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PubMed1998

Quantitative structure-function and structure-stability relationships of purposely modified proteins.

Quantitative structure-function relationships (QSFR) and quantitative structure-stability relationships (QSSR) analyses are described here. The objective of these analyses is to investigate and quantitatively describe the effect of the changes in structure of protein on its function or stability. During the analysis, the structural and physico-chemical properties of the amino acid residues are related to activity or stability data derived for the group of proteins containing systematic substitutions at certain positions. Four examples of the application of these analyses on the data obtained with proteins modified by site-directed mutagenesis experiments are provided. Structure-function relationships were studied for 15 mutants in position 172 of the haloalkane dehalogenase and 19 mutants in position 222 of the subtilisin, while the structure-stability relationships were investigated for 13 mutants in position 157 of phage T4 lysozyme and 18 mutants in position 49 of alpha-subunits tryptophan synthase. A total of 402 molecular descriptors derived from AAindex database were used to quantify amino acid properties and the multivariate statistical technique--partial least squares projections to latent structures--was used to identify those of them which are important for explanation of the activity and stability data. Quantitative models were developed and internally validated for every data set. The possibilities for further development of both analyses and their application for predictive and analytical purposes in protein engineering research are discussed.

Glutamic Acid↗

PubMed1994

Critical appraisal of research literature by expert and inexperienced physical therapy researchers.

BACKGROUND AND PURPOSE: In this study, critical appraisal skills of physical therapists who were inexperienced and expert researchers were compared and the effect of the following independent variables on the appraisal skills of novices was examined: years of physical therapy practice, postgraduate experience with research, level of comfort with research, journal reading habits, and content-specific expertise. SUBJECTS AND METHODS: Four expert and 20 inexperienced researchers critiqued the same research article. A content analysis of the expert critiques was used to develop a set of 12 items of concerns about the study. RESULTS: Experts identified a mean of 7.75 items of concern; novices identified a mean of 3.95 items. For 10 of the 12 items, a greater proportion of experts identified each concern compared with the novices. Novices had comparatively less difficulty identifying concerns with internal validity than they did identifying issues relating to construct validity. Only one of the variables--content-specific expertise--was associated with differences in critical appraisal skills among the novices. CONCLUSION AND DISCUSSION: These finding suggest that analysis of construct issues in research articles is a more advanced skill than analysis of research design and that critical appraisal of research literature is enhanced by clinical experiences related to the subject of the research report.

Physical Therapy Modalities↗

PubMed1995

How "blind" are double-blind placebo-controlled trials of benzodiazepine hypnotics?

This study examined the accuracy of insomnia patients and their treating physicians in rating whether an active hypnotic drug or a placebo was given in treatment. Forty older adults with primary insomnia were randomly assigned to either an active (temazepam) or a placebo condition using a double-blind strategy. Ratings of treatment conditions were obtained at 1 week (early treatment), 4 weeks (midtreatment), and 8 weeks (late treatment). Patients were able to accurately discriminate (beyond chance levels) between the active and placebo medications at the early (76.9% accuracy) and late treatment assessment timepoints (78.1% accuracy), but not at midtreatment (51.5% accuracy). Therapists, however, were able to make accurate discriminations at the late treatment assessment timepoint only (80% accuracy); early (69.2% accuracy) and midtreatment (47.2% accuracy) ratings did not exceed chance levels. Patients who had used hypnotic drugs prior to this trial were more accurate in their judgments of treatment conditions than those without prior exposure. The findings raise an important issue about the internal validity of the double-blind strategy, which may in fact be only a single-blind procedure.

Aged↗

PubMed2000

A comparison of neuropsychological and situational assessment for predicting employability after closed head injury.

The relationships among neuropsychological assessment, situational assessment, and judgments of future employability in 127 survivors of moderate to severe closed head injury were evaluated. Participants received a comprehensive neuropsychological battery and a situational vocational evaluation. Two groups were created, based on employment recommendation from the situational evaluation. A seven-factor model was found to account for the preponderance of variance within the neuropsychological battery used, and one factor was predictive of group assignment from situational assessment. However, the present data reinforce the predominance of findings in the literature that indicate that, in general, no individual neuropsychological test can be used to predict vocational performance in more environmentally relevant environments. Exceptions to this "rule" may occur when comparisons between results of formal neuropsychological tests and situational evaluation are limited to very simple, very circumscribed, and/or very well-defined functions. Thus, situational assessment is seen as a critical adjunct to neuropsychological assessment in making "real-world" predictions. The particular situational assessment used in this study was internally valid, an important finding given the importance of situational assessment in ecologically valid predictions.

Adolescent↗

PubMed1997

The performance of several indicators in detecting recall bias. European Study Group on Infertility and Subfecundity.

Self-reported exposure data are vulnerable to differential recall, which threatens the internal validity and thus the credibility of the study. When a proxy measure of the exposure of interest is available, it may be possible to check for the presence of recall bias due to misclassification of the exposure information. We present a number of indicators of recall bias for case-control studies, and we describe their behavior by means of computer simulations. The indicators are all based upon a comparison between self-reported exposure data and data on job titles grouped into exposure-specific matrices. The indicators are based upon the assumption that job titles are reported without differential misclassification for cases as well as controls. We also assume that exposure data are reported with the same accuracy by workers in different jobs. Under these assumptions, the proposed indicators will provide valuable-although not conclusive-signs of recall bias. The principles elaborated in this paper can be applied to other situations in which self-reported exposure data are used.

Bias↗

PubMed1994

Treatment of recurrent tension headache: a meta-analytic review.

The primary aim of this study was to investigate which treatment, patient, and study characteristics are related to treatment outcome in tension headache. Literature on the subject was obtained by searching for articles published in English through CD-rom Compact Cambridge and PSYCHLIT (1970/1993) on the subjects of headache and tension or muscle contraction in combination with therapy or treatment. Inclusion criteria were prospective design, tension headache, > or = five subjects per condition; pre- and posttreatment scores available, subjects older than 16 years. Each article was independently reviewed and its data encoded by the two authors. Finally, 78 articles with 175 treated and nontreated conditions (total of 2,866 patients) were selected for this study. Meta-analysis revealed that cognitive therapy, relaxation, or electromyelographic (EMG) biofeedback alone or in combination with relaxation were superior to no treatment and to pseudo/placebo therapy. Pharmacological and other therapies were better than no treatment. However, restricting the analyses to studies using a headache diary, the results of pharmacological therapy were comparable to those of placebo therapy. Moreover, a better treatment outcome was found in studies with a relatively short duration of headache complaints (r = -0.31) and with a relatively younger patient sample (r = -0.22). The year of publication was negatively related with improvement (r = -0.36). No relationship between treatment outcome and other treatment characteristics (duration, transfer of treatment), patient characteristics (gender, method of patient recruitment), and study characteristics (internal validity of the study, criteria for diagnosing tension headache, number of patients, drop-outs) was found. These findings suggest that treatment outcome may be affected more by patient characteristics than by treatment characteristics. Finally, some practical and research implications of these findings are discussed.

Humans↗

PubMed1994

Referred pain of peripheral nerve origin: an alternative to the "myofascial pain" construct.

The theory of myofascial pain syndrome (MPS) has been constructed around the trigger point (TrP), a region within a muscle from which local and remote pain can be evoked by palpation. Although their pathophysiology is obscure, TrPs have been regarded as the cause of myofascial pain. Spread and chronicity of pain are attributed to the activation of latent, secondary, and satellite TrPs. Although it lacks internal validity, this tautological concept has given rise to a system of empirical treatment that has been uncritically accepted by many. However, not only does the anatomical distribution of pain referred from TrPs bear a close relationship to the course of peripheral nerves, but the pain of MPS is also similar to nerve trunk pain, which is an example of somatic referred pain. Pain of peripheral nerve origin can be present without neurological deficit and with normal findings on conventional electrodiagnostic examination. In contrast to the theory of MPS, which considers the TrPs to be sites of primary hyperalgesia, this article argues that all MPS phenomena are better explained as secondary hyperalgesia of peripheral neural origin.

Humans↗

PubMed1996

Introducing Critical Appraisal to studies of animal models investigating novel therapies in sepsis.

OBJECTIVES: To discuss theoretical and practical aspects relating to the design of animal studies investigating the efficacy of novel therapeutic agents for the treatment of sepsis, and to make explicit the process whereby these studies can be evaluated for the purpose of designing clinical trials in humans. DATA SOURCES: Relevant articles from the pertinent literature were reviewed. STUDY SELECTION: Studies relevant to an evidence-based assessment of clinical studies on therapeutic efficacy, and studies relevant to the design of animal models of sepsis were selected. DATA EXTRACTION: Concepts relevant to an evidence-based assessment of the animal literature were extracted. DATA SYNTHESIS: Articles were reviewed and an evidence-based framework for the assessment of animal studies was developed. In this process, we discuss the steps that are necessary to assess the internal validity of an individual study and review topics relevant to the application of animal data to the design of clinical trials. CONCLUSIONS: The success of clinical trials of sepsis therapies is predicated on the generation and interpretation of sound preclinical data. In this review, we have attempted to outline an evidence-based approach to the assessment of preclinical animal studies evaluating novel therapeutic interventions in sepsis.

Animals↗

PubMed1996

Integration of trial, meta-analysis and cohort results with treatment guidelines.

IMPORTANCE OF GUIDELINES: Guidelines to medical practice are of vital importance because of the fast and uncontrolled introduction of new technologies, increasing amounts of information, including contradictory results, high levels of inappropriate care and increased financial pressure. Thus guidelines can help solve common problems in all health care systems worldwide. PREPARATION OF GUIDELINES: In preparing guidelines, a synthesis of results from the literature prepared by a single expert must be compared with syntheses done by others, and a consensus recommendation may then be issued. Such a recommendation will not be based exclusively on the results of controlled trials, even when they have indisputable internal validity. There is still a need for a value judgement within a particular psychological and socio-economic context. FREEDOM FOR PHYSICIAN: It is important to preserve the physician's freedom to prescribe drugs or not in conjunction with informed choice by the patient concerning the risks of any long-term drug intervention, even if this freedom of choice does not fit with the expectations of "managed' care or third-party payers.

Clinical Trials as Topic↗

PubMed1992

Statistical description of the Mini-Mental State Examination for French elderly community residents. Paquid Study Group.

The distribution of total Mini-Mental State Examination (MMSE) scores, individual items, and groups of items were studied in French elderly community residents from a random sample of 2727 subjects. Serial seven, recall three objects, and copy pentagons had the lowest percentage of correct responses, while orientation to place, naming two objects, and three objects registration had the highest percentage of correct responses. The structure of correlation of the items was studied using Principal Components Analysis. The projection of the items on the first axis reflects the tendency of the items to vary in the same direction and is compatible with the fact that the MMSE items are all indicators of the same concept: cognitive performance. The second and third axes identify clusters of highly correlated variables and provide support for the internal validity of the MMSE score for a French population. The full MMSE score seems to be a valid instrument for the evaluation of cognitive performance in community-based elderly residents.

Aged↗

PubMed2000

The Euro-Growth Study: why, who, and how.

BACKGROUND: Assessment of growth is important in health management of infants and children. Evaluation of growth performance requires anthropometric measurements, with proper interpretation depending on the use of appropriate references. Europe-specific growth references have not been available. The purpose of the present study was to generate such references for infants and children from birth to 3 years of age. The study was further intended to assess the influence of nutrition and lifestyle factors on growth. METHODS: The Euro-Growth Study was designed as a multicenter longitudinal cohort study. This report describes the study design, the sample (cohort), and the methods used. Quality control measures included standardized measurement techniques with ongoing cross-sectional and longitudinal consistency checks. Selectivity in participation and discontinuation and reproducibility of data over time were evaluated. RESULTS: Of 2,245 infants who were enrolled in the study at 22 study sites in 11 countries, 1,746 (78%) provided longitudinal data until 12 months of age, 1,205 (57%) until 24 months of age, and 1071 (48%) until 36 months of age. Anthropometric measurements were performed on 21,773 occasions. As a result of cross-sectional and longitudinal data checks, 209 data points (0.09% of all data points) were rejected. Comparison of participants's demographic data with those of nonparticipating local subjects indicated that the cohort was selective in maternal age (higher), maternal education level (higher), household location, and family structure. The withdrawal rate during the study was low (24%), and withdrawals occurred at random. Analysis of reproducibility over time resulted in the elimination of the data from one study site. CONCLUSION: The Euro-Growth Study provided longitudinal growth data from a large cohort of normal European children. Because of the chosen sampling method, the study cohort ws somewhat selective relative to the local background population. Internal validity was satisfactory in that the reproducibility of anthropometric measurements was high in 21 sites and the withdrawal rate was low and random.

Anthropometry↗

PubMed1986

The use of proxies in health surveys. Substantive and policy implications.

It has traditionally been assumed that obtaining health and illness behavior data by proxy on household members who are not present during the actual interview presents no significant threats to the internal validity of subsequent analyses. Using data on the 78,439 adults interviewed in person or by proxy (about 37% of the total adult sample) as part of the 1978 Health Interview Survey, the authors examine whether the use of proxy respondents alters the results of empirical assessments of the behavioral model of health services utilization or the policy implications that can be derived from it. Two important findings emerge from these analyses. On the one hand, failing to consider explicitly the possibility of a proxy effect (i.e., including a proxy variable in the analyses) does not alter the effect parameters estimated for the behavioral model. On the other hand, failing to consider explicitly the effect of using proxies appears to underestimate slightly physician and hospital contact rates (by 4% and 2%, respectively), as well as the volume of physician utilization. The substantive and policy implications of these findings are discussed, as are two alternative explanations that suggest that proxy-respondents simply use fewer health services either because they are "too busy" or because they are in slightly better health.

Adult↗

PubMed2001

Improving primary care for depression in late life: the design of a multicenter randomized trial.

BACKGROUND: Late life depression can be successfully treated with antidepressant medications or psychotherapy, but few depressed older adults receive effective treatment. RESEARCH DESIGN: A randomized controlled trial of a disease management program for late life depression. SUBJECTS: Approximately 1,750 older adults with major depression or dysthymia are recruited from seven national study sites. INTERVENTION: Half of the subjects are randomly assigned to a collaborative care program where a depression clinical specialist supervised by a psychiatrist and a primary care expert supports the patient's regular primary care provider to treat depression. Intervention services are provided for 12 months using antidepressant medications and Problem Solving Treatment in Primary Care according to a stepped care protocol that varies intervention intensity according to clinical needs. The other half of the subjects are assigned to care as usual. EVALUATION: Subjects are independently assessed at baseline, 3 months, 6 months, 12 months, 18 months, and 24 months. The evaluation assesses the incremental cost-effectiveness of the intervention compared with care as usual. Specific outcomes examined include care for depression, depressive symptoms, health-related quality of life, satisfaction with depression care, health care costs, patient time costs, market and nonmarket productivity, and household income. CONCLUSIONS: The study blends methods from health services and clinical research in an effort to protect internal validity while maximizing the generalizability of results to diverse health care systems. We hope that this study will show the cost-effectiveness of a new model of care for late life depression that can be applied in a range of primary care settings.

Aged↗

PubMedDate not supplied

Intervention research: establishing fidelity of the independent variable in nursing clinical trials.

BACKGROUND: Internal validity of a randomized clinical trial of a nursing intervention is dependent on intervention fidelity. Although several methods have been developed, evaluating audio or audiovisual tapes for prescribed and proscribed interventionist behaviors is considered the gold standard test of treatment fidelity. This approach requires development of a psychometrically sound instrument to meaningfully categorize and quantify interventionist behaviors. OBJECTIVE: To outline critical steps necessary to develop a treatment fidelity instrument. METHODS: A comprehensive literature review was conducted to determine procedures used by other researchers. The literature review produced five quantitative studies of treatment fidelity, all in the field of psychotherapy, and two replication studies. A synthesis of methodologies across studies combined with researchers' experiences resulted in identification of the steps necessary to develop a treatment fidelity measure. RESULTS: Seven sequential steps were identified as essential to the development of a valid and reliable measure of treatment fidelity. These steps include (a) identification of the essential elements of the experimental and control treatment modalities; (b) construction of scale items; (c) development of item scaling; (d) identification of the units for coding; (e) item testing and revision; (f) specification of rater qualifications and development of rater training program; and (g) development and completion of pilot testing to test psychometric properties. Development of the Possibilities Project Psychotherapy Coding Questionnaire is described as an illustration of the seven-step process. DISCUSSION: The results show the essential steps that are unique to the development of treatment fidelity measures and show the feasibility of using these steps to construct a psychometrically sound treatment-specific fidelity measure.

Adolescent↗

PubMed2001

The efficacy of conservative treatment in patients with whiplash injury: a systematic review of clinical trials.

STUDY DESIGN: A systematic review of the literature. OBJECTIVES: To assess the efficacy of conservative treatment in patients with whiplash injuries. SUMMARY OF BACKGROUND DATA: Many treatments are available for patients with whiplash injury, but there continues to be no evidence for their accepted use. METHODS: A computerized literature search of Medline, Embase, Cinahl, Psychlit, and the Cochrane Controlled Trial Register was performed. Studies were selected if the design was a (randomized) clinical trial; if all patients had sustained a whiplash injury; if the type of intervention was a conservative one; if pain, global perceived effect, and participation in daily activities were used as one of the outcome measures, and if the publication was written in English, French, German, or Dutch. The methodologic quality was independently assessed by two reviewers by using the Maastricht-Amsterdam list. Three quality scores were calculated using this criteria list: the Overall Methodologic Quality Score, the Internal Validity Score, and the Delphi Quality Score. The conclusion of the review was based on articles that scored a quality score of at least 50% of the maximum available score on two of three quality scores. RESULTS: Eleven studies met the inclusion criteria. Only three studies satisfied at least 50% on two of three ways of calculating a quality score, indicating overall poor methodology. There was a high rank correlation among the three ways of calculating a quality score. No statistical pooling was performed because of the heterogeneity of the interventions. This review indicates that active treatments show a beneficial long-term effect on at least one of the primary outcome measures. CONCLUSION: Caution is needed when drawing a valid conclusion on the efficacy of conservative treatments in patients with whiplash injury. It appears that "rest makes rusty," whereas active interventions have a tendency to be more effective in patients with whiplash injury.

Bed Rest↗

PubMed2006

Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy.

OBJECTIVE: To derive and internally validate a clinical prediction rule for virologic response based on CD4 cell count increase after initiation of HAART in a resource-limited setting. DESIGN AND METHODS: A retrospective cohort study at two HIV care clinics in Gaborone, Botswana. The participants were previously treatment-naive HIV-1-infected individuals initiating HAART. The main outcome measure was a plasma HIV-1 RNA level (viral load) < or = 400 copies/ml (i.e. undetectable) 6 months after initiating HAART. RESULTS: The ability of CD4 cell count increase to predict an undetectable viral load was significantly better in those with baseline CD4 cell counts < or = 100 cells/microl [area under the ROC curve (AUC), 0.78; 95% confidence interval (CI), 0.67-0.89; versus AUC, 0.60; 95% CI, 0.48-0.71; P = 0.018]. The sensitivity, specificity, and positive and negative predictive values of a CD4 cell count increase of > or = 50 cells/microl for an undetectable viral load in those with baseline CD4 cell counts < or = 100 cells/microl were 93.1, 61.3, 92.5 and 63.3%, respectively. Alternatively, these values were 47.8, 87.1, 95.0 and 24.5%, respectively, if a increase in CD4 cell count of > or = 150 cells/microl was used. CONCLUSIONS: CD4 cell count increase after initiating HAART has only moderate discriminative ability in identifying patients with an undetectable viral load, and the predictive ability is higher [corrected] in patients with lower baseline CD4 cell counts. Although HIV treatment programs in resource-constrained settings could consider the use of CD4 cell count increases to triage viral load testing, more accurate approaches to monitoring virologic failure are urgently needed.

Adolescent↗

PubMed2005

Applying clinical significance methodology to alcoholism treatment trials: determining recovery outcome status with individual- and population-based measures.

BACKGROUND: The current analysis applies clinical significance methodology to alcoholism treatment outcome research using data available from Project MATCH. Because of its high internal validity and its inclusion of multiple measures assessing multiple outcome dimensions, MATCH was considered an ideal study to explore the utility of this methodology. METHODS: Data reported here are from a total of 1,726 participants enrolled in either aftercare (n = 774) or outpatient (n = 952) arms of the study. First, a cutoff score was determined differentiating functional versus dysfunctional status on three outcome measures: percent days abstinent (PDA), mean drinks per drinking day (DDD) and negative consequences of alcohol use. Second, the reliable change in pre- to post-treatment scores on these three measures was calculated. RESULTS: The results reported herein support the importance of distinguishing between statistical and clinical significance of outcomes. During three months post-treatment, approximately one-half of the treated patients were "recovered" (i.e., both functional and reliably changed) with respect to both PDA (i.e., 51%) and negative consequences of drinking (i.e., 47%); however, only about one-third of individuals remained recovered throughout the full one-year follow-up period (i.e., 33% on PDA and 35% on negative consequences). These individual-based change outcomes compared similarly to a population-based indicator of heavy drinking. Alternatively, only about one-quarter of participants were recovered using two distinct criteria for mean DDD (i.e., 23-29%), and even fewer participants remained recovered on mean DDD over the full one-year follow-up period (i.e., about 14-18%). CONCLUSIONS: Based on study limitations, more work is required to make clinical significance methodology practically useful to alcoholism treatment trials including more precise definitions of functional status and relative change as well as better interpretation of the inter-relationship between multiple measures assessing multiple outcome domains.

Adult↗

PubMed2005

Underreporting of pregnancy-related mortality in the United States and Europe.

OBJECTIVE: Available maternal mortality statistics do not allow valid international comparisons. Our objective was to uniformly measure underreporting of mortality from pregnancy in official statistics from selected regions within the U.S. and Europe, and to provide comparable revised profiles of pregnancy-related mortality. METHODS: We developed a standardized enhanced method to uniformly identify and classify pregnancy-associated deaths from 2 U.S. states, Massachusetts and North Carolina, and 2 European countries, Finland and France, for the years 1999-2000. Identification method included the use of all data available from the death certificate as well as computerized linkage of births and deaths registers. All cases were reviewed and classified by an international panel of experts. RESULTS: Four-hundred-and-four pregnancy-associated deaths were identified and reviewed. Underestimation of mortality causally related to pregnancy based on International Classification of Diseases cause-of-death codes alone varied from 22% in France to 93% in Massachusetts. Underreporting was greater in the regions with lower initial maternal mortality ratios. The distribution of causes of pregnancy-related mortality was specific to each region. The leading causes of death were cardiovascular conditions in Massachusetts; hemorrhage, pregnancy-induced hypertension, and peripartum cardiomyopathy in North Carolina; noncardiovascular medical conditions in Finland; and hemorrhage in France. CONCLUSION: This study shows the limitations of maternal mortality statistics based on International Classification of Diseases cause-of-death codes alone. Linkage of births and deaths registers should routinely be used in the ascertainment of pregnancy-related deaths. In addition, extension of the definition of a maternal death should be considered. Beyond pregnancy-related mortality ratios, considering the specific distribution of causes-of-death is important to define prevention strategies.

Adult↗