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Recent eLetters

Displaying 1-10 letters out of 598 published

  1. Re: Beauty is in the eye of the beholder

    We appreciate the comments from Fairchild et al., and acknowledge that HRC monitoring has value in their NICU as an additional vital sign that may lead to increased provider attention. Our finding of a significantly lower correlation of HRC and proven sepsis likely stems from the difference in the definition used and highlights both a significant problem with diagnostic testing for neonatal sepsis in general (1) and the practical use of HRC outside of a clinical trial. We agree that modalities that can identify infants at risk for or with disease prior to clinical presentation can provide great clinical value. However, as with any screening test for disease, it is important to know how often the test is right and how often it is wrong.

    In response to Mr. King, CEO of MPSC, manufacturer of the HeRO System, our goal was to perform an unbiased analysis of EMR data as an opportunity to share a "real-world" experience with HRC monitoring and its association with sepsis in the NICU. As we stated in our paper, this work stemmed from the fact that we were unable to identify a published report of commonly reported indices for diagnostic testing using the HeRO System including sensitivity, specificity, negative and positive predictive value, as well as area under receiver operating curve [which were also not reported in the large RCT (2)]. We would have liked to provide those metrics for our study, but were not able to do so based on sound statistical analysis. As we stated, since every baby with an elevated score > 2 was not evaluated for sepsis at each instance that the score was elevated, accurate predictive indices cannot be determined from the data available in our report (3). We acknowledged that HRC scores are monitored continuously in our NICU but not all scores were available for analysis in the EMR. Our NICU policy is that bedside staff record HRC scores at least once per shift in the EMR but also notify the provider if scores are >2.5 and record the event. Hence, the available EMR data was not entirely intermittent. In our paper, we reported not 8% of scores that were recorded but rather that 8% (9,701) of all HRC scores recorded in the EMR (127,673) over a 30-month period were > 2. The HRC score is available to integrate into clinical care as suggested, however, our data point out the limitations to accurate identification of sepsis ahead of clinical signs, and hence prevention of death from this disease. Based on our data, the actionable signal identifying sepsis by the definition we used appears hidden in a large background of elevated scores not specific to sepsis.

    James L. Wynn, J?rn Hendrik Weitkamp, Jeff Reese, Ann Stark

    1. Wynn JL, Wong HR, Shanley TP, Bizzarro MJ, Saiman L, Polin RA. Time for a neonatal-specific consensus definition for sepsis. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2014;15(6):523-8.

    2. Moorman JR, Carlo WA, Kattwinkel J, Schelonka RL, Porcelli PJ, Navarrete CT, et al. Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: a randomized trial. The Journal of pediatrics. 2011;159(6):900-6 e1.

    3. Coggins SA, Weitkamp JH, Grunwald L, Stark AR, Reese J, Walsh W, et al. Heart rate characteristic index monitoring for bloodstream infection in an NICU: a 3-year experience. Arch Dis Child Fetal Neonatal Ed. 2015.

    Conflict of Interest:

    None declared

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  2. Re: Personality of young adults born preterm

    The correspondence by Greisen & Hansen (...) draws attention to their well conducted controlled study of the personality of very preterm born (VPT) adults in two cohorts in Denmark 1. Their study found like ours 2 higher neuroticism, lower extraversion but also higher agreeableness in adults born preterm compared to those born at term. They concluded in their paper that "overall, our study corroborates the picture of VPT individuals being less extraverted with increased neuroticism as adults and this finding seems remarkably consistent in the literature" 1, p. 7). We agree.

    However, the effect sizes of differences in individual personality traits were somewhat smaller than those found in our study. Greisen and Hansen emphasise that the effects sizes were smaller than the typical effect on IQ as a general measure of brain injury in very preterm infants. Again, we can agree as the effect sizes of differences in personality that we reported 2 are about half as large as those found by us in IQ between VPT and term controls 3. Indeed, we reported that IQ differences could not explain the differences in personality in adulthood between the groups 2. Thus, despite the remarkable consistency of findings and their pattern, what can explain differences in effect sizes? We rule out that it can be explained by the fact that our study was led by two psychologists, two statisticians and one neonatologist while most were neonatologists in the Danish study, respectively. Rather, across different outcomes whether IQ, personality or quality of life, the Danish studies indicate smaller differences between VPT and term controls than our whole population study in Bavaria or other studies in the UK. We may speculate that "Danes are smug" 4 with findings that over the last decades they are the happiest nation. They have lower income inequality, their rates of social exclusion in school such as bullying are lower 5 (a factor we found to impact on VPTs wellbeing in Germany and the UK 6) and they may thus do a better job of integrating VPT. Alternatively or additionally, we know from the Bavarian Longitudinal Study that high intensive respiratory care, i.e. ventilation, was more or less universally applied to all VPT in the mid 1980s, while many neonatal units in Denmark maintained a "Scandinavian model" of less invasive treatment with nasal CPAP treatment and "minimal handling "7. This has been shown to lead to less respiratory problems, likely less brain damage and better outcomes 8. Systematic comparisons of findings across countries are important to detect universal versus country or treatment specific effects of prematurity on long term outcome.

    Dieter Wolke Department of Psychology and Warwick Medical School Mental Health and Wellbeing Unit, University of Warwick, Coventry

    Peter Bartmann Department of Neonatology, University of Bonn Children's Hospital, Bonn

    1. Hertz CL, Mathiasen R, Hansen BM, et al. Personality in Adults Who Were Born Very Preterm. PLoS One 2013;8(6):e66881. 2. Eryigit-Madzwamuse S, Strauss V, Baumann N, et al. Personality of adults who were born very preterm. Archives of Disease in Childhood - Fetal and Neonatal Edition 2015. 3. Eryigit Madzwamuse S, Baumann N, Jaekel J, et al. Neuro-cognitive performance of very preterm or very low birth weight adults at 26 years. Journal of Child Psychology and Psychiatry 2015;56(8):857-64. 4. Christensen K, Herskind AM, Vaupel JW. Why Danes are smug: comparative study of life satisfaction in the European Union. BMJ : British Medical Journal 2006;333(7582):1289-91. 5. Elgar FJ, Craig W, Boyce W, et al. Income Inequality and School Bullying: Multilevel Study of Adolescents in 37 Countries. The Journal of adolescent health : official publication of the Society for Adolescent Medicine 2009;45(4):351-59. 6. Wolke D, Baumann N, Strauss V, et al. Bullying of Preterm Children and Emotional Problems at School Age: Cross-Culturally Invariant Effects. The Journal of Pediatrics (http://dx.doi.org/10.1016/j.jpeds.2015.02.055). 7. Verder H. Nasal CPAP has become an indispensable part of the primary treatment of newborns with respiratory distress syndrome. Acta P?diatrica 2007;96(4):482-84. 8. Wolke D. The preterm responses to the environment - long term effects? In: Cockburn F, ed. Advances in perinatal medicine. Carnforth: Parthenon Publishing, 1997:305-14.

    Conflict of Interest:

    None declared

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  3. Beauty is in the eye of the beholder

    Regarding Coggins' Heart rate characteristic index monitoring for bloodstream infection in an NICU: a 3-year experience:

    Wirschafter[1] has labeled the CDC definition a minimum estimate of infection burden, while labeling antibiotic administration a maximum estimate. The authors refuse to provide metrics such as Specificity and NPV on the grounds that establishing health of the patients was not possible. By their own logic, meeting the CDC definition may in fact confer sickness, but the absence of meeting the definition does not confer health.

    The authors admit that only 8% of HeRO Scores were recorded, and this offered an opportunity for bias. Importantly, the recorded and unrecorded HeRO Scores were incorporated into clinical decisions during care of the subjects. The presence of elevated HeRO Scores would have prompted action on the part of caregivers that altered the presence, timing, and results of blood cultures prior to antibiotic administration[2].

    As discussed above, the authors assert that PPV, NPV Sensitivity, and Specificity cannot be calculated. Yet, the authors go on to report that "17/46 (37%) had at least one score >=2 recorded in the 48 h period prior to [BSI]." THIS IS SENSITIVITY. Further, the authors report that "BSI (at any time) was observed in just 5% of patients with HRC scores >=2..." THIS IS PPV. Back-calculated from the numbers reported:

    HeRO>=2 ever versus BSI ever:

    BSI Incidence Rate: 1.9%. Sensitivity: 87%. Specificity: 68%. PPV: 5%. NPV: 99.6%. Risk Ratio: 13.4x. ROC[3]: >.78.

    The authors characterize the 37% sensitivity versus 48hr BSI as "limited," while completely ignoring the opportunity to improve the most important outcome in a significant fraction of sick neonates. An optimist might call actionable information for 37% of proven infections in the 48 hour window prior diagnosis something quite different: "extraordinary".

    Beauty is in the eye of the beholder.

    Sincerely,

    Will King, CEO

    1 - Antibiotic use for presumed neonatally acquired infections far exceeds that for central line-associated blood stream infections: an exploratory critique. Wirtschafter DD, Padilla G, Suh O, Wan K, Trupp D, Fayard EE. J Perinatol. 2011 Aug;31(8):514-8. doi: 10.1038/jp.2011.39. Epub 2011 May 5.

    2 - Infection and Other Clinical Correlates of Abnormal Heart Rate Characteristics in Preterm Infants. Sullivan BA, Grice SM, Lake DE, Moorman JR, Fairchild KD. J Pediatr. (2014) Jan 9

    3 - ROC calculated from a single threshold (HeRO = 2.0), and the corresponding Sensitivity and Specificity (87% and 68%, respectively). Sweeping across multiple thresholds would result in a more precise calculation of ROC, which could be expected to exceed 0.80.

    Conflict of Interest:

    I am CEO of MPSC, manufacturer of the HeRO System.

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  4. Proper Use of the Heart Rate Characteristics Monitor in the NICU

    In the report "Heart rate characteristics index monitoring for bloodstream infection in an NICU: a 3-year experience", Coggins and colleagues make several observations that are important for properly using the HRC (HeRO) monitor in the NICU: 1) Continuous monitoring is more effective than intermittent. Coggins analyzed scores recorded in the medical record every 12 hours, or 8% of the hourly scores; high scores may have been missed. 2) Many high HRC index scores are not associated with bloodstream infection. We have found that an acute rise in the score can also be associated with urinary tract infection, necrotizing enterocolitis, clinical sepsis, acute respiratory deterioration, surgery[1], brain injury[2][3], and administration of atropine. In some cases, a rise in the score is not associated with any apparent illness or event. 3) Some infants with septicemia do not have an acute rise in the HRC index prior to diagnosis. In the Coggins report, only 37% of the 46 intermittently-sampled cases of septicemia were associated with HRC index >2. In our analysis from the continuously-sampled RCT, 79% of the 974 cases of septicemia in 700 VLBW infants, were associated with a score >2 in the day before diagnosis[4]. 4) The HRC index monitor should never replace clinical judgement. A septic-appearing baby should get antibiotics regardless of the score, and a baby with a high score but low clinical index of suspicion for infection could be closely watched without antibiotics[5]. A scenario in which a baby might benefit is the VLBW infant whose baseline HRC index is <1 for several days, followed by a rise to >2, prompting clinicians to look more closely, send laboratory tests, and detect and treat infection before the baby has obvious clinical deterioration.

    Karen Fairchild MD, David Kaufman MD, John Kattwinkel MD

    University of Virginia School of Medicine

    1) Sullivan BA, Grice SM, Lake DE, et al. Infection and other clinical correlates of abnormal heart rate characteristics in preterm infants. J Pediatr 2014;164:775-80.

    2) Vergales BD, Zanelli SA, Matsumoto JA, et al. Depressed heart rate variability is associated with abnormal EEG, MRI, and death in neonates with hypoxic ischemic encephalopathy. Am J Perinatol 2014;31:855- 62.

    3) Fairchild KD, Sinkin R a, Davalian F, et al. Abnormal heart rate characteristics are associated with abnormal neuroimaging and outcomes in extremely low birth weight infants. J Perinatol 2014;34:375-9.

    4) Fairchild KD, Schelonka RL, Kaufman D a, et al. Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial. Pediatr Res 2013;74:570-5.

    5) Griffin MP, Lake DE, O'Shea TM, et al. Heart rate characteristics and clinical signs in neonatal sepsis. Pediatr Res 2007;61:222-7.

    Conflict of Interest:

    None declared

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  5. The MBRRACE-UK perinatal surveillance report - clarification

    We very much welcome Martin Ward Platt's review of the MBRRACE-UK perinatal surveillance report and would like to respond to a number of points that he has highlighted. The article focussed on the first perinatal surveillance report (1) from the MBRRACE-UK team and noted that it was produced from a new system of data collection after a three year gap in national perinatal surveillance. As well as changing the approach to data collection, MBRRACE-UK have introduced a number of changes to the nature of the data collected. In order to facilitate international comparisons WHO guidance was followed in terms of the inclusion criteria: i.e. all neonatal deaths resulting from a registered live births from 20 weeks gestation and all late fetal losses of 22 and 23 weeks gestation are now included. In addition the inclusion of these babies should facilitate the investigation of the wide variation in practices between units concerning whether such babies are registered as a live birth or not registered (2) which has a large impact on neonatal mortality rates. An overview of the new statistical method used to stabilise and adjust the mortality rates between populations was included in appendix 3 of the published report as well as in a short podcast which is downloadable from the MBRRACE-UK website: https://www.npeu.ox.ac.uk/mbrrace- uk/presentations. A broad summary of the methodology was presented at the report launch meeting as it was felt that the majority of the constituent audience would not be interested in the full detail of the statistical methods employed. However, although these methods are new to the UK they have been used in the US and are discussed in the references cited in the report (3,4). We agree that neonatal death is not a homogeneous group and over the next few years we will be developing different methods of exploring the various groups of deaths and this will be facilitated by the use of data for two or three years combined rather than a single year.

    The review queried the choice of the International Cause of Death and Associated Conditions (CODAC) classification system (5) by MBRRACE-UK. CODAC was chosen following consultation with an expert group primarily because it was felt it would provide a far better insight into the mechanisms involved with the various types of perinatal loss. In the past simple hierarchical systems have been used which failed to provide any insight into the cause of death for over half of all stillbirths. However, we acknowledge that this system is complex and we have established a working group to identify key problems and help produce the answers to frequently asked questions for users.

    The review highlighted the importance of moving to reports of outcomes based on individual Trusts and Health Boards. Dr Ward Platt would have been unaware at the time of writing that such reports were always intended to be produced but were delayed for this first report simply because of the time and resources needed to establish an appropriate approach in the first instance. All Trusts and Health Boards should now have received a report of their 2013 cases (based on the place of birth for all deaths) and in subsequent years this information will be produced at the same time as the geographical analysis (by commissioning or public health organisation).

    We would like to reassure readers that the methods used by MBRRACE-UK for perinatal confidential enquiries have been built on the learning from the Confidential Enquiry into Stillbirths and Deaths in Infancy and its successor bodies. Those who have been involved in the topic expert groups and panels for the enquiries carried out since 2012 will almost certainly have recognised that the enquiries have many features in common with those run by predecessor organisations.

    In this response we hope that we have addressed the concerns presented in the editorial and clarified how we have developed the MBRRACE -UK programme of work building on previous experience but using new methodologies where appropriate.

    References

    1. https://www.npeu.ox.ac.uk/downloads/files/mbrrace- uk/reports/MBRRACE-UK%20Perinatal%20Surveillance%20Report%202013.pdf 2. Smith L, Draper ES, Manktelow BN, Pritchard C, Field DJ. Comparing regional infant death rates: the influence of preterm births <24 weeks of gestation. Archives of Disease in Childhood Fetal & Neonatal Edition. 2013;98(2):F103-7. 3. The COPSS-CMS White Paper Committee, Ash AS, Fienberg SE, Louis TA, Normand S-LT, Stukel TA, et al. Statistical issues in assessing hospital performance: Committee of Presidents of Statistical Societies; 2012 [cited 2015 8 Apr]. Available from: http://www.cms.gov/Medicare/Quality- Initiatives-Patient-Assessment- Instruments/HospitalQualityInits/Downloads/Statistical-Issues-in-Assessing -Hospital-Performance.pdf 4. Mohammed MA, Manktelow BN, Hofer TP. Comparison of four methods for deriving hospital standardised mortality ratios from a single hierarchical logistic regression model. Statistical Methods in Medical Research. 2012:published online 6 November 2012. 5. Froen JF, Pinar H, Flenady V, Bahrin S, Charles A, Chauke L, et al. Causes of death and associated conditions (Codac) - a utilitarian approach to the classification of perinatal deaths. BMC Pregnancy and Childbirth. 2009;9(1):22.

    Conflict of Interest:

    None declared

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  6. Personality of young adults born preterm

    We read with interest the article by Eryigit-Madzwamuse et al (1) on the personality of young adults who were born preterm. We would like to draw the attention of the journal's readers to our recent work in the same field (2) with some important similarities and some interesting differences.

    We also studied approximately 200 cases and 200 controls and also assessed the 'big five' personality traits (neuroticism, extraversion, agreeableness, openness, and conscientiousness). Our cases were more preterm at birth (28 vs. 30 weeks), and in spite of this, the estimates of effect sizes expressed as population standard deviation (Cohen's d) were smaller for neuroticism (0.28 vs. 0.54) and for extraversion (0.30 vs. 0.45) while the effect size was similar for agreeableness (0.25 vs. 0.24).

    These differences may have led to a very different focus of the discussion section in the two articles. Eryigit-Madzwamuse et al used factor analysis (including a scale on autistic features) to build a concept of a 'socially withdrawn personality' and propose bullying in school as a link between the early neurodevelopmental impairments to the abnormalities of adult personality. We, on the other side, concluded that the effect sizes were smaller than the typical effect on IQ as a general measure of brain injury in very preterm infants. Also, the increased agreeableness could be the result of upbringing by adults appreciating the small miracle of survival. The increased agreeableness could help explain that the deficits in education, income, and family-building are surprisingly small (3).

    Were the differences in effect size due to differences in Bavarian and Danish culture as regards upbringing of children? Or was the difference in focus rather a question of seeing the glass as half empty or half full? Did it come from the fact that the authors were mainly psychologists or neonatologists, respectively?

    Yours, sincerely

    Gorm Greisen Department of Neonatology, Rigshospitalet, Copenhagen Denmark

    Bo M?lholm Hansen Department of Paediatrics, Herlev Hospital, Copenhagen, Denmark

    References 1. Eryigit-Madzwamuse S, Strauss V, Baumann N, Bartmann, Wolke D. Personality in adults who were born very preterm. Arch Dis Child Fetal Neonatal Ed 2015;100:F524-529. 2. Hertz CL, Mathiasen R, Hansen BM, Mortensen EL, Greisen G. Personality in Adults Who Were Born Very Preterm. PLoS ONE 2013; 8(6): e66881. doi:10.1371/journal.pone.0066881 3. Mathiasen R, Nybo-Andersen AM, Hansen BM, Greisen G. Social integration at the age of 30 years of individuals born before 33 weeks of gestation. Acta Paediatrica, 2007;120:96: 85.

    Conflict of Interest:

    None declared

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  7. Stopping rules for resuscitation at birth

    I read with interest the editorial by D Wilkinson and B Stenson commenting on a series of papers which suggest that current outcomes of neonates with APGAR scores of zero at 10 minutes are not universally poor. Given that stopping at 10 minutes in all cases will then lead to a number of unnecessary death they rightly ask what stopping time is appropriate.

    I wonder if this is the right question. A baby who has failed to respond to expert and prompt resuscitation by 10 or 12 minutes is likely to have a different prognosis to a baby who has had delayed or sub optimal resuscitation with possibly intubation first occurring at 10 minutes or more. We know from clinical experience that babies who requiring resuscitation due to hypovolaemia rather than prolonged fetal hypoxia often do better than their APGARs would suggest. Time from birth alone would seem to be too simplistic to predict the inevitability of death or severe disability in a very disparate group of infants.

    We need a paradigm shift possibly towards response to treatment as a predictor. Research is needed to identify a predictor that is both specific and easily clinically applicable in the first 20 minutes of life. The question is not "what is the right time" but "what is the right predictor".

    Conflict of Interest:

    None declared

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  8. Re: Herpes virus must be considered as one of the causes for late onset sepsis

    A culture-negative neonatal sepsis is more than herpes virus infection

    Ying Dong a, Christian P. Speer b

    a Department of Paediatrics, Children's Hospital of Fudan University, Shanghai, China

    b University Children's Hospital, University of Wurzburg, Wurzburg, Germany

    We highly appreciate the authors' contribution to the full picture of pathogens causing systemic late-onset neonatal infection. The letter by Dr. Batra and Dr. Smith highlights the morbidity and mortality of neonatal herpes infection, and in a broader sense, calls to our attention the differential diagnosis and treatment of culture-negative neonatal sepsis. It should be noted, however, that bacteria still remain to be the primary causative agents of neonatal sepsis, and negative culture results do not necessarily rule out the possibility of bacterial infections given the inherent limitation of culture technology and nonculturability of many potential pathogenic bacteria.1 With rapid development in molecular- based methods such as polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis, previous culture-negative cases deemed to have other pathogenic origins may actually turn out to be bacterial infections. Should the possibility of bacterial and fungal sepsis be reliably excluded, a viral etiology has to be considered. Apart from herpes virus, enteroviruses as well as parechoviruses are also demonstrated to be frequent viral causes of neonatal infections, with herpes virus identified in 17.5 per 100,000 live births and the latter two affecting up to 12% of neonates followed until one month of life. 2, 3, 4 The prevalence and the spectrum of viruses as well as the predominant virus in late-onset neonatal infections have yet to be revealed due to a lack of population- based epidemiological data. Virus infections have a spectrum of clinical manifestations ranging from nonspecific mild symptoms to sepsis-like illness which can result in rapid deterioration. 2, 3, 4 Enteroviruses, parechoviruses as well as herpes viruses were shown to be able to cause devastating infections among neonates, with risk factors and mortality rate yet to be adequately elucidated. Current data show that the mortality rate could be as high as 42% for enterovirus and 47% for herpes virus. 2, 4 Concerns about the adverse outcomes of severe viral infections prompt some clinicians to consider incorporating an antiviral agent into the empirical treatment of neonatal sepsis. However, this process may be confounded by the harm of using antiviral agents against sepsis proven otherwise and the difficulty in applying specified molecular techniques to confirm viral infections especially in resource-limited regions.

    We agree with Dr. Batra and Dr. Smith that the differentiation of systemic viral infections from bacterial late onset sepsis at presentation seem to be extremely difficult. Neonatologists and pediatricians should be highly vigilant and include viral infections in the differential diagnosis of late onset sepsis. No doubt, whenever herpes infection is suspected, a prompt treatment with acyclovir has to be initiated. However, we are hesitant to recommend intravenous acyclovir directed against herpes viruses as a routine strategy to be included in protocols on late onset sepsis. Besides the above mentioned open questions, future research should focus on rapid and reliable diagnostic procedures and markers of early diagnosis of neonatal infections which will allow a differentiation between bacterial, fungal and viral organisms. The authors have no potential conflict of interests.

    References

    1. Kellenberger E. Exploring the unknown. The silent revolution of microbiology. EMBO Rep 2001; 2:5-7.

    2. Tebruegge M, Curtis N. Enterovirus infections in neonates. Semin Fetal Neonatal Med 2009;14:222-7.

    3. Cilla A, Megias G, Suarez J, et al. Human parechovius and enterovirus in neonates: Distinct infections with overlapping features. Early Hum Dev 2015;91:475-8.

    4. Batra D, Davies P, Manktelow BN, Smith C. The incidence and presentation of neonatal herpes in a single UK tertiary centre, 2006-2013. Arch Dis Child 2014; 99:916-21.

    Conflict of Interest:

    None declared

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  9. Genomic Intensive Care: not a panacea

    Prognostication using whole genome and whole exome (WG/WE) sequencing depends on the use of a tool which - currently - has the potential to add to rather than decrease uncertainty. A problem in using information from genomic testing as a prognostic tool is the self-fulfilling nature of these 'diagnoses'. Many of these will initially be hypotheses, which become untestable unless the same genotypes are seen in family members or the variant is reported in the literature. Even where the consequences of a particular variant are known, a decision to discontinue active care of an infant is then considered to be an appropriate decision enabled by genomic methods, yet we will never know what would have happened if the baby had been supported further - perhaps the variant(s) were not (very) pathogenic?

    The form which non-directive counselling and informed consent would take in this context remains poorly evidenced. There is a need for situated empirical research into what constitutes 'informed' consent when the potential outcomes are so wide ranging. Binary classifications of the social, legal and ethical challenges into 'pro' versus 'con' lists fail to recognise that many of the advantages of these technologies are highly situated, situational and both beneficial and problematic - for example, increased diagnostic yield is an advantage, but having a diagnosis when the phenotype is highly variable and not yet apparent means counselling will be limited in its ability to provide information.

    Case 2 raises interesting challenges in that there are Gene x Environment interactions between copy number variants and adverse fetal, neonatal and childhood experiences, in terms of increased risk of psychiatric conditions in later life [1]. The failure to acknowledge the role of epigenetic factors fails to recognise the complexity of what the interpretation of prognostic information would/will be. Whilst the consequences of these complex epigenetic factors are difficult to take into account, not acknowledging them oversimplifies the situation, overstating the potential contribution of genomic information in this context.

    Without wanting to invoke genetic exceptionalism, it is difficult to see how other 'prognostic' investigations, such as MRI, can be compared with WGS/ES, given the potential for results which impact parents, both in terms of reproductive decision-making and current and future health. The extent of the role of genomics requires critical analysis and careful stewardship, as clinical, ethical, legal and social challenges emerge.

    [1] Harold GT et al. Biological and rearing mother influences on child ADHD symptoms: revisiting the developmental interface between nature and nurture. Journal of Child Psychology and Psychiatry 2013 Oct;54(10):1038-46. doi: 10.1111/jcpp.12100

    Conflict of Interest:

    None declared

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  10. CRP in the wrong context

    Unfortunately the authors have failed to understand the utility of CRP at 18-24 hours. This has a high negative predictie value but low positive predictive value. This means that while a low CRP is reassuring but a high value has to be evaluated in the clinical context. A high CRP should not be equal to a lumbar puncture. I should point that NICE guidelines do not recommend using CRP in isolation and clinical acumen should always prevail. This is a very small study over a short period of time and no information has been provided on the risk factors for infection in each of the groups.

    I call upon the reviewers to be critical of such publications as this letter may put people off using NICE guidelines which are actually a very useful and relevant set of guidelines.

    Conflict of Interest:

    None declared

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