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PubMed2006

A maximum likelihood framework for protein design.

BACKGROUND: The aim of protein design is to predict amino-acid sequences compatible with a given target structure. Traditionally envisioned as a purely thermodynamic question, this problem can also be understood in a wider context, where additional constraints are captured by learning the sequence patterns displayed by natural proteins of known conformation. In this latter perspective, however, we still need a theoretical formalization of the question, leading to general and efficient learning methods, and allowing for the selection of fast and accurate objective functions quantifying sequence/structure compatibility. RESULTS: We propose a formulation of the protein design problem in terms of model-based statistical inference. Our framework uses the maximum likelihood principle to optimize the unknown parameters of a statistical potential, which we call an inverse potential to contrast with classical potentials used for structure prediction. We propose an implementation based on Markov chain Monte Carlo, in which the likelihood is maximized by gradient descent and is numerically estimated by thermodynamic integration. The fit of the models is evaluated by cross-validation. We apply this to a simple pairwise contact potential, supplemented with a solvent-accessibility term, and show that the resulting models have a better predictive power than currently available pairwise potentials. Furthermore, the model comparison method presented here allows one to measure the relative contribution of each component of the potential, and to choose the optimal number of accessibility classes, which turns out to be much higher than classically considered. CONCLUSION: Altogether, this reformulation makes it possible to test a wide diversity of models, using different forms of potentials, or accounting for other factors than just the constraint of thermodynamic stability. Ultimately, such model-based statistical analyses may help to understand the forces shaping protein sequences, and driving their evolution.

Amino Acid Sequence↗

PubMed1982

Liaison psychiatry-otolaryngology rounds.

In an attempt to define and resolve patient and staff needs with regard to the psychological, social and economic problems in clinical otolaryngology, psychiatry/otolaryngology rounds were established in the Department of Otolaryngology 18 months ago. These weekly rounds have contributed greatly to improved patient care and better physician-nurse relations. They have also served a significant educational role for residents, medical students and other members of the patient care team. At present the rounds are attended by the inpatient nursing staff, 2 physicians, 6 residents, 3 medical students, an otolaryngologic social worker and the liaison psychiatrist. The meeting begins with a 10 minute discussion and review of current problems among the staff. Attention is then directed to the patient who will be interviewed for the day. The medical and social history are presented. Then the patient is brought in and interviewed in a non-stressful session for 20 minutes. After the patient leaves, the staff discusses the problems which the patient has encountered or poses to them, and the conference participants formulate an appropriate therapeutic plan. Among the problems which have been discussed are noncompliance, organic mental syndromes, hypochondirasis, depression, death and dying, disfigurement, loss of bodily function, and chronic pain. For those patients in whom further psychiatric evaluation and treatment are deemed necessary, the psychiatrist becomes an active participant in their clinical care.

Adult↗

PubMedDate not supplied

[The concept of functional strength in the problem of establishing objective biomechanical requirements for systems to protect and rescue aircraft crews].

This paper discusses problems related to the ambiguous formulation of biomechanical requirements for the quality of protection and rescue means. In order to objectivize these requirements, it is recommended to use the functional strength concept which reflects both mechanical (with specific features characteristic of biomechanical systems taken into account) and functional results of adverse effects. The paper also describes the potential use of this parameter in developing complex requirements for various programmed and contingent situations and probability aspects of the problem of evaluating protection and rescue means.

Accidents, Aviation↗

PubMed1999

Application of high-order boundary elements to the electrocardiographic inverse problem.

Eight-noded quadrilateral boundary elements are applied to the electrocardiographic inverse problem as an example for high-order boundary elements. It is shown that the choice of the shape functions used for approximation of the potentials has a remarkable influence on the solution obtained if the number of electrodes is smaller than the number of primary source points (under-determined equation system). Three different formulations are investigated considering a concentric spheres problem where an analytic solution is available: (a) the isoparametric formulation; (b) the quasi-first-order formulation; and (c) the pseudo-subparametric formulation as a new method. In a second step the pseudo-subparametric formulation (which provided the best results in the test problem) is applied to real word data. The transmembrane potential pattern of a 40 years old female suffering from severe heart failure and ventricular tachycardia after large anterior wall myocardial infarction is reconstructed for one time instant. Furthermore, an algorithm for the calculation of the transfer matrix is presented which avoids restrictions to the boundary element mesh caused by the placement of the electrodes.

Adult↗

PubMed2005

A general formulation for a one-sided group sequential design.

BACKGROUND: A major contribution to the statistical literature on group sequential designs was provided by Pampallona and Tsiatis who developed closed form functions that can be used to iteratively calculate the boundary points of a family of popular group sequential designs. A related area of interest is the use of conditional probability calculations to make interim decisions in stochastic curtailment procedures. PURPOSE: The purpose of the paper is to develop group sequential designs based on conditional probabilities, to compare our results to the general closed form family of designs developed by Pampallona and Tsiatis, and to relate these to commonly used stochastic curtailment procedures. METHODS: The problem and its solution are formulated and derived mathematically. A graphical interpretation of the results provides the reader with an alternative mechanism to understand the results and their significance. RESULTS: One-sided group sequential design boundary points, as closed form functions, are derived from conditional probability statements. These conditional probability statements can be interpreted as the probability, at the final analysis, of reversing the conclusion reached at an interim state. Under mild constraints, these boundary points are identical to the Pampallona and Tsiatis boundary points. At any interim stage when a boundary point is attained or surpassed we suggest a graphical approach to examine the conditional probability of reversing the interim decision at the final stage versus a range of possible parameter values. For stochastic curtailment procedures, we recommend relaxing (increasing) the conditional probability levels to at least 0.50 so that early stopping is at least as likely as for the O'Brien-Fleming procedure. LIMITATIONS: The results are limited to one-sided group sequential designs. CONCLUSIONS: Conditional probabilities of reversing interim decisions provides a useful concept to develop group sequential designs and to evaluate stochastic curtailment procedures.

Breast Neoplasms↗

PubMed1980

Use of nondifferentiable optimization in a health care problem.

Those who study health care systems (HSC) seek to model the features of health care systems of societies that are common to different countries, so as to assist those who plan health services. The mathematicians interested in nondifferentiable optimization (NDO) seek to extend the classical optimization techniques to functions that have "non-smooth" regions where no unique gradient can be defined. This article reports how a health resource allocation model was solved by minimizing a function with points of nondifferentiability. It describes how an example of the model arose in the joint strategic planning of health and personal social services in a county in England with a population of about one million. It also formulates the model as a problem of NDO. Ways to obtain numerical solutions are reviewed, and the solution of the example by NDO is compared to another method based on linear approximation.

Aged↗

PubMed2001

Altered metabolite concentrations with amiodarone generic substitution cannot be observed without monitoring.

The use of amiodarone has grown rapidly, resulting in the marketing of several generic formulations. The adequacy of the testing used to approve these formulations as bioequivalent has been questioned, and mounting clinical evidence suggests that in some patients, substitution with generic amiodarone can cause serious problems. The effects of switching amiodarone formulations may take weeks to develop, leaving the relationship between the events unrecognized. In animal models, the toxicity of desethylamiodarone, an active metabolite partly formed during amiodarone absorption, is greater than that of its parent compound. High metabolite to amiodarone ratios have been associated with clinical toxicity. Because measuring serum amiodarone and metabolite is not standard clinical practice, aberrations after switching formulations will be missed. Major changes in metabolite concentrations were documented in four patients switched to a generic formulation, suggesting that the tests used for regulatory approval failed to identify the cumulative effects of differing excipients on amiodarone metabolism during absorption. Physicians should monitor patients for several months after a switch in amiodarone formulation is made. Regulatory criteria for bioequivalence of amiodarone need to be reconsidered.

Adult↗

PubMed1985

Difficult denture patients: observations and hypothesis.

The similarities between the HRC and the DDP have been presented. The HRC has been described by many investigators in the psychoanalytic literature. Indications are that both the HRC and the DDP are working through the same mechanism. The similarities are as follows: Both types of patients are driven by a need to seek treatment from someone they will ultimately reject. A self-fulfilling prophecy develops as a cycle leading to failure. Due to lack of trust and a desire to feel important, the patient creates an atmosphere that leads to discord, hostility, anger, and frustration. Resultant discord leads to the establishment of a relationship that demands much time and energy from the helper. The helper is ultimately manipulated into a no-win situation that ends with the helper dismissing the patient, thereby completing the patient's self-fulfilling prophecy. Recurrent stress in the patient's life recycles the drive force and the need for treatment and attention starts all over again. With greater understanding of the DDP's problems, management solutions could be formulated. Management techniques might include an initial interview with trust-building strategies, the reassurance to the patient of the uniqueness of his situation to neutralize the need to create a crisis for his own identity; and challenges to point out the hopelessness of their position to activate the patient's need to prove the helper wrong. Finally, in addition to management of the patient, techniques can be developed to identify the DDP with HRC tendencies. Proper recognition and diagnosis before treatment begins can prevent many problems associated with these patients and prevent stress and discord for both dentist and patients.

Consumer Behavior↗

PubMed1994

Evidence-based care: 2. Setting guidelines: how should we manage this problem?

There are four steps in determining how to manage a clinical problem. The first is to formulate questions that are answerable; the second is to locate and synthesize the evidence needed to answer the questions; the third is to estimate the expected benefits, harms and costs of each option based on the evidence; and the fourth is to judge the relative value of the expected outcomes to conclude whether the benefits are worth the harms and costs. It is impractical to repeat these steps for every clinical decision. Therefore, implicitly or explicitly, physicians rely on guidelines, "rules" that simplify decision making about complex problems. If the methods used to develop a guideline are not explicit it is difficult or impossible to know how much confidence to place in it. Therefore, for common and important clinical problems, physicians should rely on guidelines that are systematically developed using explicit methods.

Adult↗

PubMed2000

How unspecified are disorders of children with a pervasive developmental disorder not otherwise specified? A study of social problems in children with PDD-NOS and ADHD.

This study examines possible differences and similarities between social behaviour problems in children with problems classified as pervasive developmental disorder not otherwise specified (PDD-NOS) and a group of children with problems classified as ADHD, as measured by parent questionnaires. The instruments involved were the CBCL (Child Behaviour Checklist), the ABC (Autism Behaviour Checklist) and a new instrument: the CSBQ (Children's Social Behaviour Questionnaire). In comparing the PDD-NOS group and the ADHD group, the results show that, according to parent reports, both groups have severe problems in executing appropriate social behaviour, but the PDD-NOS group can be distinguished from the ADHD group by the nature and the extent of these problems. The PDD-NOS group had significantly more social problems (as measured by the CBCL Social scale), withdrawn problems (as measured by the CBCL Withdrawn scale) and PDD-specific problems (as measured on the ABC Relating scale, the ABC Language scale, the CSBQ total score, the CSBQ Social Interaction scale and CBSQ Communication scale). In addition, although the descriptions of the social problems are global, i.e. on scale level, the results also show that the social problems of PDD-NOS children can be positively formulated and described as at least including severe social interaction problems, withdrawn behaviours and communication problems.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

The reliability and quality of cognitive case formulation.

Limited research on the reliability of cognitive case formulation suggests cognitive therapists can agree about clients' presenting problems but show poor agreement about the inferential aspects of formulation. There has been no research examining the quality of practitioners' case formulations. This study assessed whether participants with different levels of experience could produce reliable cognitive formulations using a systematic cognitive therapy case formulation method: the J. Beck Case Conceptualization Diagram. As part of continuing education workshops on cognitive case formulation, 115 mental health practitioners were given the same case description and asked to provide case formulations. Inter-rater agreement and agreement with a "benchmark" formulation provided by J. Beck were measured. The results showed that participants were able to agree with each other and with the benchmark on most descriptive aspects of the formulation but rates of agreement decreased for aspects of the formulation requiring greater levels of theory-driven inference. Based on definitions and measurements of the quality of cognitive formulations derived in this study, the quality of formulations ranged from very poor to good, with only 44% rated as being at least good enough. Both reliability and quality of case formulations were associated with levels of clinical experience and accreditation status. Implications for training and supervision are discussed.

Accreditation↗

PubMed2002

Application of direct methods to protein crystallographic phase extension.

An alternative formulation of direct methods for phase refinement using the sign probability originally introduced for breaking the phase ambiguity intrinsic in single isomorphous replacement or single-wavelength anomalous diffraction data has been proposed. This formulation can incorporate known phase information through constrained phase refinement. This formulation was tested by application to the phase-extension problem using experimental data. The results showed that this formulation was valid and promising for designing better methods for phase extension.

Algorithms↗

PubMed1993

Can analysts agree? The problems of consensus and the psychoanalytic mannequin: I. A proposed solution.

Psychoanalysis, plagued by lack of demonstrable consensus on clinical formulations, is as much endangered by overinflated agreement from stereotypical dynamic formulas: tests of psychoanalytic hypotheses derived from any such formulations may therefore rest on questionable foundations. The problems that give rise to artifactual overagreement or failure to reach agreement are here traced in earlier empirical psychoanalytic research. Review reveals that although new and inventive empirical strategies (applied in the last two decades) achieve adequate success in the area of agreement, they demonstrate little headway in ruling out that stereotypy may underlie such consensus. The present investigation offers a solution for testing agreement in complex clinical psychoanalytic propositions, in a way that sets up a "test of the mannequin": that is, whether stereotypical assumptions about the patient's dynamics are overridden (revised) by the specific character of a given patient's narrative. The mannequin concept introduces a new and epistemically crucial consideration in the making of psychodynamic formulations and is relevant to both empirically controlled and clinical contexts of observation and formulation. No psychoanalytic paradigm, whether classically ego-psychological, self-psychological, control-mastery, or object-relational, escapes this problem.

Humans↗

PubMed2003

On the dynamic stiffness of preloaded vibration isolators in the audible frequency range: modeling and experiments.

The nonlinear, preload-dependent dynamic stiffness of a cylindrical vibration isolator is examined via measurements and modeling within an audible frequency range covering 50 to 1000 Hz at various preloads. The stiffness is found to depend strongly on frequency-resulting in peaks and troughs, and on preload-particularly above 500 Hz. The problems of simultaneously modeling the rubber prestrain dependence and its audible short-term response are removed by adopting a nearly incompressible material model, being elastic in dilatation while displaying viscoelasticity in deviation. The latter exhibits a time strain separable relaxation tensor with a single function embodying its time dependence. This function is based on a continuous fractional order derivative model, the main advantage being the minimum number of parameters required to successfully model the rubber properties over a broad structure-borne sound frequency domain, while embodying a continuous distribution of relaxation time. The weak formulations corresponding to the stiffness problem are solved by an updated Lagrangian nonlinear finite-element procedure. The model and measurement results agree strikingly well with static and dynamic measurements throughout the whole frequency domain for the examined preloads.

Journal Article↗

PubMedDate not supplied

Pain management. Theological and ethical principles governing the use of pain relief for dying patients. Task Force on Pain Management, Catholic Health Association.

Pain management is a societal problem because of concerns about the use of drugs, the belief that patients are not good judges of the severity of their pain, and an alarming level of ignorance about pain and its treatment among physicians, nurses, and other healthcare providers. The result is that patients suffer pain unnecessarily, even up to the point of their death. Pain management is also a clinical-practice problem. Courses in pain and symptom management are not readily available to medical and nursing students. And in clinical practice, good pain assessment is not easy to accomplish because pain is so subjective. Fortunately, with education, doctors and nurses can vastly improve their ability to assess and manage patients' pain. Additional problems in pain management relate to the manner in which healthcare is provided today: an acute disease-oriented model of hospital care, frequent transfers, fragmented care, inadequate reimbursement, market forces that drive up costs, and maldistribution of clinical services. In improving their ability to manage pain, professionals must understand the difference between pain and suffering, acute and chronic pain, and the sensory and emotional aspects of pain. Guiding principles include Church teaching and ethical principles, such as patient self-determination, holistic care, the principle of beneficence, distributive justice, and the common good. Pain management strategies that will be instrumental in formulating effective responses to these problems include expanding professional and community education, affording pain funding priority, establishing institutional policies and protocols, forming clinical teams, encouraging hospice and home care, and requiring accreditation in pain and symptom management.

Attitude of Health Personnel↗

PubMed2004

Multivariate spline interpolation as a novel method to optimize pharmaceutical formulations.

One of the difficulties in the quantitative approach for formulation design is the difficulty in understanding the actual relationship between causal factors and individual pharmaceutical responses. In this regard, several techniques were applied to determine the relationship between causal factors and the pharmaceutical responses. The generation of response surfaces using multivariate spline interpolation (MSI) has provided rapid and detailed information. Nevertheless, no application of MSI in the pharmaceutical field has been reported to date, even though it promises potential applications. To overcome the shortcomings of the classical response surface method, we newly developed a multi-objective simultaneous optimization method, in which MSI had been incorporated. The method was applied to the optimization problem of a transdermal hydrogel formulation for ketoprofen containing several chemical enhancers. Results suggested a superior function of the MSI approach.

Administration, Topical↗

PubMed2005

An ant colony optimisation algorithm for the 2D and 3D hydrophobic polar protein folding problem.

BACKGROUND: The protein folding problem is a fundamental problems in computational molecular biology and biochemical physics. Various optimisation methods have been applied to formulations of the ab-initio folding problem that are based on reduced models of protein structure, including Monte Carlo methods, Evolutionary Algorithms, Tabu Search and hybrid approaches. In our work, we have introduced an ant colony optimisation (ACO) algorithm to address the non-deterministic polynomial-time hard (NP-hard) combinatorial problem of predicting a protein's conformation from its amino acid sequence under a widely studied, conceptually simple model - the 2-dimensional (2D) and 3-dimensional (3D) hydrophobic-polar (HP) model. RESULTS: We present an improvement of our previous ACO algorithm for the 2D HP model and its extension to the 3D HP model. We show that this new algorithm, dubbed ACO-HPPFP-3, performs better than previous state-of-the-art algorithms on sequences whose native conformations do not contain structural nuclei (parts of the native fold that predominantly consist of local interactions) at the ends, but rather in the middle of the sequence, and that it generally finds a more diverse set of native conformations. CONCLUSIONS: The application of ACO to this bioinformatics problem compares favourably with specialised, state-of-the-art methods for the 2D and 3D HP protein folding problem; our empirical results indicate that our rather simple ACO algorithm scales worse with sequence length but usually finds a more diverse ensemble of native states. Therefore the development of ACO algorithms for more complex and realistic models of protein structure holds significant promise.

Algorithms↗

PubMed1986

Formal connections between lightness algorithms.

The computational problem underlying color vision is to recover the invariant surface-spectral-reflectance properties of an object. Lightness algorithms, which recover an approximation to surface reflectance in independent wavelength channels, have been proposed as one method to compute color. This paper clarifies and formalizes the lightness problem by proposing a new formulation of the intensity equation on which lightness algorithms are based and by identifying and discussing two basic subproblems of lightness and color computation: spatial decomposition and spectral normalization of the intensity signal. Several lightness algorithms are reviewed, and a new extension (the multiple-scales algorithm) of one of them is proposed. The main computational result is that each of the lightness algorithms may be derived from a single mathematical formula, under different conditions, which, in turn, imply limitations for the implementation of lightness algorithms by man or machine. In particular, the algorithms share certain limitations on their implementation that follow from the physical constraints imposed on the statement of the problem and the boundary conditions applied in its solution.

Algorithms↗