Speech and Language Development, Hearing, and Feeding in Patients With Genetically Confirmed Crouzon Syndrome With Acanthosis Nigricans: A 36-Year Longitudinal Retrospective Review of Patients at the Oxford Craniofacial Unit.

OBJECTIVE: Crouzon syndrome with acanthosis nigricans (CAN) is caused by the specific mutation c.1172C>A (p.Ala391Glu) in the fibroblast growth factor receptor 3 gene, and has an estimated prevalence of 1:1,000,000 births. Most cases occur de novo; however, autosomal dominant inheritance may occur. The clinical presentation typically includes craniosynostosis, midface and maxillary hypoplasia, choanal atresia/stenosis, hydrocephalus, and intracranial hypertension. Patients develop acanthosis nigricans, a hyperkeratotic skin disorder. The authors present the first known study to investigate the speech, language, hearing, and feeding of patients with CAN. METHODS: A retrospective case-note review of patients with a genetically confirmed diagnosis of CAN attending the Oxford Craniofacial Unit during a 36-year period (1987-2023) was undertaken. RESULTS: Participants were 6 patients with genetically-confirmed CAN (5 females, 1 male), all cases arose de novo. All patients had craniosynostosis (n = 5/6 multisuture synostosis, n = 1/6 left unicoronal synostosis). Hydrocephalus was managed through ventriculoperitoneal shunt in 67% (n = 4/6) of patients, and 67% (n = 4/6) had a Chiari 1 malformation. Patients had a complex, multifactorial feeding history complicated by choanal atresia/stenosis (100%; n = 6/6), and significant midface hypoplasia. All patients required airway management through tracheostomy (83%; n = 5/6); and/or continuous positive airway pressure (67%; n = 4/6). All patients underwent adenotonsillectomy (100%; n = 6/6). Initial failure to thrive, low weight, and/or height were seen in 100% (n = 6/6) patients; 80% (n = 4/5) had reflux; 100% (n = 6/6) had nasogastric, or percutaneous endoscopic gastrostomy based feeding during their treatment journey. All patients had hearing loss (100%; n = 6/6). Early communication difficulties were common: receptive language disorder (50%; n = 3/6); expressive language disorder (50%; n = 3/6); and speech sound disorder in 50% (n = 3/6)-necessitating the use of Makaton in 80% of patients (n = 3/5). CONCLUSIONS: Patients with CAN experience significant respiratory, neurological, and structural obstacles to hearing, speech, language, and feeding. The authors present a recommended pathway for management to support patients in these domains.

A comparison of brain retraction mechanisms using finite element analysis and the effects of regionally heterogeneous material properties.

Finite element (FE) simulations of the brain undergoing neurosurgical procedures present us with the great opportunity to better investigate, understand, and optimize surgical techniques and equipment. FE models provide access to data such as the stress levels within the brain that would otherwise be inaccessible with the current medical technology. Brain retraction is often a dangerous but necessary part of neurosurgery, and current research focuses on minimizing trauma during the procedure. In this work, we present a simulation-based comparison of different types of retraction mechanisms. We focus on traditional spatulas and tubular retractors. Our results show that tubular retractors result in lower average predicted stresses, especially in the subcortical structures and corpus callosum. Additionally, we show that changing the location of retraction can greatly affect the predicted stress results. As the model predictions highly depend on the material model and parameters used for simulations, we also investigate the importance of using region-specific hyperelastic and viscoelastic material parameters when modelling a three-dimensional human brain during retraction. Our investigations demonstrate how FE simulations in neurosurgical techniques can provide insight to surgeons and medical device manufacturers. They emphasize how further work into this direction could greatly improve the management and prevention of injury during surgery. Additionally, we show the importance of modelling the human brain with region-dependent parameters in order to provide useful predictions for neurosurgical procedures.

Neuroendoscopic lavage for the management of neonatal post-haemorrhagic hydrocephalus: a retrospective series.

INTRODUCTION: Intraventricular haemorrhage (IVH) is a common complication of preterm birth, and optimal treatment remains uncertain. Neuroendoscopic lavage (NEL) has gained interest as a method for removal of intraventricular haematoma, with outcomes suggesting it to be safe and potentially effective. METHODS: A retrospective review was carried identifying infants who underwent NEL for post-IVH hydrocephalus at our institution. Data was extracted on patient baseline demographics, comorbidities, complications, re-operation requirement, and neurodevelopmental outcomes. RESULTS: Twenty-six patients (17 male) were identified, who underwent NEL at a mean age of 39 weeks and 4 days. Eighteen patients underwent simultaneous endoscopic third ventriculostomy (ETV). Mean patient follow-up was 57.7 months ± 11.8 months. A total of 17/26 patients went on to require a ventriculoperitoneal shunt (VPS). Nine patients did not require further surgical management of hydrocephalus; all had been managed with NEL + ETV. The relative risk of requiring VPS with NEL + ETV compared with NEL alone was 0.500 (CI: 0.315-0.794; p = 0.0033). The 24-month survival rate of VPS inserted following NEL was 64.7%. Exactly 5/26 (19.2%) had post-procedure complications: 2 CSF leaks (7.7%), 2 infections (7.7%), and 1 rebleed within 72 h of NEL (3.8%). On long-term follow-up, 22/25 patients achieved good motor outcome, either walking independently or with mobility aids. A total of 8/15 children attended mainstream schooling with adaption. DISCUSSION: NEL is safe and potentially efficacious treatment for neonatal IVH. The procedure may reduce shunt dependence and, for those who require CSF diversion, improve shunt survival. Neurodevelopmentally, good motor and cognitive outcome can be achieved.

Clinical signs, interventions, and treatment course of three different treatment protocols in patients with Crouzon syndrome with acanthosis nigricans.

OBJECTIVE: Crouzon syndrome with acanthosis nigricans (CAN) is a rare and clinically complex subtype of Crouzon syndrome. At three craniofacial centers, this multicenter study was undertaken to assess clinical signs in relation to the required interventions and treatment course in patients with CAN. METHODS: A retrospective cohort study of CAN was performed to obtain information about the clinical treatment course of these patients. Three centers participated: Erasmus Medical Centre, Rotterdam, the Netherlands; John Radcliffe Hospital, Oxford, United Kingdom; and Hôpital Necker-Enfants Malades, Paris, France. RESULTS: Nineteen patients (5 males, 14 females) were included in the study. All children were operated on, with a mean of 2.2 surgeries per patient (range 1-6). Overall, the following procedures were performed: 23 vault expansions, 10 monobloc corrections, 6 midface surgeries, 11 foramen magnum decompressions, 29 CSF-diverting surgeries, 23 shunt-related interventions, and 6 endoscopic third ventriculostomies, 3 of which subsequently required a shunt. CONCLUSIONS: This study demonstrates that patients with the mutation c.1172C>A (p.Ala391Glu) in the FGFR3 gene have a severe disease trajectory, requiring multiple surgical procedures. The timing and order of interventions have changed among patients and centers. It was not possible to differentiate the effect of a more severe clinical presentation from the effect of treatment order on outcome.

Septo-optic dysplasia.

Septo-optic dysplasia (SOD) or de Morsier's syndrome is a rare congenital disorder characterized by a classic triad of: (a) optic nerve hypoplasia, (b) agenesis of septum pellucidum and corpus callosum, and (c) hypoplasia of the hypothalamic-pituitary axis. This chapter will outline the key information regarding the etiology and epidemiology of this syndrome with a focus on its comprehensive management. Particular attention will be paid to the diagnostic stage and the most relevant differential diagnosis, before moving to the complexities of its treatment. In fact, although SOD is not curable, many aspects of this syndrome can be improved through a tailored multidisciplinary approach consisting in hormonal replacement, corrective ophthalmological surgery, management of epileptic seizures, and active neuropsychological support.

UK Chiari 1 Study: protocol for a prospective, observational, multicentre study.

INTRODUCTION: Chiari 1 malformation (CM1) is a structural abnormality of the hindbrain characterised by the descent of the cerebellar tonsils through the foramen magnum. The management of patients with CM1 remains contentious since there are currently no UK or international guidelines for clinicians. We therefore propose a collaborative, prospective, multicentre study on the investigation, management and outcome of CM1 in the UK: the UK Chiari 1 Study (UKC1S). Our primary objective is to determine the health-related quality of life (HRQoL) in patients with a new diagnosis of CM1 managed either conservatively or surgically at 12 months of follow-up. We also aim to: (A) determine HRQoL 12 months following surgery; (B) measure complications 12 months following surgery; (C) determine the natural history of patients with CM1 treated conservatively without surgery; (D) determine the radiological correlates of presenting symptoms, signs and outcomes; and (E) determine the scope and variation within UK practice in referral patterns, patient pathways, investigations and surgical decisions. METHODS AND ANALYSIS: The UKC1S will be a prospective, multicentre and observational study that will follow the British Neurosurgical Trainee Research Collaborative model of collaborative research. Patients will be recruited after attending their first neurosurgical outpatient clinic appointment. Follow-up data will be collected from all patients at 12 months from baseline regardless of whether they are treated surgically or not. A further 12-month postoperative follow-up timepoint will be added for patients treated with decompressive surgery. The study is expected to last three years. ETHICS AND DISSEMINATION: The UKC1S received a favourable ethical opinion from the East Midlands Leicester South Research Ethics Committee (REC reference: 20/EM/0053; IRAS 269739) and the Health Research Authority. The results of the study will be published in peer-reviewed medical journals, presented at scientific conferences, shared with collaborating sites and shared with participant patients if they so wish.

An Integrated Approach to the Management of Meningoencephalocoeles.

ABSTRACT: Meningoencephalocoeles are congenital herniations of meningeal and cerebral tissues through a cranial defect. They occur most commonly in South-East Asia, and are relatively rare amongst European ancestry populations, with an estimated prevalence of 1/40,000 live births. The treatment of congenital meningoencephalocoeles is primarily surgical and are best managed by dedicated multi-disciplinary craniofacial teams. The authors performed a retrospective case review of all primary meningoencephalocoeles managed in the Oxford University Hospitals NHS Foundation Trust between 1986 and 2012. Twenty-nine cases (13 frontal, 9 occipital, 2 parietal, and 5 basal) were included in this study. The median age at presentation was 11 months (range 0-60 years). Twenty-five cases presented with an external mass; 3 with recurrent meningitis and 1 with otorrhoea. Twenty-six cases underwent surgery, and 17 of these were managed by an integrated approach between 2 or more surgical specialties. Twenty out of 26 operations were performed via a transcranial approach. The authors describe a particularly complex case in order to highlight the challenges associated with management of meningoencephalocoeles, the surgical technique employed, and the importance of a multidisciplinary surgical approach. This is the largest reported case series of meningoencephalocoeles managed in a single hospital in the United Kingdom. Designated craniofacial units with access to multidisciplinary surgical specialties provide a safe and optimal setting for the management of meningoencephalocoeles.

Feeding, Communication, Hydrocephalus, and Intracranial Hypertension in Patients With Severe FGFR2-Associated Pfeiffer Syndrome.

BACKGROUND: Pfeiffer syndrome is associated with a genetic mutation of the FGFR2 (or more rarely, FGFR1) gene, and features the combination of craniosynostosis, midface hypoplasia, broad thumbs and broad great toes. Previous research has identified a wide spectrum of clinical phenotypes in patients with Pfeiffer syndrome. This study aimed to investigate the multifactorial considerations for speech, language, hearing and feeding development in patients with severe genetically-confirmed Pfeiffer syndrome. METHODS: A 23-year retrospective case-note review of patients attending the Oxford Craniofacial Unit was undertaken. Patients were categorized according to genotype. Patients with mutations located in FGFR1, or outside the FGFR2 IgIII domain-hotspot, or representing known Crouzon/Pfeiffer overlap substitutions were excluded. Twelve patients with severe FGFR2-associated Pfeiffer syndrome were identified. RESULTS: Patients most commonly had pansynostosis (n = 8) followed by bicoronal (n = 3), and bicoronal and sagittal synostosis (n = 1). Seven patients had a Chiari I malformation. Four patients had a diagnosis of epilepsy. Ten patients had with hydrocephalus necessitating ventriculoperitoneal shunt insertion.Feeding difficulties were common (n = 10/12) and multifactorial. In 5/12 cases, they were associated with pansynostosis, hydrocephalus, tracheostomy and tube feeding in infancy.Hearing data were available for 10 patients, of whom 9 had conductive hearing loss, and 8 required hearing aids. Results indicated that 3/4 patients had expressive language difficulties, 3/4 had appropriate receptive language skills. 6/12 patients had a speech sound disorder and abnormal resonance. CONCLUSION: This study has identified important speech, language, hearing and feeding issues in patients with severe FGFR2-associated Pfeiffer syndrome. Results indicate that a high rate of motor-based oral stage feeding difficulties, and pharyngeal stage swallowing difficulties necessitating regular review by specialist craniofacial speech and language therapists.

Central Retinal Artery Occlusion Following Prone Transcranial Surgery for Craniosynostosis and Discussion of Risk Factors.

Vision loss is a known rare complication of prone positioning during surgery. Vision loss following prone surgery is most commonly attributed to direct pressure on the eye but can also be caused by central retinal artery occlusion (CRAO) in the absence of pressure on the eye. Central retinal artery occlusion has not been previously described following prone transcranial surgery for craniosynostosis. We present two cases of monocular CRAO following prone calvarial expansion. A multidisciplinary root cause analysis suggested that raised intracranial pressure and intraoperative tranexamic acid may have been risk factors for the development of CRAO in these cases as no conventional risk factors for CRAO following prone surgery were present. Because of this, we retrospectively reviewed all prone transcranial procedures performed at the Oxford Craniofacial Unit for the presence of raised intracranial pressure and intraoperative tranexamic acid use. A total of 662 prone procedures have been performed between 1994 and March, 2019. Tranexamic acid has been used routinely in all transcranial procedures since 2012 and in the last 311 consecutive prone cases. Fifty-one (7.7%) prone procedures were performed for raised intracranial pressure, and tranexamic acid was used in the 33 most recent of these. Since the implementation of standard intraoperative administration of tranexamic acid there have been 2 cases of CRAO following prone surgery. The overall incidence of CRAO was 0.3% but was 6% in the context of raised intracranial pressure and tranexamic acid use. Prone positioning raised intracranial pressure and tranexamic acid use together may represent a potent combination of risk factors for CRAO.

Neuro-Ophthalmological Manifestations Of Septo-Optic Dysplasia: Current Perspectives.

Septo-optic dysplasia (SOD), also known as de Morsier syndrome, is a rare congenital disorder belonging to the group of mid-line brain malformations. Despite the highly variable phenotypic penetration, its classical triad include a) optic nerve hypoplasia (ONH), b) agenesis of septum pellucidum and corpus callosum, and c) hypoplasia of the hypothalamo-pituitary axis. SOD has stringent diagnostic criteria requiring 2 or more features of the classic triad, therefore it represents a separate entity from other conditions such as ONH and achiasmia syndromes which share only some of these aspects, or SOD plus syndrome which is characterized by additional cortical abnormalities. Starting from its etiology and epidemiology, this narrative review focuses on the management of SOD patients, including their diagnosis, treatment and follow-up. To date, SOD is not curable; nonetheless, many of its symptoms can be improved through a tailored approach, consisting of hormonal replacement, corrective ophthalmological surgery and neuropsychological support.

Language Development, Hearing Loss, and Intracranial Hypertension in Children With TWIST1-Confirmed Saethre-Chotzen Syndrome.

Saethre-Chotzen syndrome (SCS) is an autosomal dominant condition defined by mutations affecting the TWIST1 gene on chromosome 7p21.1. Previous research has identified an elevated prevalence of intracranial hypertension and hearing impairment associated with this syndrome. This study aimed to investigate the influence of hearing history and presence of intracranial hypertension on language development in children with SCS.A retrospective study note analysis was performed for all patients with a confirmed TWIST1 gene abnormality who attended the Oxford Craniofacial Unit and underwent a language assessment over a 22-year period. Intracranial pressure monitoring, hearing status, and language outcomes were examined in detail.Thirty patients with genetically confirmed SCS and language assessment data were identified. Twenty-eight patients underwent surgical intervention; 10 presented with intracranial hypertension (5 prior to, and 5 after primary surgical intervention). Language data coinciding with the presentation of intracranial hypertension were available for 8 children. About 44% of children with intracranial hypertension presented with concurrent receptive and expressive language delay (n = 4/8). For both children (n = 2) with longitudinal language data available, the onset of intracranial hypertension reflected a concurrent decline in language skills. Audiometric data were available for 25 children, 80% (n = 20/25) had a history of hearing loss. About 50% of these had confirmed conductive hearing loss with middle ear effusion and the other 50% had presumed conductive hearing loss with middle ear effusion. About 100% of the children with available hearing data in our study had evidence of middle ear effusion in at least 1 ear. Results also indicated that 43% (n = 13/30) of the children presented with receptive and/or expressive language delay during childhood.Given the importance of hearing for language development and the preliminary findings of a potential decline in language skills in children during periods of intracranial hypertension, regular follow-up of hearing, language, and intracranial hypertension are indicated in children with SCS.

Decompressive surgery for Chiari I malformation in children without dural repair: a still effective and safe procedure?

PURPOSE: There are numerous publications about the technical aspects of decompressive surgery for Chiari I malformation highlighting many variations of this procedure. Each approach has its followers. Bony decompression of the foramen magnum alone or with the removal of a portion of the posterior arch of C1, dural splitting with keeping arachnoid intact, and durotomy are described. Dural closure is done with various materials. We retrospectively reviewed foramen magnum decompression without dural repair (FMDWDR) following the technique used by Gardener and Williams as an option in pediatric patients with Chiari I malformation in terms of complication rate and clinical outcome. METHODS: The surgical database of our unit identified 65 consecutive children who underwent FMDWDR surgery for Chiari I malformation between 2009 and 2016. The retrospective assessment included patient demographics, clinical data, surgical technique, revision rate, complications, and clinical outcome. RESULTS: Durotomy without repair was performed in 65 patients. Complications included aseptic meningitis and subdural hematoma respectively in three cases, intradiploic CSF collections in three patients, and CSF leaks in six children. The CSF leak rate has reduced dramatically after introducing a technical modification. Revision surgery was performed in seven cases. None of the patients was identified with postoperative hydrocephalus or infection. There was no mortality and no long-term surgical morbidity. In terms of clinical outcome, 52 patients reported postoperative improvement, 10 were clinically unchanged, and three noticed worsening of symptoms. CONCLUSION: Applying a "T"-shaped fascial incision which allows a watertight closure of the fascia FMDWDR is still a safe and effective treatment option for Chiari I malformation in children.

Do equestrian helmets prevent concussion? A retrospective analysis of head injuries and helmet damage from real-world equestrian accidents.

OBJECTIVES: To collect and analyse helmets from real-world equestrian accidents. To record reported head injuries associated with those accidents. To compare damage to helmets certified to different standards and the injuries associated with them. METHODS: Two hundred sixteen equestrian helmets were collected in total. One hundred seventy-six helmets from amateur jockeys were collected via accident helmet return schemes in the UK and USA, while 40 helmets from professional jockeys were collected by The Irish Turf Club. All helmet damage was measured, and associated head injury was recorded. RESULTS: Eighty-eight percent (189) of equestrian fall accidents returned an injury report of which 70% (139) reported a head injury. Fifty-four percent (75) of head injury cases had associated helmet damage while 46% had no helmet damage. Reported head injuries consisted of 91% (126) concussion, 4% (6) skull fractures, 1 (0.7%) subdural hematoma, 1 (0.7%) cerebral edema and 5 (3.6%) diffuse axonal injury (DAI). It is also shown that helmets certified to the most severe standard are overrepresented in this undamaged group (p <0.001). CONCLUSIONS: It is clear that despite jockeys wearing a helmet, large proportions of concussion injuries still occur in the event of a jockey sustaining a fall. However, the data suggest it is likely that helmets reduce the severity of head injury as the occurrence of skull fracture is low. The proportion of undamaged helmets with an associated head injury suggests that many helmets may be too stiff relative to the surface they are impacting to reduce the risk of traumatic brain injury (TBI). It may be possible to improve helmet designs and certification tests to reduce the risk of head injury in low-severity impacts.

Staged Raising of a Coronal Flap for Fronto-Orbital Advancement and Remodeling in Saethre-Chotzen Syndrome Complicated by Sinus Pericranii.

This article reports the surgical management of a 3-month-old girl with Saethre-Chotzen syndrome, who presented with bicoronal synostosis and a large midline sinus pericranii with abnormal cerebral venous drainage via scalp veins. Raised intracranial pressure was demonstrated on monitoring, indicating the need for calvarial expansion necessitating a coronal access incision. A 2-staged delayed raising of the coronal flap was performed to reduce the potential risk of cerebral venous infarction. Monitoring for clinical sequelae and a computerised tomography venogram followed each of these procedures, demonstrating successful redirection of the venous drainage of the brain posteriorly. Finally, a successful fronto-orbital advancement and remodeling procedure was performed with no complications.

Should all paediatric patients with presumed idiopathic scoliosis undergo MRI screening for neuro-axial disease?

BACKGROUND: Idiopathic scoliosis is a relatively common childhood condition affecting 0.47-5.2% of the population. Traditional interventions focus on orthopaedic correction of the curve angle. There is a spectrum of patients with scoliosis who are found to have neuro-axial abnormality on full MRI of the spine, but not all surgeons request imaging in the absence of neurological symptoms. There is evidence to suggest that treatment of neuro-axial disease may improve scoliosis curve outcome. We therefore sought to estimate what proportion of patients with normal neurology and scoliosis are found to have neuro-axial abnormality on full MRI imaging of the spine, in particular Chiari malformation and syringomyelia. RESULTS: Out of 11 identified studies consisting of 3372 paediatric patients (age < 18 years), mean weighted proportion demonstrates that 14.7% of patients with scoliosis (Cobb angle > 20°) and normal neurological examination will demonstrate a neuro-axial abnormality on full MRI imaging of the spine. Of patients, 8.3 and 8.4% were found to have Chiari malformation and syringomyelia, respectively. CONCLUSIONS: Up to one in seven paediatric patients with scoliosis and normal neurological examination will demonstrate neuro-axial disease on MRI imaging of the spine. Given that younger age and earlier age of decompression is associated with improvement in curve angle, it seems important that MRI screening be considered in all patients regardless of neurological examination findings. There is a potentially long-term benefit in these patients. Multi-cross institutional prospective studies are encouraged to further investigate effect on curve angle.

Long-Term Results in Isolated Metopic Synostosis: The Oxford Experience over 22 Years.

BACKGROUND: Metopic synostosis causing trigonocephaly is treated by fronto-orbital advancement and remodeling to correct the deformity and cerebral distortion and to treat intracranial hypertension in a small number of cases. The aim of this study was to evaluate complications, revisions, and long-term outcomes. METHODS: A retrospective chart review was performed on consecutive metopic craniosynostosis patients treated between February of 1995 and February of 2017 at the Oxford Craniofacial Unit. RESULTS: Two hundred forty-five patients with isolated metopic synostosis were seen. Two hundred two patients underwent fronto-orbital advancement and remodeling. Fifty patients were girls and 152 patients were boys. Mean age at surgery was 16.8 months. Mean weight preoperatively was 12 kg. All patients received blood transfusion. Mean postoperative stay was 6 days. Average follow-up time was 8 years (range, 0.5 to 22 years). There were eight major complications (4 percent). Six patients (2.9 percent) required secondary calvarial expansion for late raised intracranial pressure. Thirty-one (15 percent) had other subsequent procedures, including wire removal and forehead shape contouring with alloplastic onlay. Raised intracranial pressure before surgery was confirmed in two cases by intracranial pressure monitoring. CONCLUSIONS: Trigonocephaly is caused by metopic synostosis and is treated by fronto-orbital advancement and remodeling to restore both internal and external skull configuration. After surgery, the authors identified a 2.9 percent risk of late raised intracranial pressure requiring a secondary calvarial expansion, necessitating prolonged follow-up in all cases. Temporal hollowing and forehead contour defects were not uncommon. This is the largest reported series of metopic synostosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Mechanistic models versus machine learning, a fight worth fighting for the biological community?

Ninety per cent of the world's data have been generated in the last 5 years (Machine learning: the power and promise of computers that learn by example Report no. DES4702. Issued April 2017. Royal Society). A small fraction of these data is collected with the aim of validating specific hypotheses. These studies are led by the development of mechanistic models focused on the causality of input-output relationships. However, the vast majority is aimed at supporting statistical or correlation studies that bypass the need for causality and focus exclusively on prediction. Along these lines, there has been a vast increase in the use of machine learning models, in particular in the biomedical and clinical sciences, to try and keep pace with the rate of data generation. Recent successes now beg the question of whether mechanistic models are still relevant in this area. Said otherwise, why should we try to understand the mechanisms of disease progression when we can use machine learning tools to directly predict disease outcome?