Uncertain futures and unsolicited findings in pediatric genomic sequencing: guidelines for return of results in cases of developmental delay.

BACKGROUND: Massively parallel sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), may reveal unsolicited findings (UFs) unrelated to the diagnostic aim. Such techniques are frequently used for diagnostic purposes in pediatric cases of developmental delay (DD). Yet policy guidelines for informed consent and return of UFs are not well equipped to address specific moral challenges that may arise in these children's situations. DISCUSSION: In previous empirical studies conducted by our research group, we found that it is sometimes uncertain how children with a DD will develop and whether they could come to possess capacities for autonomous decision-making in the future. Parents sometimes felt this brought them into a Catch-22 like situation when confronted with choices about UFs before undergoing WES in trio-analysis (both the parents' and child's DNA are sequenced). An important reason for choosing to consent to WES was to gain more insight into how their child might develop. However, to make responsible choices about receiving or declining knowledge of UFs, some idea of their child's future development of autonomous capacities is needed. This undesirable Catch-22 situation was created by the specific policy configuration in which parents were required to make choices about UFs before being sequencing (trio-analysis). We argue that this finding is relevant for reconfiguring current policies for return of UFs for WES/WGS and propose guidelines that encompass two features. First, the informed consent process ought to be staged. Second, differing guidelines are required for withholding/disclosing a UF in cases of DD appropriate to the level of confidence there is about the child's future developmental of autonomous capacities. CONCLUSION: When combined with a dynamic consent procedure, these two features of our guidelines could help overcome significant moral challenges that present themselves in the situations of children undergoing genomic sequencing for clarifying a DD.

Hope, but never expect? Comparing parents' pre- and post-disclosure attitudes toward return of results from diagnostic exome sequencing for their child.

BACKGROUND: Counseling for whole-exome sequencing (WES) could benefit from aligning parents' pre- and post-disclosure attitudes. A few studies have qualitatively compared parents' pre- and post-disclosure attitudes toward receiving WES results for their child in a diagnostic setting. This study explored these attitudes in the context of children with a developmental delay. METHODS: Semi-structured interviews were conducted with parents (n = 27) of 16 children undergoing diagnostic WES in trio-analysis, both before and after receiving results. RESULTS: Three key insights emerged. First, the distinction between hoping and expecting was relevant for shaping parents' experiences with receiving results related to the primary indication. Second, parents of young children whose development of autonomous capacities was uncertain sometimes found themselves in a situation resembling a Catch-22 when confronted with decisions about unsolicited findings (UFs): an important reason for consenting to WES was to gain a better picture of how the child might develop, but in order to make responsible choices about UFs, some ideas of their child's development is needed. Third, default opt-ins and opt-outs helped parents fathom new kinds of considerations for accepting or declining UFs in different categories, thereby aiding decision-making. CONCLUSION: Results from this study are relevant for counseling and policy development.

Parents, their children, whole exome sequencing and unsolicited findings: growing towards the child's future autonomy.

In a previous study we found that parents of children with developmental delay (DD) favoured acceptance of unsolicited findings (UFs) for medically actionable conditions in childhood, but that preferences diverged for UFs with no medical actionability, or only in adulthood, and regarding carrier status. Sometimes the child's future autonomy formed a reason for withholding UFs for the present, despite an unfavourable prognosis concerning the child's cognitive capabilities. This might be different for children undergoing whole exome sequencing (WES) for reasons other than DD and who are expected to exert future autonomy. This is the focus of the current study. We conducted nine qualitative, semi-structured interviews with parents of children, ages <1-15, after consenting to WES, but prior to feedback of results, and with three adolescent children. Several parents wished to receive any information that might in whatever way be relevant to the health and well-being of their child, and to a lesser extent wished the inclusion of information about non-actionable disorders and information concerning carrier status of autosomal recessive disorders. Although parents understood the rationale behind the centre's UFs disclosure policy, they also felt that they needed this information in order to be able to exert their parental responsibility and take good care of a child still dependent on them. Parents reason from their notion of parental responsibility but are also inclined to take adolescent children's preferences seriously and acknowledge the child's incipient autonomy as a ground for granting an increasing degree of self-determination on the road to adulthood.

The effect of menaquinone-7 (vitamin K2) supplementation on osteocalcin carboxylation in healthy prepubertal children.

Vitamin K contributes to bone health, probably through its role as cofactor in the carboxylation of osteocalcin. Intervention studies in adults have demonstrated that markedly higher osteocalcin carboxylation is obtained by intakes of vitamin K well above the current recommended dietary intake. However, the relationship between increased vitamin K2 intake and enhanced osteocalcin carboxylation has never been shown in healthy children. The objective was to study the effect of 45 microg menaquinone-7 (MK-7; one of the vitamin K2 species) on the circulating levels of undercarboxylated osteocalcin (ucOC) and carboxylated osteocalcin (cOC) in healthy prepubertal children. We hypothesised that MK-7 supplementation will reduce the ucOC:cOC ratio (UCR), indicating an improved vitamin K status. The present study is a double-blind randomised placebo-controlled trial examining the effect of 8 weeks MK-7 supplementation on the carboxylation of osteocalcin in healthy children (n 55). Serum levels of ucOC, cOC and MK-7 were measured at baseline and after 8 weeks, together with bone markers and coagulation parameters. The UCR was used as an indicator of vitamin K status. In the MK-7-supplemented group (n 28), the circulating concentration of inactive ucOC reduced and the UCR improved whereas the concentration of MK-7 increased. Within the placebo group, ucOC, cOC, UCR and MK-7 did not significantly change over time. In both groups, bone markers and coagulation parameters remained constant over time. These findings demonstrate that in healthy, prepubertal children, modest supplementation with MK-7 increases circulating concentrations of MK-7 and increases osteocalcin carboxylation.

Vitamin K status is associated with childhood bone mineral content.

In adult bone, vitamin K contributes to bone health, probably through its role as co-factor in the carboxylation of osteocalcin. In children, the significance of vitamin K in bone-mass acquisition is less well known. The objective of this longitudinal study was to determine whether biochemical indicators of vitamin K status are related to (gains in) bone mineral content (BMC) and markers of bone metabolism in peripubertal children. In 307 healthy children (mean age 11.2 years), BMC of the total body, lumbar spine and femoral neck was determined at baseline and 2 years later. Vitamin K status (ratio of undercarboxylated (ucOC) to carboxylated (cOC) fractions of osteocalcin; UCR) was also measured at both time points. Markers of bone metabolism, sex steroids, vitamin D status and growth hormones were measured at baseline only. Large variations in the levels of the UCR were found at both time-points, indicating a substantial interindividual difference in vitamin K status. Improvement of vitamin K status over 2 years (n 281 children) was associated with a marked increase in total body BMC (r -49.1, P<0.001). The UCR was associated with pubertal stage, markers of bone metabolism, sex hormones and vitamin D status. A better vitamin K status was associated with more pronounced increase in bone mass in healthy peripubertal children. In order to determine the significance of these findings for childhood bone health, additional paediatric studies are needed.

Whole-exome sequencing in pediatrics: parents' considerations toward return of unsolicited findings for their child.

Parents' preferences for unsolicited findings (UFs) from diagnostic whole-exome sequencing (WES) for their children remain largely unexplored. Our aim was to gain insight into parental considerations favoring acceptance/decline of UFs pertaining to their child. We conducted 20 qualitative, semistructured interviews with parents (n=34) of children with a developmental delay, aged <1 to 17 years, after consenting to WES, but before feedback of results. Key findings from our study were that all parents favored acceptance of UFs for medically actionable conditions in childhood, but that preferences and considerations diverged for UFs with no medical actionability, or only in adulthood, and regarding carrier-status. Sometimes non-medical utility considerations (considerations of usefulness of knowing UFs, not rooted in (preventive) medical treatment or controls) were given in favor of disclosure of UFs. Sometimes the child's future autonomy formed a reason to withhold UFs at present, despite an unfavorable prognosis concerning the child's cognitive capabilities. Some parents only preferred receiving UFs if these findings were directly related to their reasons for seeking a diagnosis. These findings are essential for developing morally responsible policy and for counseling. Further research should focus on whether considerations of non-medical utility alone can justify disclosure of UFs and whether reasons for seeking a diagnosis place further constraints on what UFs may be returned/withheld. How parents can be aided in contemplating different scenarios regarding their child's future development also deserves further inquiry.

Competence assessment in minors, illustrated by the case of bariatric surgery for morbidly obese children.

Clinicians have to assess children's competence frequently. In order to do justice to children who are competent to make decisions and to protect incompetent children, valid assessment is essential. We address this issue by using bariatric surgery for morbidly obese minors as a case study. Our previous research indicated that opponents of bariatric surgery tend to be sceptical of the competence of adolescents to consent and inclined to set more stringent standards than proponents. Furthermore, there is the concern that minors wanting surgery are less able to make an autonomous decision than minors who do not wish to undergo surgery. Hence, few patients may be qualified as eligible. We argue for a risk-related standard, so that concerns are met, while at the same time preventing to set the bar too high, excluding paediatric patients who are most likely to benefit from surgery. This standard is also applicable in gastroenterology practice.

The controversy over pediatric bariatric surgery: an explorative study on attitudes and normative beliefs of specialists, parents, and adolescents with obesity.

Despite the reported limited success of conventional treatments and growing evidence of the effectiveness of adult bariatric surgery, weight loss operations for (morbidly) obese children and adolescents are still considered to be controversial by health care professionals and lay people alike. This paper describes an explorative, qualitative study involving obesity specialists, morbidly obese adolescents, and parents and identifies attitudes and normative beliefs regarding pediatric bariatric surgery. Views on the etiology of obesity-whether it should be considered primarily a medical condition or more a psychosocial problem-seem to affect the specialists' normative opinions concerning the acceptability of bariatric procedures as a treatment option, the parents' feelings regarding both being able to influence their child's health and their child being able to control their own condition, and the adolescents' sense of competence and motivation for treatment. Moreover, parents and adolescents who saw obesity as something that they could influence themselves were more in favor of non-surgical treatment and vice versa. Conflicting attitudes and normative views-e.g., with regard to concepts of disease, personal influence on health, motivation, and the possibility of a careful informed consent procedure-play an important role in the acceptability of bariatric surgery for childhood obesity.

Circulating calcification inhibitors and vascular properties in children after renal transplantation.

Pediatric transplant patients are known to have vascular abnormalities. The calcification inhibitors matrix Gla protein (MGP) and fetuin-A play an important role in the pathophysiology of vascular calcification. In the cross-sectional study reported here, we examined the circulating levels of fetuin-A and MGP in children after renal transplantation compared to healthy children and the association of these factors with vascular properties of the carotid artery. Levels of MGP and fetuin-A together with vascular properties of the carotid artery were determined in 29 pediatric renal transplant recipients and 54 healthy controls. The level of fetuin-A was decreased in the transplant group relative to the control group (P=0.005), whereas the level of MGP (both non-phosphorylated MGP and non-carboxylated MGP) did not differ between groups. The intima-media thickness (P<0.001) and the elasticity (P=0.002) of the carotid artery were significantly increased in children after renal transplantation compared to healthy children. No associations between vascular parameters and calcification inhibitors were found in either group. Circulating levels of MGP and fetuin-A could not be identified as independent predictors of vascular stiffness or other carotid artery parameters in pediatric renal transplant recipients. Future prospective studies in pediatric ESRD and transplant patients are needed to learn more about the role of calcification inhibitors in relation to the prevention of vascular damage.

Pronounced elevation of undercarboxylated osteocalcin in healthy children.

The vitamin K-dependent protein osteocalcin is thought to play an important role in bone metabolism. Osteocalcin contains glutamic acid (Gla) residues, which have a high affinity for calcium. Vitamin K acts as an indispensable cofactor for the formation of these residues. Inadequate dietary vitamin K intake results in the synthesis of undercarboxylated (i.e. inactive) osteocalcin (ucOC). In adults, low vitamin K status of bone is associated with low bone density and increased risk of osteoporotic fractures. Little is known about vitamin K status and bone health in children. We used a cross-sectional study design to compare the vitamin K status of bone in healthy children (n = 86) with that of adults (n = 30). In children, a marked elevation of the ratio of ucOC/carboxylated osteocalcin (cOC), indicative of a poor vitamin K status, was observed. This difference persisted after adjusting for age, gender, puberty, height, weight. Furthermore, a marked correlation between the bone markers for bone metabolism and ucOC and cOC was found in the children's group. These findings suggest a pronounced low vitamin K status of bone during growth. The question remains, however, whether children would benefit from higher vitamin K intake, for instance, by improved bone health or stronger bones.