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1.  When the truth isn’t too hard to handle: An event-related potential study on the pragmatics of negation 
Psychological science  2008;19(12):1213-1218.
Our brains rapidly map incoming language onto what we hold to be true. Yet there are claims that such integration and verification processes are delayed in sentences containing negation words like ‘not’. However, research studies have often confounded whether a statement is true and whether it is natural thing to say during normal communication. In an event-related potential (ERP) experiment, we aimed to disentangle effects of truth-value and pragmatic licensing on the comprehension of affirmative and negated real-world statements. As in affirmative sentences, false words elicited a larger N400 ERP than true words in pragmatically licensed negated sentences (e.g., “In moderation, drinking red wine isn’t bad/good…”), whereas true and false words elicited similar responses in unlicensed negated sentences (e.g., “A baby bunny’s fur isn’t very hard/soft…”). These results suggest that negation poses no principled obstacle for readers to immediately relate incoming words to what they hold to be true.
PMCID: PMC3225068  PMID: 19121125
Multidetector contrast enhanced computed tomography with acquisition of 0.625-mm thick transverse images was used to measure the extent of appendicular osteosarcoma in 10 dogs. The measured length of tumor based on CT was compared to the true length of tumor using histopathology. There was a statistically significant association with good correlation between the true length of osteosarcoma compared to the length of intramedullary/endosteal abnormalities on CT with a mean overestimation of 1.8% (SD = 15%). There was not a statistically significant association between the true tumor length and the length of periosteal proliferation on CT with a mean overestimation of 9.7% (SD = 30.3%). There was a statistically significant association, but with poor correlation, between the true tumor length compared to the length of abnormal contrast enhancement with a mean overestimation of 9.6% (SD = 34.8%). The extent of intramedullary/endosteal CT abnormalities assessed from submillimeter transverse images may be of value in assessing patient candidacy and surgical margins for limb-sparing surgery
PMCID: PMC3868340  PMID: 22413965
canine; computed tomography; CT; dog; OSA; osteosarcoma; multidetector
3.  Right and Righteous: Children’s Incipient Understanding and Evaluation of True and False Statements 
Two studies examined young children’s early understanding and evaluation of truth-telling and lying, and the role that factuality plays in their judgments. Study 1 (104 2- to 5-year-olds) found that even the youngest children reliably accepted true statements and rejected false statements, and that older children’s ability to label true and false statements as “truth” and “lie” emerged in tandem with their positive evaluation of true statements and “truth” and their negative evaluation of false statements and “lie.” The findings suggest that children’s early preference for factuality develops into a conception of “truth” and “lie” that is linked both to factuality and moral evaluation. Study 2 (128 3- to 5-year-olds) found that, whereas young children exhibited good understanding of the association of true and false statements with “truth,” “lie,” “mistake,” “right,” and “wrong,” they showed little awareness of assumptions about speaker knowledge underlying “lie” and “mistake.” The results further support the primacy of factuality in children’s early understanding and evaluation of truth and lies.
PMCID: PMC3891696  PMID: 24436637
4.  Anterior tibial artery aneurysm: Case report and literature review 
We present a patient with a true anterior tibial artery aneurysm without any causative history.
A 59 year old male was referred with a swelling on his left lateral ankle which he noticed 2 months ago, with symptoms of soaring pain. Additional radiological research showed a true arterial tibialis anterior aneurysm. True anterior tibial artery aneurysm is a rare condition. The aneurysm was repaired by resection and interposition of a venous bypass.
Patients may complain about symptoms like calf pain, distal ischemia, paresthesias due to nerve compression and the presence of a pulsating or increasing mass. Symptomatic aneurysms require surgical intervention, where bypass with a venous saphenous graft have shown good patency and endovascular treatment have shown good short term results. Asymptomatic and small aneurysm can be followed for several years with DUS.
Clinical features, radiographic findings, surgical management, and a review of the literature on true anterior tibial aneurysms are discussed.
PMCID: PMC3604659  PMID: 23333847
Arteria tibialis anterior; True aneurysm; Aneurysm
5.  Speciality interests and career calling to medicine among first-year medical students 
The construct of calling has recently been applied to the vocation of medicine. We explored whether medical students endorse the presence of a calling or a search for a calling and how calling related to initial speciality interest. 574 first-year medical students (84 % response rate) were administered the Brief Calling Survey and indicated their speciality interest. For presence of a calling, the median response was mostly true for: ‘I have a calling to a particular kind of work’ and moderately true for: ‘I have a good understanding of my calling as it applies to my career’. For search for a calling, median response was mildly true: ‘I am trying to figure out my calling in my career’ and ‘I am searching for my calling as it applies to my career’. Mann–Whitney U (p < 0.05) results indicate that students interested in primary care (n = 185) versus non-primary care (n = 389) are more likely to endorse the presence of a calling. Students were more likely to endorse the presence of a calling rather than a search for a calling, with those interested in primary care expressing stronger presence of a calling to medicine.
PMCID: PMC3576487  PMID: 23670652
Speciality; Calling; Medical students; Career
6.  Balancing the Role of Priors in Multi-Observer Segmentation Evaluation 
Journal of signal processing systems  2008;55(1-3):185-207.
Comparison of a group of multiple observer segmentations is known to be a challenging problem. A good segmentation evaluation method would allow different segmentations not only to be compared, but to be combined to generate a “true” segmentation with higher consensus. Numerous multi-observer segmentation evaluation approaches have been proposed in the literature, and STAPLE in particular probabilistically estimates the true segmentation by optimal combination of observed segmentations and a prior model of the truth. An Expectation–Maximization (EM) algorithm, STAPLE’S convergence to the desired local minima depends on good initializations for the truth prior and the observer-performance prior. However, accurate modeling of the initial truth prior is nontrivial. Moreover, among the two priors, the truth prior always dominates so that in certain scenarios when meaningful observer-performance priors are available, STAPLE can not take advantage of that information. In this paper, we propose a Bayesian decision formulation of the problem that permits the two types of prior knowledge to be integrated in a complementary manner in four cases with differing application purposes: (1) with known truth prior; (2) with observer prior; (3) with neither truth prior nor observer prior; and (4) with both truth prior and observer prior. The third and fourth cases are not discussed (or effectively ignored) by STAPLE, and in our research we propose a new method to combine multiple-observer segmentations based on the maximum a posterior (MAP) principle, which respects the observer prior regardless of the availability of the truth prior. Based on the four scenarios, we have developed a web-based software application that implements the flexible segmentation evaluation framework for digitized uterine cervix images. Experiment results show that our framework has flexibility in effectively integrating different priors for multi-observer segmentation evaluation and it also generates results comparing favorably to those by the STAPLE algorithm and the Majority Vote Rule.
PMCID: PMC2879662  PMID: 20523759
Ground truth; Bayesian decision; Precision; Segmentation; Multi-observer; Sensitivity; Specificity; STAPLE; Validation
7.  Testing the Calibration of Classification Models from First Principles 
The accurate assessment of the calibration of classification models is severely limited by the fact that there is no easily available gold standard against which to compare a model’s outputs. The usual procedures group expected and observed probabilities, and then perform a χ2 goodness-of-fit test. We propose an entirely new approach to calibration testing that can be derived directly from the first principles of statistical hypothesis testing. The null hypothesis is that the model outputs are correct, i.e., that they are good estimates of the true unknown class membership probabilities. Our test calculates a p-value by checking how (im)probable the observed class labels are under the null hypothesis. We demonstrate by experiments that our proposed test performs comparable to, and sometimes even better than, the Hosmer-Lemeshow goodness-of-fit test, the de facto standard in calibration assessment.
PMCID: PMC3540450  PMID: 23304285
8.  Performance of a commercial polymerase chain reaction test for endocervical Chlamydia trachomatis infection in a university hospital population. 
OBJECTIVES: To examine the accuracy of a commercial polymerase chain reaction (PCR) test (Amplicor CTR, Roche Diagnostic Systems, Branchburg NJ) for identification of endocervical chlamydial infections through both laboratory evaluation and among a diverse teaching hospital patient population. METHODS: Testing of reliable threshold inocula and reproducibility were carried out using laboratory stock organisms. Paired endocervical samples from patients with a wide range of indications were tested by PCR and an established culture procedure, and discrepant pairs were further analyzed to determine true results. RESULTS: Laboratory evaluation suggested that one copy of target DNA from a viable organism consistently yielded a positive result, and test reproducibility was very good, with an overall coefficient of variation of 15%. Compared to true results in 1,588 paired clinical samples from 1,489 women with a 10% prevalence of infection, the PCR test and culture yielded respective sensitivities of 87.4% and 78.0%, and negative predictive values of 98.6% and 97.6%. Specificity and positive predictive value for both tests were 100%. Cost per specimen was nearly identical at $18.84 and $18.88 respectively. Polymerase inhibitors and organisms lacking target DNA were not found in false-negative PCR samples. CONCLUSION: This commercial PCR test is accurate, cost-competitive, and much faster than culture for diagnosis of endocervical chlamydia infections in our population of intermediate prevalence of chlamydial infection.
PMCID: PMC1784812  PMID: 9894178
9.  Biosynthesis of Biotin in Microorganisms V. Control of Vitamer Production 
Journal of Bacteriology  1967;94(6):1846-1853.
Use of a yeast-lactobacillus differential microbiological assay permitted investigation into the synthesis of biotin vitamers by a variety of bacteria. A major portion of the biotin activity was found extracellularly. The level of total biotin (assayable with yeast) greatly exceeded the level of true biotin (assayed with lactobacillus). Values for intracellular biotin generally showed good agreement between the assays, suggesting the presence of only true biotin within the cells. Bioautographic analysis of the medium after growth of each organism revealed the presence of large amounts of a vitamer which corresponded to dl-desthiobiotin on the basis of Rf value and biological activity. Biotin, when detected at all, was at very low concentrations. Also, an avidin-uncombinable vitamer was synthesized by a majority of the bacteria. Addition of d-biotin to the growth medium prevented completely the synthesis of both vitamers of biotin. d-Biotin-d-sulfoxide had no effect on the synthesis of desthiobiotin or the avidin-uncombinable vitamer. Addition of dl-desthiobiotin did not prevent its own synthesis nor that of the other vitamer. Control of vitamer synthesis is therefore highly specific for d-biotin. The avidin-uncombinable vitamer was produced only at repressed levels in the presence of high concentrations of both d-biotin and dl-desthiobiotin, which suggested that it is not a degradation product of these substances. A possible mechanism for the overproduction of the biosynthetic precursors of biotin is presented.
PMCID: PMC276913  PMID: 4965364
10.  Use of 129caesium, 99Tcm stannous pyrophosphate, and a combination of the two in the assessment of myocardial infarction. 
British Heart Journal  1978;40(8):874-882.
Acutely damaged myocardium was shown in 103 patients with suspected acute myocardial infarction using 99Tcm pyp. A significant incidence of false positive and false negative results occurred, 'true' results being defined by standard clinical, electrocardiographic, and enzyme criteria. Localisation of infarction compared reasonably well with standard electrocardiographic criteria but more frequently suggested true posterior involvement. Serial estimates of infarct size may be of value in the recognition of infarct extension during the acute phase. Viable perfused myocardium was shown in 63 patients with a variety of cardiac disorders using 129Cs. The technique gives a reliable indication of anterior infarction but tends to underestimate inferior infarction. There was good correlation with the electrocardiogram with regard to localisation and extent of infarction. Nineteen patients received both isotopes and were included in each of the above groups. The combination permits further assessment of equivocal results Furthermore as 129Cs demonstrates both previous and recent infarction and 99Tcm pyp accumulates only in acutely damaged myocardium it was possible to estimate the extent of previous and recent myocardial damage.
PMCID: PMC483502  PMID: 687489
11.  Cardiac tumours simulating collagen vascular disease. 
British Heart Journal  1986;55(6):592-595.
Cardiac tumours can mimic collagen vascular disease and they are often accompanied by profound systemic upset. Both benign and malignant tumours may present in this way. Three cases of cardiac tumour, two malignant and one benign, are reported with just such a presentation. A review of fifteen similar case reports showed that a spectrum of different collagen vascular diseases was diagnosed and treated before the true diagnosis emerged. In half of these cases the cardiac tumour was only diagnosed at necropsy. The diagnosis of collagen vascular disease should not be made in the absence of corroborative laboratory data. In cases of malignant cardiac tumour, and less commonly with atrial myxoma, M mode and cross sectional echocardiography may not exclude the diagnosis. There may be a good response to steroid treatment in cases of suspected but not confirmed collagen vascular disease in which the true diagnosis is cardiac tumour.
PMCID: PMC1236767  PMID: 3718799
12.  Surgery of post-myocardial infarction scars. Early and late results in 70 patients. 
British Heart Journal  1980;43(4):436-439.
Immediate and late postoperative results in 70 patients undergoing resection of a true left ventricular aneurysm (50 patients) and of an asynergic area (20 patients) are presented. The operative mortality was 14 per cent. Predicted survival by actuarial methods was 80 per cent at one year after operation and 65 per cent at six years. Functional improvement was obvious with most of the survivors falling in NYHA class I or II. Factors influencing operative mortality were the clinical indication for operation and the anatomical lesion. Late postoperative results were better for true aneurysms than for asynergic areas. An asynergic area was usually associated with multiple coronary vessel lesions and a diffusely ischaemic myocardium. An aneurysm was often associated with a single coronary vessel disease and with good function of the non-infarcted myocardiun.
PMCID: PMC482307  PMID: 7397043
13.  A two-step approach combining the Gompertz growth model with genomic selection for longitudinal data 
BMC Proceedings  2010;4(Suppl 1):S4.
We used the Gompertz growth curve to model a simulated longitudinal dataset provided by the QTLMAS2009 workshop and applied genomic evaluation to the derived model parameters and to a model-predicted trait value.
Prediction of phenotypic information from the Gompertz curve allowed us to obtain genomic breeding value estimates for a time point with no phenotypic records. Despite that the true model used to simulate the data was the logistic growth model, the Gompertz model provided a good fit of the data. Genomic breeding values calculated from predicted phenotypes were highly correlated with the breeding values obtained by directly using the respective observed phenotypes. The accuracies between the true and estimated breeding value at time 600 were above 0.93, even though t600 was outside the time range used when fitting the data. The analysis of the parameters of the Gompertz curve successfully discriminated regions with QTL affecting the asymptotic final value, but it was less successful in finding QTL affecting the other parameters of the logistic growth curve. In this study we estimated the proportion of SNPs affecting a given trait, in contrast with previously reported implementations of genomic selection in which this parameter was assumed to be known without error.
The two-step approach used to combine curve fitting and genomic selection on longitudinal data provided a simple way for combining these two complex tasks without any detrimental effect on breeding value estimation.
PMCID: PMC2857846  PMID: 20380758
14.  Openness versus Secrecy in Scientific Research Abstract 
Episteme (Edinburgh)  2006;2(3):135-147.
Openness is one of the most important principles in scientific inquiry, but there are many good reasons for maintaining secrecy in research, ranging from the desire to protect priority, credit, and intellectual property, to the need to safeguard the privacy of research participants or minimize threats to national or international security. This article examines the clash between openness and secrecy in science in light of some recent developments in information technology, business, and politics, and makes some practical suggestions for resolving conflicts between openness and secrecy.
“By academic freedom I understand the right to search for the truth and to publish and teach what one holds to be true. This right also implies a duty; one must not conceal any part of what one has recognized to be true. It is evident that any restriction of academic freedom serves to restrain the dissemination of knowledge, thereby impeding rational judgment and action.”
Albert Einstein, quotation inscribed on his statute in front of the National Academy of Sciences, Washington, DC.
PMCID: PMC2991133  PMID: 21113394
15.  ‘SGoFicance Trace’: Assessing Significance in High Dimensional Testing Problems 
PLoS ONE  2010;5(12):e15930.
Recently, an exact binomial test called SGoF (Sequential Goodness-of-Fit) has been introduced as a new method for handling high dimensional testing problems. SGoF looks for statistical significance when comparing the amount of null hypotheses individually rejected at level γ = 0.05 with the expected amount under the intersection null, and then proceeds to declare a number of effects accordingly. SGoF detects an increasing proportion of true effects with the number of tests, unlike other methods for which the opposite is true. It is worth mentioning that the choice γ = 0.05 is not essential to the SGoF procedure, and more power may be reached at other values of γ depending on the situation. In this paper we enhance the possibilities of SGoF by letting the γ vary on the whole interval (0,1). In this way, we introduce the ‘SGoFicance Trace’ (from SGoF's significance trace), a graphical complement to SGoF which can help to make decisions in multiple-testing problems. A script has been written for the computation in R of the SGoFicance Trace. This script is available from the web site
PMCID: PMC3012107  PMID: 21209966
16.  Evaluation of diagnostic accuracy in detecting ordered symptom statuses without a gold standard 
Biostatistics (Oxford, England)  2011;12(3):567-581.
Our research is motivated by 2 methodological problems in assessing diagnostic accuracy of traditional Chinese medicine (TCM) doctors in detecting a particular symptom whose true status has an ordinal scale and is unknown—imperfect gold standard bias and ordinal scale symptom status. In this paper, we proposed a nonparametric maximum likelihood method for estimating and comparing the accuracy of different doctors in detecting a particular symptom without a gold standard when the true symptom status had an ordered multiple class. In addition, we extended the concept of the area under the receiver operating characteristic curve to a hyper-dimensional overall accuracy for diagnostic accuracy and alternative graphs for displaying a visual result. The simulation studies showed that the proposed method had good performance in terms of bias and mean squared error. Finally, we applied our method to our motivating example on assessing the diagnostic abilities of 5 TCM doctors in detecting symptoms related to Chills disease.
PMCID: PMC3114651  PMID: 21209155
Bootstrap; Diagnostic accuracy; EM algorithm; MSE; Ordinal tests; Traditional Chinese medicine (TCM); Volume under the ROC surface (VUS)
17.  Ultrasound Reference Chart Based on IVF Dates to Estimate Gestational Age at 6–9 weeks' Gestation 
ISRN Obstetrics and Gynecology  2012;2012:938583.
Accurate determination of gestational age underpins good obstetric care. We assessed the performance of six existing ultrasound reference charts to determine gestational age in 1268 singleton IVF pregnancies, where “true” gestational age could be precisely calculated from date of fertilisation. All charts generated dates significantly different to IVF dates (P < 0.0001 all comparisons). Thus we generated a new reference chart, The Monash Chart, based on a line of best fit describing crown-rump length across 6 + 1 to 9 + 0 weeks of gestation (true gestational age) in the IVF singleton cohort. The Monash Chart, but none of the existing charts, accurately determined gestational age among an independent IVF twin cohort (185 twin pairs). When applied to 3052 naturally-conceived singletons scans, The Monash Chart generated estimated due dates that were different to all existing charts (P ≤ 0.004 all comparisons). We conclude that commonly used ultrasound reference charts have inaccuracies. We have generated a CRL reference chart based on true gestational age in an IVF cohort that can accurately determine gestational age at 6–9 weeks of gestation.
PMCID: PMC3409520  PMID: 22888449
18.  Pancreatic Cystic Neoplasms: Predictors of Malignant Behavior and Management 
Pancreatic cystic neoplasms are being increasingly identified with the widespread use of advanced imaging techniques. In the absence of a good radiologic or pathologic test to preoperatively determine the dianosis, clinical characteristics might be helpful. The objectives of this analysis were to define the incidence and predictors of malignancy in pancreatic cysts.
Patients and Methods:
Patients with true pancreatic cysts who were treated at our institution were included. Patients with documented pseudocysts were excluded. Demographic data, clinical manifestations, radiological, surgical, and pathological records of those patients were reviewed.
Eighty-one patients had true pancreatic cyst. The mean age was 47 ± 15.5 years. There were 28.4% serous cystadenoma, 21% mucinous cystadenoma, 6.2% intraductal papillary tumors, 8.6% solid pseudopapillary tumors, 1.2% neuroendocrinal tumor, 3.7% ductal adenocarcinoma, and 30.9% mucinous cystadenocarcinoma. Malignancy was significantly associated with men (P = 0.04), older age (0.0001), cysts larger than 3 cm in diameter (P = 0.001), presence of solid component (P = 0.0001), and cyst wall thickening (P = 0.0001). The majority of patients with malignancy were symptomatic (26/28, 92.9%). The symptoms that correlated with malignancy included abdominal pain (P = 0.04) and weight loss (P = 0.0001). Surgical procedures were based on the location and extension of the lesion.
The most common pancreatic cysts were serous and mucinous cysts. These tumors were more common in females. Old age, male gender, large tumor, presence of solid component, wall thickness, and presence of symptoms may predict malignancy in the cyst.
PMCID: PMC3603490  PMID: 23319038
Cystadenocarcinoma; cystadenoma; enucleation; pancreatic cyst; pseudocyst
19.  Statistical Methods for Evaluating DNA Methylation as a Marker for Early Detection or Prognosis 
Disease Markers  2007;23(1-2):113-120.
We summarize standard and novel statistical methods for evaluating the classification accuracy of DNA methylation markers. The choice of method will depend on the type of marker studied (qualitative/quantitative), the number of markers, and the type of outcome (time-invariant/time-varying). A minimum of two error rates are needed for assessing marker accuracy: the true-positive fraction and the false-positive fraction. Measures of association that are computed from the combination of these error rates, such as the odds ratio or relative risk, are not informative about classification accuracy. We provide an example of a DNA methylation marker that is strongly associated with time to death (logrank p = 0.0003) that is not a good classifier as evaluated by the true-positive and false-positive fractions. Finally, we would like to emphasize the importance of study design. Markers can behave differently in different groups of individuals. It is important to know what factors may affect the accuracy of a marker and in which subpopulations the marker may be more accurate. Such an understanding is extremely important when comparing marker accuracy in two groups of subjects.
PMCID: PMC3850861  PMID: 17325431
Sensitivity; specificity; ROC curves; survival data
20.  Quantitative analysis of EGR proteins binding to DNA: assessing additivity in both the binding site and the protein 
BMC Bioinformatics  2005;6:176.
Recognition codes for protein-DNA interactions typically assume that the interacting positions contribute additively to the binding energy. While this is known to not be precisely true, an additive model over the DNA positions can be a good approximation, at least for some proteins. Much less information is available about whether the protein positions contribute additively to the interaction.
Using EGR zinc finger proteins, we measure the binding affinity of six different variants of the protein to each of six different variants of the consensus binding site. Both the protein and binding site variants include single and double mutations that allow us to assess how well additive models can account for the data. For each protein and DNA alone we find that additive models are good approximations, but over the combined set of data there are context effects that limit their accuracy. However, a small modification to the purely additive model, with only three additional parameters, improves the fit significantly.
The additive model holds very well for every DNA site and every protein included in this study, but clear context dependence in the interactions was detected. A simple modification to the independent model provides a better fit to the complete data.
PMCID: PMC1184061  PMID: 16014175
21.  Assessment of the accuracy and role of self-recorded blood pressures in the management of hypertension. 
Self-recording of the blood pressure by patients away from hospital or office ("home blood pressure") has been advocated as providing a better estimate of "true" blood pressure. The reliability of home blood-pressure recording has been assessed only by standard indirect methods which themselves are subject to considerable error and variability. The accuracy of self-recorded blood pressures was therefore assessed in 57 patients with essential hypertension by comparison with simultaneous measurements of clinic blood pressures and with intra-arterial blood pressures recorded at home and at hospital. Home systolic blood pressures showed good agreement with clinic and intra-arterial pressures, but home diastolic blood pressures overestimated intra-arterial pressures, as did clinic diastolic pressures. The clinic and home diastolic pressures showed good agreement. There was considerable variability in individual differences comparing the indirect and intra-arterial methods, though the two indirect methods showed much closer agreement. This study suggests that home blood pressures are as accurate as clinic readings but may be recorded more frequently and thus provide more useful information. Neither is likely to approximate the intra-arterial blood pressure.
PMCID: PMC1500674  PMID: 6816333
22.  Comprehensive Evaluation of Protein Structure Alignment Methods: Scoring by Geometric Measures 
Journal of molecular biology  2005;346(4):1173-1188.
We report the largest and most comprehensive comparison of protein structural alignment methods. Specifically, we evaluate six publicly available structure alignment programs: SSAP, STRUCTAL, DALI, LSQMAN, CE and SSM by aligning all 8,581,970 protein structure pairs in a test set of 2930 protein domains specially selected from CATH v.2.4 to ensure sequence diversity.
We consider an alignment good if it matches many residues, and the two substructures are geometrically similar. Even with this definition, evaluating structural alignment methods is not straightforward. At first, we compared the rates of true and false positives using receiver operating characteristic (ROC) curves with the CATH classification taken as a gold standard. This proved unsatisfactory in that the quality of the alignments is not taken into account: sometimes a method that finds less good alignments scores better than a method that finds better alignments. We correct this intrinsic limitation by using four different geometric match measures (SI, MI, SAS, and GSAS) to evaluate the quality of each structural alignment. With this improved analysis we show that there is a wide variation in the performance of different methods; the main reason for this is that it can be difficult to find a good structural alignment between two proteins even when such an alignment exists.
We find that STRUCTAL and SSM perform best, followed by LSQMAN and CE. Our focus on the intrinsic quality of each alignment allows us to propose a new method, called “Best-of-All” that combines the best results of all methods. Many commonly used methods miss 10–50% of the good Best-of-All alignments.
By putting existing structural alignments into proper perspective, our study allows better comparison of protein structures. By highlighting limitations of existing methods, it will spur the further development of better structural alignment methods. This will have significant biological implications now that structural comparison has come to play a central role in the analysis of experimental work on protein structure, protein function and protein evolution.
PMCID: PMC2692023  PMID: 15701525
comparison of structural alignment; protein structure alignment; protein structure comparison; geometric measures; ROC curves
23.  From evidence to action 
Acta Orthopaedica  2009;80(1):113-118.
ABSTRACT Good guidelines will help us to take evidence into practice. In a survey among Dutch orthopedic surgeons, development and use of evidence-based guidelines was perceived as one of the best ways of moving from opinion-based to evidence-based orthopedic practice. The increasing number of guidelines means that knowing how to make a critical appraisal of guidelines is now a key part of every surgeon’s life. This is particularly true because guidelines use varying systems to judge the quality of evidence and the strength of recommendations. In this manuscript we discuss what a guideline is, where we can find guidelines, how to evaluate the quality of guidelines, and finally provide an example on the different steps of guideline development. Thus, we show that good guidelines are a summary of the best available evidence and that they provide a graded recommendation to help surgeons in evidence-based practice.
PMCID: PMC2823247  PMID: 19234892
24.  The evolution of judgement bias in indirect reciprocity 
Indirect reciprocity is a form of reciprocity where help is given to individuals based on their reputation. In indirect reciprocity, bad acts (such as not helping) reduce an individual's reputation while good acts (such as helping) increase an individual's reputation. Studies of indirect reciprocity assume that good acts and bad acts are weighted equally when assessing the reputation of an individual. As different information can be processed in different ways, this is not likely to be the case, and it is possible that an individual could bias an actor's reputation by putting more weight to acts of defection (not helping) than acts of co-operation (helping) or vice versa. We term this difference ‘judgement bias’, and build an individual-based model of image scoring to investigate the conditions under which it may evolve. We find that, if the benefits of co-operation are small, judgement bias is weighted towards acts perceived to be bad; if the benefits are high, the reverse is true. Our result is consistent under both scoring and standing strategies, and we find that allowing judgement bias to evolve increases the level of co-operation in the population.
PMCID: PMC2660969  PMID: 19141419
information processing; social information; co-operation; game theory; reputation; tragedy of the commons
25.  Deriving cell survival curves from the overall responses of irradiated tumours: analysis of published data for tumour spheroids. 
British Journal of Cancer  1987;56(3):309-314.
Curves of growth delay (GD) or 'cure' after graded doses of radiation have been analysed for 16 lines of human and animal tumours grown as multicellular spheroids in vitro. Dose-survival curves were derived for those cellular units from which spheroids regrow after unsuccessful irradiation (spheroid-regenerating cellular units, SRU). For 10 sets of data from 6 spheroid lines, the Do's and extrapolation numbers of the SRU derived by GD could be compared with the response of the clonogenic cells of the spheroids. For Do, a good correlation (r = 0.910) was found between the two; this was true also for Do derived from curves of spheroid 'cure' (7 sets of data from 6 spheroid lines) and clonogenic cells (r = 0.986). Using GD, the correlation of extrapolation numbers was less good (r = 0.682), the values for SRU commonly being higher than those for clonogenic cells. This may reflect features of the growth curves of spheroids after the lower range of doses of radiation. For human and animal tumour spheroids of 250 microns or less, derived Do ranged from 0.5 to 2.5 Gy. For spheroids of 350 microns or more, derived Do for animal tumour lines ranged from 3.4 to 4.2 Gy, for human lines from 1.5 to 2.1 Gy.
PMCID: PMC2002203  PMID: 3663479

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