Determining Risk in Pediatric Research with No Prospect of Direct Benefit: Time for a National Consensus on the Interpretation of Federal Regulations

United States federal regulations for pediatric research with no prospect of direct benefit restrict institutional review board (IRB) approval to procedures presenting: 1) no more than “minimal risk” (§ 45CFR46.404); or 2) no more than a “minor increase over minimal risk” if the research is commensurate with the subjects' previous or expected experiences and intended to gain vitally important information about the child's disorder or condition (§ 45CFR46.406) (DHHS 2001). During the 25 years since their adoption, these regulations have helped IRBs balance subject protections with the pursuit of scientific knowledge to advance children's welfare. At the same time, inconsistency in IRB application of these regulations to pediatric protocols has been widespread, in part because of the ambiguity of the regulatory language. During the past decade, three federally-charged committees have addressed these ambiguities: 1) the National Human Research Protections Advisory Committee (NHRPAC) (Washington, DC), 2) the Institute of Medicine (IOM) Committee on the Ethical Conduct of Clinical Research Involving Children (Washington, DC); and 3) the United States Department of Health and Human Services Secretary's Advisory Committee for Human Research Protections (SACHRP) (Washington, DC). The committees have reached similar conclusions on interpretation of language within regulations § § 45CFR46.404 and 406; these conclusions are remarkably consistent with recent international recommendations and those of the original National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1977) National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1977. Report and recommendations: Research involving children, Washington, DC: U.S. Government Printing Office.  [Google Scholar] report from which current regulations are based. Drawing on the committees' public reports, this article identifies the ethical issues posed by ambiguities in regulatory language, summarizes the committees' deliberations, and calls for a national consensus on recommended criteria.     

Construction and implementation of a low-cost electronic experiment control interface

Low-cost electronic experiment control boards (ECBs), developed by Walter and Palya (1984), were constructed and implemented for use at the Naval Aerospace Medical Research Laboratory. Each ECB was wired to control experiments using animals as subjects. The ECBs have been connected to IBM-compatible microcomputers and serve essentially as intelligent interfaces between the subject and the microcomputer. Relative advantages and disadvantages of the control board, including construction and programming techniques, as well as cost, are discussed.     

The influence of the interaction of weight and volume on subjective heaviness

A model previously proposed for the size-weight illusion (Cross & Rotkin, 1975) was found unsatisfactory because the postulated volume parameter was not independent of the unit of measurement of weight and the model yielded a paradoxical prediction that the perceived heaviness of small objects should decrease as their weight increased. A new model was proposed based on Stevens and Rubin’s (1970) finding that heaviness functions are a family of con-verging power functions and some of Cross and Rotkin’s developments. The model was ex-amined by estimating its parameters from data previously reported by Cross and Rotkin, Stevens and Rubin, and Kolehmainen and Mikkonen (1970). The equations was found to fit each set of data well. Four independent estimates of a volume parameter of the model were in close agreement, .18, .21, .21, and .24, which is consistent with the model. nt]mis|This research was supported by Grants A0151 and A9582 from the National Research Council of Canada.     

Human Participants in Engineering Research: Notes from a Fledgling Ethics Committee

For the past half-century, issues relating to the ethical conduct of human research have focused largely on the domain of medical, and more recently social–psychological research. The modern regime of applied ethics, emerging as it has from the Nuremberg trials and certain other historical antecedents, applies the key principles of: autonomy, respect for persons, beneficence, non-maleficence, and justice to human beings who enter trials of experimental drugs and devices (Martensen in J Hist Med Allied Sci 56(2):168–175, 2001). Institutions such as Institutional Review Boards (in the U.S.) and Ethics Committees (in Europe and elsewhere) oversee most governmentally-funded medical research around the world, in more than a hundred nations that are signers of the Declaration of Helsinki (World Medical Association 2008). Increasingly, research outside of medicine has been recognized to pose potential risks to human subjects of experiments. Ethics committees now operate in the US, Canada, the U.K. and Australia to oversee all governmental-funded research, and in other jurisdictions, the range of research covered by such committees is expanding. Social science, anthropology, and other fields are falling under more clear directives to conduct a formal ethical review for basic research involving human participants (Federman et al. in Responsible research: a systems approach to protecting research participants. National Academies Press, Washington, 2003, p. 36). The legal and institutional response for protecting human subjects in the course of developing non-medical technologies, engineering, and design is currently vague, but some universities are establishing ethics committees to oversee their human subjects research even where the experiments involved are non-medical and not technically covered by the Declaration of Helsinki. In The Netherlands, as in most of Europe, Asia, Latin America, or Africa, no laws mandate an ethical review of non-medical research. Yet, nearly 2 years ago we launched a pilot ethics committee at our technical university and began soliciting our colleagues to submit their studies for review. In the past year, we have become officially recognized as a human subjects ethics committee for our university and we are beginning the process of requiring all studies using human subjects to apply for our approval. In this article, we consider some of the special problems relating to protecting human participants in a technology context, and discuss some of our experiences and insights about reviewing human subjects research at a technical university, concluding: that not less than in medical studies, human participants used in technology research benefit from ethical committees’ reviews, practical requirements for publications, grants, and avoiding legal liability are also served by such committees, and ethics committees in such contexts have many similarities to, but certain other special foci than medical ethics committees. We believe that this experience, and these observations, are helpful for those seeking to establish such committees in technology research contexts, and for framing the particular issues that may arise in such contexts for the benefit of researchers, and nascent committees seeking to establish their own procedures.     

A report on the development and prospects of Medical Psychology in the Federal Republic of Germany

For eight years Medical Psychology has been an integral part of medical pre-examination as well as of research and teaching in the Federal Republic of Germany, and a great deal of psychological knowledge is taught to the medical student under this heading. Besides mere theory the medical student is supposed to acquire behavior based on psychological findings which will be important to him in medical practice. Nevertheless, students often complain that teaching is too far from reality, due to the fact that Medical Psychology is part of the first, more theoretical, period of medical eduction, even though one of the main objects of this new field is the analysis of the interaction between patient and physician.     

Report on the National Commission: Good as gold

The National Commission for the Protection of Human Subjects of Bio-medical and Behavioral Research ended its work by substantially endorsing the status quo which places primary reliance on local Institutional Review Boards for subject protection. This was predictable because of the commission's researcher-dominated composition which permitted it to assume that(1) research is good;(2) experimentation is almost never harmful to subjects; and (3) researcher-dominated IRBs can adequately protect the interests of human subjects. The successor Presidential Commission can learn much by reexamining these premises.     

Deficient inhibitory control in attention deficit hyperactivity disorder

The purpose of this study was to examine two executive control processes — response inhibition and re-engagement of responses after inhibition in children with attention deficit hyperactivity disorder (ADHD). Thirty-three children with ADHD and 22 normal control children of similar age (7 to 11 years) and mean IQ (107) were tested with the change paradigm. ADHD subgroups were defined by the context in which the ADHD symptoms predominated (in the home only; at school only; and in both, i.e., pervasive ADHD). Children with marked oppositional defiant or conduct disorder were excluded. Children with ADHD exhibited deficits in inhibitory control and in response re-engagement. Deficits were greatest in pervasive ADHD and, to a lesser extent, in those with ADHD limited to the school context. ADHD limited to the home context showed the least deficit. These results replicate an earlier study that found deficient inhibitory control in pervasive ADHD and demonstrate that the deficit in ADHD involves a second aspect of executive control.We are grateful to Anne Rhodes and Isobelle Williams for their assistance in the conduct of this research. This research was supported by grants from Health and Welfare Canada and the Medical Research Council of Canada. This paper was prepared with the assistance of Medical Publications, The Hospital for Sick Children, Toronto, Ontario.     

Interactional processes in families with disruptive boys: Patterns of direct and indirect influence

Patterns of direct and indirect influence were investigated in interactions among 44 families with disruptive boys. Positive and negative behaviors were assessed for spouses and parent-child dyads, in different laboratory situations. For direct or reciprocal influence, positive behaviors in the father-child dyads were positively correlated; mothers' positive behaviors were positively correlated with boys' negative behaviors, suggesting an unexpected pattern of inverse reciprocity. For indirect influences, the following associations were found: Fathers' negative behaviors toward their children predicted the children's negative behaviors toward their mothers, and mothers' negative behaviors toward their children predicted the children's negative behaviors toward their fathers, suggesting a form of setting event or displaced behavior pattern. The children's negative behaviors toward their mothers correlated with the fathers' behaviors toward the mothers, suggesting a modeling pattern. These indirect paths underline the relevance of taking into account family interlocked relationships when studying child disruptiveness.This study was funded by the Social Sciences and Humanities Research Council of Canada (SSHRC), the Québec Social Research Council (CQRS), and the Québec FCAR programs for research centers and research teams. We are also indebted to Jacinthe Sirois and Danielle Boisvcrt for documentation assistance, to Lyse Desmarais-Gervais for her help in data processing, and to Patricia L. Dobkin for revision.     

Aversive conditioning in the sociopath

Results of two experiments on differential conditioning of the skin conductance (SCR) in sociopaths and normal control subjects are described. In the first experiment it was found that an equal number of sociopaths and control subjects were aware of the conditioning contingency. However, only the normal subjects displayed reliable differential SCR conditioning. Sociopaths showed a dissociation between verbal learning and conditioning of a physiological change. The second experiment examined the differential conditioning of normal subjects and sociopaths in partial remission. The number of aware subjects in the two groups did not differ. Aware subjects in both groups showed differential SCR conditioning. Differential conditioning in sociopaths did not persist over trials as it did in control subjects. A deficiency in ACTH 4–10 as well as neurological dysfunctions were considered possible factors in the etiology of sociopathy. Further research on the relation of neuropeptides to the etiology and treatment of sociopathy is suggested.     

Stability of weak second-order semantics

By extending the underlying data structure by new elements, we also extend the intput/output relation generated by a program i.e., no existing run is killed, and no new one lying entirely in the old structure is created. We investigate this stability property for the weak second order semantics derived from nonstandard time models. It turns out that the light face, i.e., parameterless collection principle always induces stable semantics, but the bold face one may be unstable. We give an example where an elementary extension kills a bold face run showing also that the light face semantics is strictly weaker than the bold face one.The research was partially carried out while the author visited McGill University, Montreal, Canada, and was supported in part by the Natural and Sciences and Engineering Research Council of Canada     

Affect and sensation seeking

The notion that affective responses differentiate high from low sensation-seekers was investigated. Male subjects with extremely high (N=13) or low (N=13) scores on Form V of the Sensation Seeking Scale (SSS) were presented with tones of 60, 80, and 100 dB in successive blocks of 10 tones each. Although measures of arousal (verbal self-reports and physiological measures of the orienting response) did not differentiate between high and low sensation-seekers, a self-report measure of pleasure did: Whereas reported pleasure of the low sensation-seekers began high and declined as tones became successively louder, the reported pleasure of the high sensation-seekers remained more constant across the blocks of tones.The research on which this paper was based was supported by Grant MT-4511 from the Medical Research Council of Canada to Robert Hare.     

Schilder and Pavlov’s theory of higher nervous activity

In the late 1920s, the Viennese psychoanalyst Paul Schilder, after performing a conditioning experiment with human subjects, criticized I. P. Pavlov’s concept of “experimental neurosis.” Schilder maintained that subjective reports by conditioned human subjects were more informative than the objectively observed behavior of conditioned dogs. In 1932, Pavlov published a rejoinder to Schilder’s critique in theJournal of the American Medical Association. Pavlov maintained that Schilder misunderstood the value and implications of the scientific, objective method in the study of experimental neurosis. In 1934, Schilder subjected Pavlov’s theory of higher nervous activity to an incisive critique in a 1935 article inImago. Schilder objected to Pavlov’s narrow, reductionist conceptualization of the conditional reflex. Schilder reiterated his view that the psychological, subjective explanation of the conditional reflex is preferable to the physiological, objective explanation, and that the inference of cortical phenomena from experimental findings might be improper. Neither Pavlov nor any of his disciples replied to Schilder. The author provides an apology for the Pavlovian position, suggesting that Schilder was unfamiliar with early and late writings of Pavlov.     

Electrooculographic indices of changes in simulated flying performance

Recent investigations have revealed statistically reliable relationships between signal detection by human subjects performing vigilance tasks and changes in the electrophysiologically recorded waveform of the eyeblink. Thus, this relatively simple and easy-to-obtain measure may have potential use as a predictor of impaired performance. This report describes a study in which eyeblink data were recorded on analog tape while subjects (instrument-rated pilots) “flew” a computer-generated flight plan in a General Aviation Trainer (GAT-1). Eyeblink data were reduced and scored with an adaptation of software from the Washington University Behavioral Research Laboratory. Subjects’ “flying” performance was evaluated with the Pilot Performance Evaluating System (PPES) implemented on a Digital Equipment Corporation (DEC), PDP-11/34 computer. The PPES samples each of four primary flight instruments once per second. It scores performance by generating a combined error score for each maneuver it assigns on the flight-plan display in the cockpit. The PPES/GAT-1 linkup has proved to be a valuable research tool with which to realistically evaluate stress effects and physiological correlates of flying performance in a laboratory setting. This study examined the relationships between eyeblink and flying performance scores collected during a pilot-fatigue study. Analysis of the data supports the use of computers cored eye movement measures as predictors of flying performance decrements.     

The use of microprocessors in a timeshared computer facility for research,development, and teaching

The use of microprocessors in a timeshared computer facility at the Learning Research and Development Center, University of Pittsburgh, is described for applications in research, development, and teaching. Modes of usage are described, as are the advantages of microprocessor interfaces for on-line experimentation.     

Parenting Adolescents: Examining the Factor Structure of the Alabama Parenting Questionnaire for Adolescents

The Alabama Parenting Questionnaire (APQ) is a well studied assessment of parenting practices for school-age children, especially in relation to child externalizing behaviors. Given the developmental changes between school-age children and adolescents and subsequent changes to parenting approaches during that time, the utility of a public-accessed measure to span across a broad age range is of high clinical and empirical importance. This study investigated the psychometric properties of the APQ in a community sample of 376 parents of adolescents. In an Exploratory Factor Analysis the data suggested a 4-factor solution similar in composition to the original 5-factor model. Proposed factors for the APQ when given to parents of adolescents included Positive and Involved Parenting, Parental Monitoring, Discipline Practices, and Discipline Process.     

The case of Debbie revisited: A literary perspective

The publication in theJournal of the American Medical Association of a narrative entitled “It's Over, Debbie,” in which a gynecology resident apparently performs euthanasia, has stirred considerable debate characterized by varying interpretations not only of the ethical issues involved but of the meaning of the text itself. Formal analysis reveals the narrative to be strikingly literary in its ambiguity, its foregrounding of its own textuality, and its dominant structure of repetition and reversal. The analysis points to features that account for some of the varying interpretations in the debate, and it calls into question the relation of the text to whatever events it may represent and to how the resident may have perceived these events.     

Comparison of child and adult vibrotactile thresholds as a function of frequency and duration

Psychophysical thresholds for the detection of sinusoidal vibration of the thenar eminence of the hand were determined for children and adults. The subjects in the child group were between 8 and 11 years old, and the adults were between 20 and 39 years old. Measurements were made for vibration frequencies ranging from 18 to 700 Hz and stimulus durations ranging from 28 to 1,000 msec. For both children and adults, thresholds were a Il-shaped function of stimulus frequency. However, the exact form of the function was influenced by the age of the subjects. At frequencies above 200 Hz, thresholds were virtually identical for children and adults, but below this frequency children were more sensitive than adults. This finding, in combination with known changes in the anatomy of the Pacinian corpuscle with age, is in agreement with a filter model of this cutaneous receptor. Furthermore, variation of stimulus duration resulted in data in agreement with the theory that two classes of mechanoreceptors, Pacinian and non-Pacinian, mediate the perception of vibration.     

Children with AIDS in the public schools: The ethical issues

The question of whether to allow children with AIDS to attend public school generates explosive emotions and has wide-reaching consequences. This paper focuses on the perspective of parents of well children who may be asked to attend school with children who have AIDS. These parents are poised at the heart of the dilemma: they are the ethical “bottom line,” and an argument that fails to satisfy them ought not to satisfy anyone. The conflicting commitments these parents face are first to the parentchild covenant which requires them to act in their child's best interests, and second, to the principles of beneficence and justice, which require them not to further burden a sick child with ostracism and isolation. Almost exact parallels exist between this issue and that of proxy consent by parents for children's participation in low-risk, non-therapeutic research. The lengthy and important debate between Paul Ramsey and Richard McCormick on this question is analyzed, concluding that McCormick's position in favor of thoughtful proxy consent is the more compelling. Returning to the question of allowing children with AIDS to attend school, the essay shows why the parallels are persuasive. On the ethical level, the apparent conflict of obligations is almost exactly the same; on the pragmatic level, the essay shows why sharing a classroom with a child who has AIDS is comparable to the “low-risk” category that the National Commission for the Protection of Human Subjects found acceptable in its 1978 guidelines. The essay concludes that parents of healthy childrenmay and ought to accept the presence of children with AIDS in the public school.     

Emotional Impulsivity in Children with ADHD Associated with Comorbid—Not ADHD—Symptomatology

Children with ADHD often demonstrate sudden and intense shifts in both positive and negative affect. This study examined the role of diagnostic status on emotional impulsivity in children utilizing ecological momentary assessment (EMA). Parents of 64 8–12 year old children (15 ADHD-only; 27 ADHD-comorbid; 22 control) completed a diagnostic structured interview and then an EMA protocol, rating the child’s affect thrice daily for 28 days. Analysis of covariance (ANCOVA) suggested that children with ADHD and a comorbid disorder demonstrated significantly more EMA-derived emotional impulsivity than children with ADHD only and control children. No difference was found between children with ADHD only and control children. This study suggested that children with ADHD demonstrate significantly higher levels of emotional impulsivity than control children only in the presence of a comorbid disorder.