as well.

Congenital toxoplasmosis presenting as isolated acute chorioretinitis in the neonate.

We describe a neonate with congenital ocular toxoplasmosis that presented as isolated, acute bilateral retinochoroiditis. Although toxoplasmic retinochoroiditis is not rare, it is quite unusual to diagnose congenital toxoplasmosis based on isolated bilateral retinochoroiditis in an otherwise healthy neonate. Bilateral retinochoroiditis can be caused by syphilis, herpes virus, cytomegalovirus, and toxoplasmosis. Because specific treatments now exist for these conditions, it is important to establish proper diagnosis so that treatment can be initiated promptly. The differential diagnosis, work-up, and management of retinochoroiditis in the newborn is presented and discussed.

Psychomotor performance after forward-facing impact.

An experiment to assess psychomotor performance before and after forward-facing (-Gx) impact was conducted using the AFAMRL Horizontal Decelerator Facility. There were 10 volunteer subjects who participated in 50 tests at 4 impact levels (0 G or sham, 8 G, 10 G, and 12 G). Two initial head positions were explored at the highest impact level. The manikin psychomotor task, a complex reaction time and accuracy task, was used to evaluate performance. Linear and angular accelerations were measured at the head. Although there was a weak correlation between angular head acceleration and prolonged post-impact reaction time, no compelling statistical evidence was found to support the hypothesis that psychomotor performance is degraded with increasing impact severity at these test levels. The highest test level explored in this study may not have been sufficient to produce a change in performance or, alternatively, the manikin task may not have been sufficiently sensitive to measure a change in performance if one was present. In addition, significantly lower angular head acceleration was observed at the 12-G test level when the head was rotated forward initially rather than prepositioned upright against the headrest. The potential for temporary stunning of aircrew members during operational crash landings or ditchings may be reduced by rotating the head forward prior to an imminent crash if time permits.

Effect of seat cushions on human response to +Gz impact.

Human response to vertical (+Gz) impact acceleration was evaluated as a function of various seat cushions, including current operational cushions used in such aircraft as the A-10, F-15, and F-111 and proposed alternative cushions comprised of rate-dependent, slow-recovery polyurethane foams. There were 133 tests conducted of volunteer subjects in seven different experimental conditions, using a vertical deceleration tower facility. The mean peak acceleration of the impact carriage for these tests was 9.85 G (S.D. = 0.07) and the mean carriage velocity change was 8.01 m X s-1 (S.D. = 0.05). Resultant seat loads and head and chest accelerations were significantly higher for the F-111 cushion than for the rate-dependent foam cushions, which included cushions comprised of Confor foam or Temper foam. Resultant head and chest accelerations were also significantly higher for the ACES II cushion than for the rate-dependent foam cushions. Therefore, from an impact protection standpoint, the operational cushions were inferior to the proposed alternative cushions. Operational use of rate-dependent foam cushions is recommended to improve the impact protection performance of escape systems. Flight tests conducted by the USAF Strategic Air Command have shown that these cushions enhance crewmember sitting comfort during long-duration missions.

Comparison of human impact response in restraint systems with and without a negative G strap.

A test program to assess the influence of a negative G strap on restraint dynamics and human impact response was conducted at AFAMRL. There were 131 experimental-level impact tests with volunteer subjects performed in eight different test conditions. Forward-facing (-Gx) impacts were carried out on a horizontal accelerator, while vertical (+Gz) impact tests were done on a vertical drop tower facility. In both axes, the experimental exposure was an approximate half-sine waveform with peak acceleration up to 10 G and velocity change up to 9.2 m X s-1. Subjects were restrained to the test vehicle using either the PCU-15/P torso harness and lap belt, which is used operationally in such aircraft as the A-20 and F-15, or a conventional double shoulder strap and lap belt configuration. In one half of the test conditions, fixed-length negative G straps were incorporated into these restraint systems. In the other test conditions, the unmodified restraint systems were evaluated. Adding the negative G strap to either restraint system had clearly beneficial effects. These included decreasing the tendency toward submarining in forward-facing impacts, providing better occupant-seat coupling during free falls, and improving vertical impact protection. Sufficient benefits appear to result from use of the negative G strap to warrant a recommendation for its incorporation into selected USAF restraint systems, such as the PCU-15/P torso harness and lap belt. Additional data analysis revealed that the conventional double shoulder strap and lap belt restraint provided better forward-facing and vertical impact protection than the PCU-15/P torso harness and lap belt configuration. Further research at AFAMRL is planned to identify restraint harness features which may improve the performance of current and future impact protection systems.

Vertical impact evaluation of the F/FB-111 crew restraint configuration, headrest position, and upper extremity bracing technique.

An experiment to assess the influence of changes in restraint harness configuration, fore-aft headrest position, and upper extremity bracing technique on human response to impact was conducted using the AFAMRL Vertical Deceleration Tower. A total of 201 tests was performed with volunteer subjects in 11 test conditions to evaluate 3 restraint harnesses, 3 arm bracing conditions, and 4 seat adjustment configurations. The test fixture, restraint harness, and subject were instrumented to obtain pertinent objective data during each experiment. Measured parameters included acceleration of the impact carriage and test seat, velocity of the carriage, loads reacted at the seat, loads measured at the restraint harness attachment points, triaxial translational accelerations at the head and chest of the subject, and body segment displacements. The mean peak carriage acceleration for the 161 experimental level tests was 10.5 G (S.D. = 0.18) and the mean carriage velocity change was 7.89 m/s (S.D. = 0.05). Resultant head and chest accelerations were increased in a proposed, modified F/FB-111 restraint system compared to the operational F/FB-111 restraint system. These findings contributed to the decision not to implement the proposed modification. Also, the arms crossed bracing position for F/FB-111 ejectees preparing for landing impact of the crew module was associated with higher seat loads than the arms extended position. With the arms extended and braced on the anterior thighs or knees, loads are transmitted through the extremities to the footrest thereby reducing loading of the vertebral column. Operational use of the arms extended position prior to anticipated vertical impact accelerations may be helpful in reducing the vertebral fracture rate associated with these mechanical force environments.

Knee ligament injury during lateral impact.

A volunteer woman subject incurred injury to her right knee consisting of a torn anterior cruciate ligament and stretched medial collateral ligament during a lateral (+Gy) impact test. Similar injury has not been reported in the English-language literature an accidental sideward automotive crashes or lateral impact experimentation involving humans. The primary mechanism which produced this injury was external tibial rotation on the femur with the knee flexed. The factors contributing to the injury included extraordinarily forceful leg bracing by the subject, her knee joint laxity or hypermobility, and the absence of side supports to limit lower extremity flailing during the impact response. In future lateral impact tests, women subjects should be used with caution and any subject with abnormal joint mobility should be excluded from participation.

The Virtual Anatomy Lab: a hands-on anatomy learning environment.

This paper introduces the Virtual Anatomy Lab software platform for coordinating on-line gross anatomy learning sessions over time.

Spatial-symbolic Query Engine in Anatomy.

OBJECTIVES: Currently, the primary means for answering anatomical questions such as 'what vital organs would potentially be impacted by a bullet wound to the abdomen?' is to look them up in textbooks or to browse online sources. In this work we describe a semantic web service and spatial query processor that permits a user to graphically pose such questions as joined queries over separately defined spatial and symbolic knowledge sources. METHODS: Spatial relations (e.g. anterior) were defined by two anatomy experts, and based on a 3-D volume of labeled images of the thorax, all the labeled anatomical structures were queried to retrieve the target structures for every query structure and every spatial relation. A web user interface and a web service were designed to relate existing symbolic information from the Foundational Model of Anatomy ontology (FMA) with spatial information provided by the spatial query processor, and to permit users to select anatomical structures and define queries. RESULTS: We evaluated the accuracy of results returned by the queries, and since there is no independent gold standard, we used two anatomy experts' opinions as the gold standard for comparison. We asked the same experts to define the gold standard and to define the spatial relations. The F-measure for the overall evaluation is 0.90 for rater 1 and 0.56 for rater 2. The percentage of observed agreement is 99% and Cohen's kappa coefficient reaches 0.51. The main source of disagreement relates to issues with the labels used in the dataset, and not with the tool itself. CONCLUSIONS: In its current state the system can be used as an end-user application but it is likely to be of most use as a framework for building end-user applications such as displaying the results as a 3-D anatomical scene. The system promises potential practical utility for obtaining and navigating spatial and symbolic data.