The patient's view on rare disease trial design - a qualitative study.

BACKGROUND: Clinical trials in rare diseases are more challenging than trials in frequent diseases. Small numbers of eligible trial participants, often complicated by heterogeneity among rare disease patients, hamper the design and conduct of a 'classical' Randomized Controlled Trial. Therefore, novel designs are developed by statisticians. However, it is important to be aware of possible design aspects that may jeopardize the feasibility of trial conduct. If the burden of participation is considered out of proportion by patients or parents, recruitment may fail or participants may drop out before trial completion. In order to maximize the chance of success of trials in small populations, it is important to know which aspects of trial design are considered important by patients. RESULTS: We have interviewed all ten members of the Patient Think Tank (PTT) of the ASTERIX project, a European research consortium on methodology for clinical trials in small populations. The PTT members are rare disease patient representatives who have completed extensive training in clinical trial methodology. We have analyzed the interviews qualitatively according to Grounded Theory using a thematic analysis, and we structured the topics in four chronologically ordered themes: 1. Involvement in trial design; 2. Opinions on trial design; 3. Trial participation; 4. Phase after the trial. Our main findings are that the PTT-members recommend that patients are involved in trial design from an early stage on, and have influence on the outcomes and measurement instruments that are chosen in the trial, the length of the study, the choice of participants, and the information that is sent to potential participants. Also, according to the PTT-members, patient groups should consider setting up disease registries, placebo groups should be minimized, and more education on clinical trials is advised. CONCLUSIONS: Rare disease patient representatives who have been educated about clinical trial methodology think it is important to involve patient representatives in research at an early stage. They can be of advice in trial design in such a way that the ratio of potential benefit and burden of trial participation as well as the chosen outcome measures and in- and exclusion criteria are optimized.

The nature of the global effect beyond the first eye movement.

When two or more visual objects appear in close proximity, the initial oculomotor response is systematically aimed at a location in between the objects, a phenomenon named the global effect. The global effect is known to arise when saccades are initiated relatively quickly, immediately after the presentation of a display, but it has also been shown that a global effect may occur much later in time, even for eye movements beyond the first. That is, when participants are searching for a complex target among complex distractor objects, it can take several eye movements to hit the target, and these eye movements mainly land at intermediate locations. It is debatable whether these findings are caused by the same mechanisms as those involved in the more typical global effect studies, studies in which much simpler search tasks are employed. In the current two experiments, we examined whether and under which circumstances a global effect can be found for a second oculomotor response in a search display containing two simple objects. Experiment 1 showed that the global effect only occurs when the presentation of the target and distractor objects is delayed, until after the first oculomotor response is initiated. Experiment 2 demonstrated that identity information, rather than spatial information, is crucial for the occurrence of the global effect. These results suggest that the global effect is not due to a failure to dissociate between the locations of multiple objects, but a failure to determine which one is the target.

Do people desire to be healthier than other people? A short note on positional concerns for health.

Contrary to traditional economic postulates, people do not only care about their absolute position but also about their relative position. However, empirical evidence on positional concerns in the context of health is scarce, despite its relevance for health care policy. This paper presents a first explorative study on positional concerns in the context of health. Using a 'two-world' survey method, a convenience sample of 143 people chose between two options (having more in absolute terms or having more in relative terms) in several health and non-health domains. Our results for the non-health domains compare reasonably well to previous studies, with 22-47% of respondents preferring the positional option. In the health domain, these percentages were significantly lower, indicating a stronger focus on absolute positions. The finding that positional concerns are less prominent in the health domain has important implications for health policy, for instance in balancing reduction of socio-economic inequalities and absolute health improvements.

Does early intensive multifactorial treatment reduce total cardiovascular burden in individuals with screen-detected diabetes? Findings from the ADDITION-Europe cluster-randomized trial.

AIMS: To describe the total cardiovascular burden (cardiovascular morbidity or mortality, revascularization or non-traumatic amputation) in individuals with screen-detected diabetes in the ADDITION-Europe trial and to quantify the impact of the intervention on multiple cardiovascular events over 5 years. METHODS: In a pragmatic, cluster-randomized, parallel-group trial in four centres (Denmark; Cambridge, UK; the Netherlands; and Leicester, UK), 343 general practices were randomized to screening plus routine care (n = 1379 patients), or screening and promotion of target-driven, intensive treatment of multiple risk factors (n = 1678). We estimated the effect of the intervention on multiple cardiovascular events after diagnosis of diabetes using the Wei, Lin and Weissfeld method. RESULTS: Over 5.3 years, 167 individuals had exactly one cardiovascular event, 53 exactly two events, and 18 three or more events. The incidence rates (95% CI) of first events and any event per 1000 person-years were 14.6 (12.8-16.6) and 20.4 (18.2-22.6), respectively. There were non-significant reductions in the risk of a first (hazard ratio 0.83, 95% CI 0.65-1.05) and second primary endpoint (hazard ratio 0.70, 95% CI 0.43-1.12). The overall average hazard ratio for any event was 0.77 (95% CI 0.58-1.02). CONCLUSIONS: Early intensive multifactorial treatment was not associated with a significant reduction in total cardiovascular burden at 5 years. Focusing on first events in cardiovascular disease prevention trials underestimates the total cardiovascular burden to patients and the health service.

Screening for type 2 diabetes. Lessons from the ADDITION-Europe study.

AIMS: To describe and compare attendance rates and the proportions of people identified with Type 2 diabetes mellitus in people with previously unknown diabetes who participated in screening programmes undertaken in general practice in the UK, Denmark and the Netherlands as part of the ADDITION-Europe study. METHODS: In Cambridge, routine computer data searches were conducted to identify individuals aged 40-69 years at high risk of Type 2 diabetes using the Cambridge Diabetes Risk Score. In Denmark, the Danish Diabetes Risk Score was mailed to individuals aged 40-69 years, or completed by patients visiting their general practitice. In the Netherlands, the Hoorn Symptom Risk Questionnaire was mailed to individuals aged 50-69 years. In these three centres, high-risk individuals were invited to attend subsequent steps in the screening programme, including random blood glucose, HbA(1c) , fasting blood glucose and/or oral glucose tolerance test. In Leicester, eligible people aged 40-69 years were invited directly for an oral glucose tolerance test. In all centres, Type 2 diabetes was defined according to World Health Organization 1999 diagnostic criteria. RESULTS: Attendance rates ranged from 20.2% (oral glucose tolerance test in Leicester without pre-stratification) to 95.1% (random blood glucose in opportunistic screening in Denmark in high-risk people). The percentage of people with newly detected Type 2 diabetes from the target population ranged from 0.33% (Leicester) to 1.09% (the Netherlands). CONCLUSIONS: Screening for Type 2 diabetes was acceptable and feasible, but relatively few participants were diagnosed in all participating centres. Different strategies may be required to increase initial attendance and ensure completion of screening programmes.

Diabetes Care Protocol: effects on patient-important outcomes. A cluster randomized, non-inferiority trial in primary care.

AIMS: The Diabetes Care Protocol (DCP) combines task delegation, intensification of diabetes treatment and feedback. It reduces cardiovascular risk in Type 2 diabetes (T2DM) patients. This study determines the effects of DCP on patient-important outcomes. METHODS: A cluster randomized, non-inferiority trial, by self-administered questionnaires in 55 Dutch primary care practices: 26 practices DCP (1699 patients), 26 usual care (1692 patients). T2DM patients treated by their general practitioner were included. Main outcome was the 1-year between-group difference in Diabetes Health Profile (DHP-18) total score. SECONDARY OUTCOMES: DHP-18 subscales, general perceived health [Medical Outcomes Study 36-Items Short Form Health Survey (SF-36), Euroqol 5 Dimensions (EQ-5D) and Euroqol visual analogue scale (EQ-VAS)], treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire; DTSQ status) and psychosocial self-efficacy (Diabetes Empowerment Scale Short Form; DES-SF). Per protocol (PP) and intention-to-treat (ITT) analyses were performed: non-inferiority margin Delta=-2%. At baseline 2333 questionnaires were returned and 1437 1 year thereafter. RESULTS: Comparing DCP with usual care, DHP-18 total score was non-inferior: PP -0.88 (95% CI -1.94 to 0.12), ITT -0.439 (95% CI -1.01 to 0.08), SF-36 'health change' improved: PP 3.51 (95% CI 1.23 to 5.82), ITT 1.91 (95% CI 0.62 to 3.23), SF-36 'social functioning' was inconclusive: PP-1.57 (95% CI-4.3 to 0.72), ITT-1.031 (95% CI-2.52 to -0.25). Other DHP and SF-36 scores were inconsistent or non-inferior. DHP-18 'disinhibited eating' was significantly worse in PP analyses. For EQ-5D/EQ-VAS, DTSQ and DES-SF, no significant between-group differences were found. CONCLUSION: DCP does not seem to influence health status negatively, therefore diabetes care providers should not shrink from intensified treatment. However, they should take possible detrimental effects on 'social functioning' and 'disinhibited eating' into account.

[Fewer caesarean sections for breech presentation following external cephalic version according to a protocol in a special office visit]. / Minder keizersneden wegens stuitligging dankzij geprotocolleerde uitwendige versie in een speciaal spreekuur.

OBJECTIVE: Identification of determinants affecting the outcome of external cephalic version (ECV) in breech presentation, and investigation of the impact of ECV--performed according to a standardized protocol in an outpatient clinic--on the mode of delivery. DESIGN: Retrospective analysis. METHOD: In 2003 a standardized protocol of ECV was developed in the outpatient clinic for obstetrics of the Catharina Hospital in Eindhoven, the Netherlands; it was tested in 'version office visits'. Obstetric characteristics of all pregnant women who underwent attempts of ECV in the clinic from January 2004 until June 2006 during these sessions, and the subsequent births, were analysed. 85% of all ECVs were performed by the same hospital midwife and gynaecologist, in accordance with the protocol. RESULTS: ECV was successful in 96 of 209 pregnant women (46%). In 1 pregnant woman an emergency caesarean section was performed after ECV because of partial abruptio placentae. Nulliparity, incomplete breech presentation and low birth weight of the baby were associated with a lower success rate of ECV in this study. In the group with a successful ECV the percentage of caesarean deliveries was substantially lower (9 versus 83%; odds ratio: 0.21; 95% CI: 0.09-0.51). CONCLUSION: A regular team consisting of a hospital midwife and a gynaecologist working according to a standardized protocol for ECV in a case of breech presentation proved successful: the number of term breech presentations substantially diminished and therefore the percentage of caesarean sections was lower in the group in which ECV had been successful. This could have considerable impact on health care in the Netherlands in terms of reduced maternal morbidity and cost savings.

Diagnostic accuracy for different strategies of image-guided breast intervention in cases of nonpalpable breast lesions.

To find out whether ultrasound-guided fine-needle aspiration (FNA) and ultrasound and stereotactic-guided large core needle biopsy (LCNB) are reliable alternatives to needle-localised open breast biopsy (NLBB) in daily practice, we performed a retrospective study and evaluated the validity of these methods. In all, 718 women with 749 nonpalpable breast lesions from three Dutch Hospitals were included, and the validity of the various methods for diagnosis was assessed. This was carried out according to a method described by Burbank and Parker for evaluating the quality of an image-guided breast intervention. We compared our results with the outcome of the COBRA study. Overall, all diagnostic strategies (NLBB, FNA, LCNB ultrasound and stereotactic guided) show comparable agreement rates. However, the miss rates differ: 2% for NLBB, 3% for COBRA (LCNB in study setting), 5% for FNA and 8-12% for LCNB in practice. Fine-needle aspiration was nonconclusive in 29%, and shows an overestimation for DCIS in 9%. The DCIS underestimate rate in NLBB was 8%. For the assessment of lesions consisting of microcalcifications only and to exclude malignancy in all other lesions, a 14-gauge needle should be used. Ultrasound-guided intervention can be performed in a large percentage of nonpalpable lesions. Lesions consisting only of microcalcifications on mammography need special attention.

Diagnostic strategies in non-palpable breast lesions.

The number of non-palpable breast lesions is growing. Needle-localised breast biopsy (NLBB) is the gold standard for evaluating these lesions. Cost-saving techniques and less invasive alternatives such as core-needle biopsy (LCNB) and fine-needle aspiration (FNA) have emerged. The aim of this study was to find out if the lesions of patients who were sent directly for surgery to undergo a NLBB differed from lesions of patients who were send for a non-operative procedure. Furthermore, if a benign result was obtained, we assessed the total and kind of subsequent diagnostic procedures that were undertaken. A retrospective study on 718 women with 749 non-palpable breast lesions was performed. In 58% of women with non-palpable breast lesion, a non-surgical procedure was chosen. Lesions sent directly for surgery were more frequently not visible on ultrasound (62%) and mainly consisted of microcalcifications only (56%). In 45%, this primary surgical approach could have been avoided. If the non-operative procedure showed a non-malignant result, 41% of these women received an additional surgical diagnostic procedure. These figures obtained from routine daily practice show the importance of protocols in order to standardise diagnostic procedures and prevent unnecessary surgery.

Visual marking beside the mark: prioritizing selection by abrupt onsets.

In a standard visual marking experiment, observers are presented with a display containing one set of elements (old elements) followed after a certain time interval by a second set of elements (new elements). The task of observers is to search for a target among the new elements. Typically, the time to find the target depends only on the number of new elements in the display and not on the number of old elements, showing that observers search only among the new elements. This effect of prioritizing new elements over old elements is explained in terms of top-down inhibition of old objects-that is, visual marking (Watson & Humphreys, 1997). The present study addressed whether this prioritizing is in fact mediated by top-down inhibition of old objects, as suggested by Watson and Humphreys (1997), or whether it is mediated by the abrupt onsets of the newly presented elements (Yantis & Jonides, 1984). In three experiments, the presentations of the old and new elements were or were not accompanied by a luminance change. The results showed that if new elements were equiluminant with the background, no visual marking occurred, suggesting that new elements must have a luminance onset in order to be prioritized over old elements. Implications for current theories on visual selection are discussed.

Illusory conjunctions die hard: a reply to Prinzmetal, Diedrichsen, and Ivry (2001).

M. Donk (1999) showed that various data patterns that have been considered as evidence for the existence of illusory conjunctions may be due to errors of target-nontarget confusion, an account that challenges the mere existence of illusory conjunction. In a reply, W. Prinzmetal, J. Diedrichsen, and R. B. Ivry (2001) argued against this conclusion, claiming that some earlier findings can be explained only when one assumes that illusory conjunctions exist. The current article shows that Prinzmetal et al.'s claims cannot refute any of Donk's earlier conclusions, suggesting indeed that one can only conclude that "illusory conjunctions are an illusion."

Feature localization and identification.

Theories on visual search differ substantially with respect to the relationship they assume between localization and identification processes. The aim of the present study was to rigorously compare the alternative theoretical notions on how localization and identification processes are related. In two experiments, participants searched for a target with a unique line orientation among distractors containing another orientation. Localization and identification performance were measured in combination, as function of display size and target eccentricity. To compare the alternative theories, formal binomial models were developed and compared with respect to their goodness of fit to the individual data. The formal analyses showed that the model assuming identification processes to be conditioned on localization processes provided the best fit to the individual data. Furthermore, maximum likelihood estimates of the parameter corresponding to identification processes were differently affected by display size than identification performance was. The results were discussed in terms of their implication for current theories on visual search.

The association between induced and spontaneous abortion and risk of breast cancer in Slovenian women aged 25-54.

The risk of breast cancer may be increased by induced or spontaneous abortion. The evidence for this association was evaluated in a population based case-control study in Slovenia, where 624 women aged 25-54 years with breast cancer diagnosed during 1988-1990 were matched for age and site of residence with controls randomly selected from the Slovenian Population Registry. Odds ratios (OR) and 95% confidence intervals (CI) were obtained by conditional logistic regression analyses. Spontaneous abortion was not associated with a significantly increased risk of breast cancer (nulliparous women: OR=1.41, 95% CI 0.22-9.01; uniparous women: OR=0.98, 95% CI 0.50-1.91; women with parity 2 or more: OR=1.40, 95% CI 0.91-2.15). Induced abortion was not associated with a statistically significant elevated risk. The risk of breast cancer was higher in nulliparous women (OR=2.49, 95% Cl 0.68-9.09), and was less among women who had more deliveries. In uniparous women, the risk of breast cancer appeared higher when the induced abortion took place before a first full-term pregnancy (OR=1.94, 95% CI 0.70-5.39) rather than after a first full-term pregnancy (OR=1.22, 95% CI 0.71-2.10) but neither of these odds ratios reached significance. We found no significant association between spontaneous abortion or induced abortion and breast cancer risk. This study found an elevated, but not statistically significant, risk associated with induced abortion among nulliparous women and among parous women when the induced abortion was before the first full-term pregnancy.

Human monitoring behavior in a multiple-instrument setting: independent sampling, sequential sampling or arrangement-dependent sampling.

This study aims at contributing to the understanding of human monitoring behavior in multiple instrument settings. Eye movements were recorded so as to test whether sampling behavior is more consistent with traditional normative models (Senders, 1983) or with alternative approaches that emphasize heuristics and strategies rather than quantitative modelling. A core assumption of normative modelling concerns the premise that sampling one instrument is independent of the other instruments in an array. This assumption was tested in three experiments. In a first experiment, subjects monitored four independent continuous stochasts so as to detect critical situations. In a fast condition, two instruments were paired with two relatively fast changing instruments. In a slow condition, the two instruments were paired with two relatively slow changing instruments. Sampling one instrument appeared to be independent of the rates of change of the other instruments in the array. Furthermore, sampling was a function of the information generation rates of the individual instruments. This is in accordance with normative modelling. However, the spatial arrangement of the instruments on the display as well as the presence of a central fixation point strongly affected sampling behavior. In a second experiment, subjects monitored six instruments. In addition, there was no central fixation point. The results indicated again that a perceptual heuristic was used in that the spatial arrangement of the instruments on the display affected sampling behavior. Horizontal transitions occurred more often than would be predicted on the basis of independent sampling. Diagonal transitions occurred less often than would be predicted. Finally, a third experiment tested whether this preference for sampling by means of horizontal eye movements at the expense of diagonal eye movements would, under conflict situations, affect the mean sampling interval of specific instruments. In a four-instrument monitoring task, sampling intervals of two slow and two fast independent instruments were compared in different spatial arrangements. Sampling intervals strongly depended on the arrangement of the instruments on the display. Human monitoring seems to be biased by a tendency towards sampling by means of horizontal transitions at the cost of diagonal transitions. Under certain conditions, this tendency might make sampling intervals unrelated to the information generation rates of the individual instruments.

The effect of secondary task load on visual sampling behaviour.

This paper investigates a dual-task experiment, which looked at whether periodical sampling (Senders 1983) of relatively fast changing instruments results from an imperfect internal representation of these instruments, or whether it merely represents a strategy adopted by the observer to overcome overload situations. Subjects either monitored a fast or a slow instrument in combination with a difficult, easy or no tracking task. The results indicated that sampling behaviour was generally unaffected by the external load imposed by the tracking task, suggesting that periodical sampling results from an imperfect internal representation and is not the result of a strategic decision of the observer to overcome overload.

Resources and dual-task performance; resource allocation versus task integration.

This study aims at contributing to the explanation of dual-task performance in terms of either resource allocation or of task interference and integration. Twenty-four subjects carried out, single and in combination, a motor interval production task and a perceptual target detection task on the basis of combined memory and display search. The demands of the target detection task were varied by increasing or decreasing the presentation rate of successive search displays. Furthermore, the presentation rate was either constant or variable. The dual-task condition had a negative effect on interval production, the extent of which was unaffected by either rate or variability of display presentation. This means that there was no evidence for synchronizing interval production with display presentation, so that the major opportunity for task integration did not substantiate. It is suggested that the two tasks use different resource pools in addition to a common mechanism, the limited capacity of which causes a general interference in dual-task conditions.

The regulation of pollen tube growth in Douglas-fir following high doses of ionizing radiation.

Acute irradiation of Douglas-fir (Pseudotsuga menziesii [Mirb.] Franco) pollen by X-rays enhances pollen tube elongation. To determine whether this effect was due to physical damage of the pollen membranes or to metabolic processes, irradiated and control pollen were grown under conditions of anoxia. Thus, it was determined that physical damage only could be of minor importance. As parameters for metabolic processes RNA- and protein synthesis were studied. The only difference between irradiated and control pollen with respect to RNA synthesis was the time at which it started. Protein synthesis in vitro revealed that polyribosomes from irradiated pollen were more active than those from control pollen at lower concentrations. These results were confirmed by in ovo experiments with both polysomal preparations. The results indicate that X-ray irradiation is interfering with the main regulatory mechanism of pollen tube growth, which is de- and re-masking of, mainly, presynthesized mRNA.