APPARATUS AND METHOD FOR ASSESSMENT OF SUSCEPTIBILITY TO CONDITIONS HAVING A CRANIOFACIAL MORPHOLOGICAL RELATIONSHIP

TECHNICAL FIELD

[ 0001 ] The present invention relates to methods and apparatus for assessment of susceptibility of a patient to a condition and in particular to methods and apparatus for assessment of susceptibility of a patient to a condition using craniofacial photogrammetry.

[ 0002 ] The invention has been developed primarily for use as a methods and apparatus for assessment of susceptibility of a patient to a clinical condition which has a craniofacial morphological relationship, that is, the condition may exhibit particular craniofacial features in the patient, or alternatively may be influenced or caused by the patient's particular craniofacial features - an example condition being obstructive sleep apnoea syndrome - using digital (or digitised) craniofacial photographs of the patient and will be described hereinafter with reference to this application. However, it will be appreciated that the invention is not limited to this particular field of use and may for example be adapted for assessment of the patient's susceptibility or risk to other clinical conditions which affect the patient's craniofacial morphology.

BACKGROUND OF THE INVENTION

[ 0003 ] Any discussion of the background art throughout the specification should in no way be considered as an admission that such background art is prior art, nor that such background art is widely known or forms part of the common general knowledge in the field. [ 0004 ] Obstructive sleep apnoea (OSA) is a very common disorder associated with snoring, repetitive upper airway collapse during sleep, oxygen desaturation and intermittent hypoxia [see Malhotra A, White DP, Obstructive sleep apnoea, Lancet 2002;360:237-245; or Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S, The occurrence of sleep-disordered breathing among middle-aged adults N Engl J Med 1993;328: 1230-1235]. Snoring and OSA are highly prevalent disorders: 50% of men and 20-30% of women snore; 25% of men and 9% of women have sleep-disordered breathing. This results in sleep fragmentation and consequent decrements in daytime functioning, such as excessive daytime sleepiness and neurocognitive impairment. OSA is associated with cardiovascular morbidity, motor vehicle accident risks and overall mortality [Marin JM, Carrizo SJ, Vicente E, Agusti AGN, Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: An observational study, Lancet 2005;365: 1046-1053].

[ 0005 ] The diagnosis of OSA is cumbersome because of the need for specialist assessment and overnight monitoring in a sleep laboratory; the latter is expensive, labour intensive and resource limited [Flemons WW, Douglas NJ, Kuna ST, Rodenstein DO, Wheatley J, Access to diagnosis and treatment of

patients with suspected sleep apnea, American Journal of Respiratory & Critical Care Medicine 2004;169:668-672]. As a result, the recognition of OSA in the community is low, and the majority of sufferers of OSA are as yet undiagnosed [Young T, Evans L, Finn L, Palta M, Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women, Sleep 1997;20:705-706]. Hence, there is a tremendous clinical need to develop a method to improve recognition and diagnosis of OSA in the community.

[ 0006 ] Whilst obesity is a major risk factor for OSA, many patients are not obese. It is recognised from studies using radiological techniques that craniofacial morphology plays an important role in the development of OSA [Miles PG, Vig PS, Weyant RJ, Forrest TD, Rockette HE, Jr, Craniofacial structure and obstructive sleep apnea syndrome— a qualitative analysis and meta-analysis of the literature, Am J Orthod Dentofacial Orthop 1996; 109: 163-172; or Okubo M, Suzuki M, Horiuchi A, Okabe S, Ikeda K, Higano S, Mitani H, Hida W, Kobayashi T, Sugawara J, Morphologic analyses of mandible and upper airway soft tissue by MRI of patients with obstructive sleep apnoea hypopnea syndrome, Sleep 2006;29:909-915]. Narrowing of the facial skeleton can result in a narrow upper airway and a predisposition to OSA. It is thought that the interaction between craniofacial morphology and obesity determines the likelihood and severity of OSA in the majority of patients [Ferguson KA, Ono T, Lowe AA, Ryan CF, Fleetham JA, The relationship between obesity and craniofacial structure in obstructive sleep apnea, Chest 1995;108:375-381; or Watanabe T, Isono S, Tanaka A, Tanzawa H, Nishino T, Contribution of body habitus and craniofacial characteristics to segmental closing pressures of the passive pharynx in patients with sleep-disordered breathing, American Journal of Respiratory & Critical Care Medicine 2002; 165:260-265]. At one end of the spectrum are patients whose OSA is entirely due to obesity and the associated deposition of fat around the airway structures. At the other end of the spectrum are patients whose airway narrowing is solely due to craniofacial skeletal abnormalities. The majority of patients fall somewhere between these two extremes. [ 0007 ] Clinical algorithms have been developed to predict the likelihood of OSA in patients; however, these algorithms are limited to determining a risk factor for OSA based on data such as patient demographics and obesity (e.g. body mass index, neck circumference). Craniofacial morphology and risk factors are rarely considered [Maislin G, Pack AI, Kribbs NB, Smith PL, Schwartz AR, Kline LR, Schwab RJ, Dinges DF, A sur\>ey screen for prediction of apnea, Sleep 1995;18:158-166; or Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP, Using the berlin questionnaire to identify patients at risk for the sleep apnea syndrome, Annals of Internal Medicine 1999;131:485-491].

[ 0008 ] Overall, the accuracy of these clinical algorithms is suboptimal to justify their routine use in the clinical diagnosis of OSA. The limited inclusion of craniofacial morphology data into prediction models relates to the impractical nature of the currently available craniofacial measurement tools. For example, Tsai et al [A decision rule for diagnostic testing in obstructive sleep apnea, Am J Respir Crit

Care Med, 2003; 167:1427-1432] did include intra-oral and craniofacial factors in their attempt to predict OSA, using manual measurements obtained by a ruler. Notably their approach resulted in a significant proportion (60%) of subjects remaining unclassified in terms of OSA risk, vastly limiting its clinical application. [ 0009 ] Craniofacial anthropometry techniques using callipers or rulers have previously been employed; however suffer from their time consuming procedures and poor inter-operator accuracy. Radiological techniques such as cephalometric x-rays, Computerised Tomography (CT) scans, or Magnetic Resonance Imaging (MRI) scans have also been proposed, however, these techniques have a limited role due to their expense, availability, radiation exposure (except MRI which exposes patients to magnetic fields), and inconvenience to the patient.

[ 0010 ] There has been limited work in the field of orthodontics looking at correlations between cephalometric x-rays and clinical photography of the face and head, but not in the context of OSA. For example, Zhang et al [Correlations between cephalometric and facial photographic measurements of craniofacial form, am J Orthod Dentofacial Orthop, 2007; 131:67-71] found only modest correlations between analogous photographic and cephalometric x-ray measurements, suggesting that they measure different aspects of facial morphology. Another example of the use of craniofacial photography was in congenital central hypoventilation syndrome, an unrelated condition to OSA, in order to demonstrate characteristic abnormalities in craniofacial morphology [Todd ES, Weinberg SM, Berry-Kravis EM, Silvestri JM, Kenny AS, Rand CM, Zhou L, Maher BS, Marazita ML, Weese-Mayer DE, Facial phenotype in children and young adults with phox2b-determined congenital central hypoventilation syndrome: Quantitative pattern of dysmorphology, Pediatr Res 2006;59:39-45]. Prediction of OSA based mainly on clinical parameters and a single neck measurement obtainable from a lateral head and neck photograph has been examined in the context of ethnic differences in OSA susceptibility, but the approach taken is impractical in the clinical context [Lam B, Ip MSM, Tench E, Ryan CF, Craniofacial profile in Asian and white subjects with obstructive sleep apnoea, Thorax 2005;60:504-510].

[ 0011 ] The current diagnostic pathways for these conditions are complex, and the demand for services far outweighs supply and thus, there is an overwhelming need for simplified diagnostic methods. That is, a need exists for a clinically practical, inexpensive and non-invasive method of quantitative craniofacial assessment of a patient's risk of a condition such as OSA or others where the condition is related to the patient's craniofacial morphology.

SUMMARY OF THE INVENTION

[ 0012 ] In a first aspect, there is provided a method for assessing the presence of a condition in a patient or the patient's susceptibility to the condition, comprising the steps of: obtaining at least one photograph or image of the patient's craniofacial features; identifying a plurality of craniofacial

landmarks derived from the photograph; calculating at least one measurement of the patient's craniofacial morphology from at least two of the landmarks; comparing the at least one measurement with craniofacial morphology measurements identified as being indicative of the presence of or susceptibility to the condition; and on the basis of the comparing, providing an assessment of the presence of the condition in the patient or the patient's susceptibility to the condition.

[ 0013 ] In this first aspect, the method for assessing the presence of a condition in a patient or the patient's susceptibility to the condition, at least one photograph or image of the patient's craniofacial features is obtained. A plurality of craniofacial landmarks derived from the photograph are identified and their locations recorded relative to the photograph or image. At least one measurement of the patient's craniofacial morphology is calculated from at least two of the landmarks, and the measurements may be calculated from two, three, four, five, six, seven or more of the landmarks as per requirements. The at least one measurement is compared with craniofacial morphology measurements which are identified as being indicative of the presence of or susceptibility to the condition. As a result of the comparison to indicative craniofacial features, an assessment of the presence of the condition in the patient or the patient's susceptibility to the condition is thus provided.

[ 0014 ] In a particular arrangement, two photographs of the patient may be obtained comprising a frontal photograph and a profile photograph of the patient. The photographs may be calibrated such that absolute measurements may be calculated from the identified craniofacial landmarks. Alternatively, the photograph may be an uncalibrated image and the calculated measurements may be relative measurements comprising either angular measurements or a ratio of one or more measurements. In another arrangement a single three dimensional photograph or image of the patient may be obtained. The three dimensional image may provide frontal and profile aspects of the patient for further analysis. The three dimensional image may be a calibrated image such that absolute measurements may be calculated from the identified craniofacial landmarks. Alternatively, the three dimensional image may be an uncalibrated image and the calculated measurements may be either angular measurements or relative measurements comprising a ratio of one or more measurements.

[ 0015 ] The craniofacial landmarks identified may be selected from the group of Tragion (L), Tragion (R), Gordon (L), Gonion (R), Euryon (L), Euryon (R), Exocanthion (L), Exocanthion (R), Endocanthion (L), Endocanthion (R), Alare (L), Alare (R), Neck (L), Neck (R), Tragion, Exocanthion, Supraorbital ridge, Glabella, Nasion, Subnasion, Stomion, Sublabiale, Gnathion, Mentum, Cervical point, Thyroid, Cricoid, Neck plane, Sternal notch, Gonion, Ramus, Opisthocranion, Vertex, Anterior neck, Posterior neck, Columella of nose, Labiale superius, Labiale inferius, Cheilion (L) or Cheilion (R). The landmarks may be automatically identified with the use of a facial recognition software package.

[ 0016 ] At least one or a plurality of measurements of the patient's craniofacial morphology may be calculated, each measurement being derived from at least two of the craniofacial landmarks. The measurement or measurements may be selected from the group of a lineal measurement, an angular measurement, an areal measurement, or a volumetric measurement. Where a plurality of measurements are calculated, the measurements may be from a selection of one or more lineal measurements, angular measurements, circumferential measurements, areal measurements, or volumetric measurements.

[ 0017 ] The at least one calculated measurement may comprise at least one lineal measurement selected, with reference to Table 4, from the group of upper face depth, upper face depth - horizontal, upper face depth - diagonal, mid face depth 1, mid face depth 1 - horizontal, mid face depth 1 - diagonal, mid face depth 2, mid face depth 2 — horizontal, lower face depth 1, lower face depth 1 - horizontal, lower face depth 1 - diagonal, lower face depth 2, lower face depth 2 - horizontal, lower face depth 2 - diagonal, total face height — vertical, total face height, nose height — vertical, nose height, upper face height - vertical, upper face height, lower face height 1 - vertical, lower face height 1, lower face height 2

- vertical, lower face height 2, anterior mandibular height — vertical, anterior mandibular height, mandibular length 1, mandibular length 1 - diagonal, mandibular length 2, mandibular length 2 - diagonal, mandibular length 1 - horizontal, posterior mandibular height - vertical, posterior mandibular height, lateral face height, maxillary mandibular depth 1, maxillary mandibular depth 2, maxillary length

- horizontal, tragion-cervical distance, tragion-cervical distance - diagonal, tragion-thyroid distance, tragion-thyroid distance - diagonal, tragion-cricoid distance, tragion-cricoid distance - diagonal, thyromental distance - horizontal, thyromental distance, cricomental distance - horizontal, cricomental distance, sternomental distance - horizontal, sternomental distance, sternomental distance — vertical, thyro-mandibular distance - vertical, thyro-mandibular distance, crico-mandibular distance - vertical, crico-mandibular distance, sterno-mandibular distance - vertical, sterno-mandibular distance, sterno- tragion distance - vertical, cricomental space distance, total craniofacial height, maximum cranial length, neck depth, face width, mandible width, maximum cranial width, eye width, intercanthal width, biocular width, nose width, neck width, neck perimeter or lip measurements (upper lip height, lower lip height, lateral lip height, upper vermilion, lower vermilion, mouth breadth).

[ 0018 ] The at least one calculated measurement may comprise at least one angular measurement selected from the group of maxillary depth angle, mandibular depth angle 1, mandibular depth angle 2, mandibular depth angle 3, maxillary-mandibular relationship angle 1, maxillary-mandibular relationship angle 2, maxillary-mandibular relationship angle 3, mandibular-nasion angle 1, mandibular-nasion angle 2, mandibular-subnasion angle 1, mandibular-subnasion angle 2, natural head position angle, head base inclination angle, mandibular plane angle 1, mandibular plane angle 2, facial axis angle, thyromental angle, cervico-mental angle, mandibular width-length angle, face width-mid face depth angle, face base width-lower face depth angle, or nasolabial angle.

[ 0019 ] The at least one calculated measurement may comprise at least one areal measurement selected from the group of thyromental space area (sag), cricomental space area (sag), anterior neck space area (sag), submandibular soft tissue area (sag), anterior neck soft tissue area (sag), total anterior neck soft tissue area (sag), posterior neck soft tissue area (sag), total neck soft tissue area (sag), neck circumference s area (ax), cranial base-maxillary triangle area (sag), maxillary triangle area (sag), mandibular triangle area (sag), maxillary-mandibular box area (sag), mandibular pharyngeal triangle area (sag), maxillary- mandibular pharyngeal box area (sag), tragion-neck area 1 (sag), tragion-neck area 2 (sag), mandibular cricoid area (ax), cranial base triangle area (ax), cranial base area 1 (ax), cranial base area 2 (ax), maxillary triangle area (ax), or mandibular triangle area (ax).

IQ [ 0020 ] The at least one calculated measurement may comprise at least one volumetric measurement selected from the group of middle cranial fossa volume, maxillary volume, mandibular volume, maxillary-mandibular volume 1 , neck soft tissue volume 1 , neck soft tissue volume 2, neck soft tissue volume 3, total anterior neck soft tissue volume 1, total anterior neck soft tissue volume 2, total anterior neck space volume 1, total anterior neck space volume 2, tragion neck soft tissue volume 1, tragion neck

I ₅ soft tissue volume 2, tragion neck soft tissue volume 3, tragion neck soft tissue volume 4, posterior neck soft tissue volume, or total neck soft tissue volume.

[ 0021 ] In one arrangement, where a plurality of measurements are calculated, the measurements may be selected from the group of face width, eye width, mandibular length, sterno-mandibular distance, mandibular-nasion angle, crico-mental space area, cervico-mental angle, neck cross-sectional area, 2Q tragion-neck soft tissue volume, or neck circumference.

[ 0022 ] In another arrangement where a plurality of measurements are calculated, the measurements may be selected from the group of face width, eye width, total facial height, mid-face width, or neck circumference.

[ 0023 ] In another arrangement where a plurality of measurements are calculated, the measurements 2 ₅ being selected from the group of face width, eye width, total facial height, mid-face width, neck circumference, or the lip measurements.

[ 0024 ] The method may further comprise the step of calculating the patient's body mass index (BMI), neck circumference (NC), waist circumference (WC) and comparing the at least one measurement with craniofacial morphology measurements and the BMI, NC, WC to provide an assessment of either the 0 presence of the condition in the patient or the patient's susceptibility to the condition. The method may further comprise the step of obtaining and calculating intra-oral measurements of the patients and comparing the at least one measurement with craniofacial morphology measurements and the intra-oral measurements to provide an assessment of either the presence of the condition in the patient or the patient's susceptibility to the condition. The method may also comprise a combination of questionnaire,

craniofacial photographic analysis and/or portable monitoring systems (for example a portable sleep monitor in the case of OSA) for assessing the presence or susceptibility of the condition. Such a questionnaire could include, but not be limited to, information regarding snoring, witnessed apnoeas, daytime symptoms (including sleepiness), history of co-existent medical disorders (for example hypertension, cardiovascular or cerebrovascular disease, metabolic syndrome or type 2 diabetes). The method may also comprise a combination of photographic analysis and intra-oral measurements, taken manually or by photographic means, for assessing the presence or susceptibility of the condition. Specific examples of intra-oral measurements include, but are not limited to, hard palate height, maxillary depth, maxillary width (at a number of tooth levels), mandibular width (at a number of tooth levels), presence of anterior or posterior cross bites, overjet, and overbite.

[ 0025 ] The method for assessing the presence of a condition in a patient or the patient's susceptibility to the condition may be a method for assessing the presence of a condition which either affects or is influenced by the patient's craniofacial morphology. The craniofacial morphologic condition may be the presence of obstructive sleep apnoea in a patient or the patient's susceptibility to obstructive sleep apnoea.

[ 0026 ] Where a frontal calibrated photograph and a profile calibrated photograph are obtained and a plurality of measurements are calculated, the measurements may be selected from the group of face width, eye width, cervico-mental angle and mandibular length 1. The assessment of either the presence of the condition in the patient or the patient's susceptibility (probability) to OSA is computed using the formula l/[l+exp(-z)] wherein z = [A+ B X (face width) + C X (eye width) + D x (cervico-mental angle) + E X (mandibular length I)] where A, B, C, D and E are constants, the face width, eye width and mandibular length 1 measurements are expressed in centimetres and the cervico-mental angle measurement is expressed in degrees.

[ 0027 ] Where a frontal uncalibrated photograph and a profile uncalibrated photograph are obtained and a plurality of measurements are calculated, the measurements may be selected from the group of face width, eye width, cervico-mental angle and mandibular-nasion angle. The assessment of either the presence of the condition in the patient or the patient's susceptibility (probability) to OSA is computed using the formula l/[l+exp(-z)] wherein z - [A+ B X (face width / eye width) + C X (cervico-mental angle) + D x (mandibular-nasion angle)] where A, B, C and D are constants and the measurements of the cervico-mental angle and the mandibular-nasion angle are each expressed in degrees.

[ 0028 ] According to a second aspect, there is provided, a method of diagnosing a condition in a patient, wherein the condition exhibits craniofacial morphology, the method comprising the steps of: obtaining at least one photograph or image of the patient's craniofacial features; identifying a plurality of craniofacial landmarks derived from the photograph; calculating at least one measurement of the

patient's craniofacial morphology from at least two of the landmarks; comparing the at least one measurement with craniofacial morphology measurements identified as being indicative of the presence of or susceptibility to the condition; and on the basis of the comparing, providing diagnosis the condition in the patient. [ 0029 ] According to a third aspect, there is provided a clinical assessment device for assessing the presence of a condition in a patient or the patient's susceptibility to the condition, comprising: means for obtaining at least one photograph or image of the patient's craniofacial features; means for identifying a plurality of craniofacial landmarks derived from the photograph; means for calculating at least one measurement of the patient's craniofacial morphology from at least two of the landmarks; means for comparing the at least one measurement with craniofacial morphology measurements identified as being indicative of the presence of or susceptibility to the condition; and on the basis of the comparing, means for providing an assessment of the presence of the condition in the patient or the patient's susceptibility to the condition.

[ 0030 ] According to a fourth aspect, there is provided, an assessment of the presence of a condition in a patient or the patient's susceptibility to the condition, comprising: means for obtaining at least one photograph or image of the patient's craniofacial features; means for identifying a plurality of craniofacial landmarks derived from the photograph; means for calculating at least one measurement of the patient's craniofacial morphology from at least two of the landmarks; means for comparing the at least one measurement with craniofacial morphology measurements identified as being indicative of the presence of or susceptibility to the condition; and on the basis of the comparing, means for providing an assessment of the presence of the condition in the patient or the patient's susceptibility to the condition.

[ 0031 ] According to a fifth aspect, there is provided, a computer system comprising, a computer processor and memory, the memory comprising software code stored therein for execution by the computer processor of a method for assessing the presence of a condition in a patient or the patient's susceptibility to the condition, the method comprising the steps of: obtaining at least one photograph or image of the patient's craniofacial features; identifying a plurality of craniofacial landmarks derived from the photograph; calculating at least one measurement of the patient's craniofacial morphology from at least two of the landmarks; comparing the at least one measurement with craniofacial morphology measurements identified as being indicative of the presence of or susceptibility to the condition; and on the basis of the comparing, providing an assessment of the presence of the condition in the patient or the patient's susceptibility to the condition. The computer system may further comprises a camera for obtaining the at least one photograph. Where the photograph is not in a digital format, the computer system may further comprise means for digitising the photograph such that the craniofacial landmarks may be derived therefrom.

[ 0032 ] According to a sixth aspect, there is provided a computer readable medium, having a program recorded thereon, where the program is configured to make a computer execute a procedure for assessing the presence of a condition in a patient or the patient's susceptibility to the condition using at least one photograph or image of the patient's craniofacial features, the software product comprising: code for identifying a plurality of craniofacial landmarks on the at least one photograph; code for calculating at least one measurement of the patient's craniofacial morphology from at least two of the landmarks; code for comparing the at least one measurement with craniofacial morphology measurements identified as being indicative of the presence of or susceptibility to the condition; and code for providing an assessment on the basis of the comparing of the presence of the condition in the patient or the patient's susceptibility to the condition.

[ 0033 ] The methods, apparatus, and systems described in any one of the first to sixths aspects may have application in the medical application of facial biometrics to conditions exhibiting craniofacial morphology such as OSA, orthodontics, otorhinolaryngology (ENT), or cosmetic surgery. The methods or systems may be considered a platform technology with wide ranging application including, but not being limited to:

• A Research tool, particularly in large epidemiological studies, including genetic studies in which craniofacial phenotyping is relevant eg. OSA.

• A diagnostic tool in clinical practice, either in specialist or primary care.

• A management tool in clinical practice, to assist in triaging patients to appropriate therapies (eg, dental versus surgical versus medical treatments).

• A direct-to-consumer diagnostic tool (for example an internet based system) for risk assessment to a particular condition in the patient.

• A large scale screening program for identifying subjects at risk of conditions such as OSA (e.g. similar to other government funded screening initiatives). • Potential in occupational health and safety (e.g. identifying commercial drivers at risk to particular conditions which may affect their abilities at work, of which OSA is a particular example).

[ 0034 ] The methods, apparatus, and systems described in any one of the first to sixths aspects may also be applicable to diagnosis and assessment of a variety of conditions or diseases in a patient which either affect the patient's craniofacial morphology, are influenced by or is a result of the patient's craniofacial morphology, or for which craniofacial phenotyping is relevant, including for example, but not being limited to: Achrondroplasia, Amelogenesis Imperfecta-1, Angelman's Syndrome, Apert Syndrome, Beckwith-Wiedemann Syndrome, Beare-Stevenson Cutis Gyrata Syndrome, Beckwith- Wiedemann Syndrome, Bloom Syndrome, Choanal Stenosis, Chondrodysplasia Punctata, Cleidocranial Dysplasia, Craniosynostosis, Crouzon Syndrome, Dentinogenesis Imperfecta, Diastrophic Dysplasia,

Digeorge Syndrome, Down's Syndrome, Ectodermal Dysplasia, Ehlers-Danlos Syndrome, Epidermolysis Bullosa, Fragile X Syndrome, Goldenhar Syndrome, Greig Cephalopolysyndactyly Syndrome, Hallerman-Streiff Syndrome, Holoprosencephaly, Hypochondroplasia, Hypophosphatasia, Infantile, Jackson- Weiss Syndrome, Kallmann Syndrome- 1, Klippel-Feil Syndrome, Leprechaunism, Marfan Syndrome, Mccune-Albright Syndrome, Metaphyseal Chondrodysplasia, Murk Jansen Type, Nager Syndrome, Neonatal Osseous Dysplasia 1, Neuromata, Mucopolysaccharidoses (Eg. Hurler And Hunter Syndromes), Mucosal, With Endocrine Tumors, Obstructive Sleep Apnoea Syndrome, Osteogenesis Imperfecta, Osteopetrosis, Pachyonychia Congenita, Jackson-Lawler Type, Pallister-Hall Syndrome, Pfeiffer Syndrome, Prader-Willi Syndrome, Reiger Syndrome, Rubinstein-Taybi Syndrome, Saethre- Chotzen Syndrome, Shprintzen-Goldberg Syndrome, Simpson Dysmorphia Syndrome, Sjogren Syndrome, Stickler Syndrome, Temporomandibular Disorders, Thanatophoric Dysplasia, Tooth Agenesis, Familial, Treacher Collins Mandibulofacial Dysostosis, Robin Sequence, Velocardiofacial Syndrome, Waardenburg Syndrome, Williams-Beuren Syndrome, and some head and neck cancers. The condition may be obstructive sleep apnoea. BRIEF DESCRIPTION OF THE DRAWINGS

[ 0035 ] Arrangements of the present invention will now be described, by way of an example only, with reference to the accompanying drawings wherein:

[ 0036 ] Figures IA and IB are schematic representations of the method and system for providing as assessment of the presence of a condition in a patient or the patient's susceptibility to the condition, in accordance with any one of the above aspects;

[ 0037 ] Figures 2A and 2B are a schematic diagrams outlining the setup in a clinical setting for obtaining standardised frontal and profile photographs respectively of the patient for analysis;

[ 0038 ] Figure 3 is a depiction of a prototype laser calibrated digital apparatus for obtaining calibrated photographs of the patient; [ 0039 ] Figures 4A and 4B are respectively example frontal and profile photographs of a patient, wherein a number of relevant landmark locations in the patient's craniofacial morphology derived from the photograph have been identified;

[ 0040 ] Figures 5A and 5B are the frontal and profile photographs of Figures 4A and 4B which have been marked to indicate a range of potential lineal and angular measurements which may be calculated from the landmarks identified in Figures 4A and 4B;

[ 0041 ] Figure 6 is a close up photograph of the profile photograph of Figure 4B indicating the patient's cricomental space distance measurement;

[ 0042 ] Figure 7A is a schematic diagram used in the calculation of measurements from the patient's craniofacial landmarks;

[ 0043 ] Figure 7B is a sample of the types of angular measurements that may be calculated from the patient's craniofacial landmarks; [ 0044 ] Figures 8A to 8R show schematically a sample of the areal measurements that may be calculated from the patient's craniofacial landmarks;

[ 0045 ] Figure 9 is a schematic diagram used in the calculation of volumetric measurements from the patient's craniofacial landmarks;

[ 0046 ] Figures 1OA to 1OG show schematically a sample of the volumetric measurements that may be calculated from the patient's craniofacial landmarks;

[ 0047 ] Figure 11 is a receiver operating characteristics (ROC) curve demonstrating the percentage of patient's correctly classified as having OSA using a calibrated photographic technique;

[ 0048 ] Figure 12 is an ROC curve demonstrating the percentage of patient's correctly classified as having OSA using an uncalibrated photographic technique; [ 0049 ] Figures 13A to 13E are examples of Classification And Regression Tree (CART) analysis diagrams using a variety and number of different craniofacial measurements for the assessment of OSA in a sample of subjects; and

[ 0050 ] Figure 14 is a schematic depiction of an example computer apparatus for the implementation of the method and system for providing as assessment of the presence of a condition in a patient or the patient's susceptibility to the condition, in accordance with any one of the above aspects as described herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[ 0051 ] The ability to predict clinical outcomes is of seminal importance in the physician-patient relationship. For physicians, the ability to understand the most likely end point of a patient's clinical course may allow the modification of disease surveillance and treatment in such a way that improved outcomes can be achieved.

[ 0052 ] As has been mentioned above, there are a number of methods that have been previously used for either diagnosing the presence of or assessing a patient's risk to a condition such as OSA. These methods, however, provide inadequate reliability in the diagnosis of the condition, or are impractical in a primary clinical care environment where the method and or tools required for implementation of the method must be easy to use with adequate reliability.

[ 0053 ] The inventors have surprisingly discovered that with respect to a condition which exhibits craniofacial morphology, either as a result of genetic/hereditary or environmental/phenotypic factor, the risk assessment and or diagnosis of the condition in a patient may be evaluated using a simple photographic technique. With a precise and reliable technique to objectively quantify craniofacial anatomy, it is possible to develop a model to predict the presence and severity of a condition which exhibits craniofacial morphology (eg. OSA) using mathematical and regression analyses.

[ 0054 ] In use of the methods, apparatus or systems of the arrangements of the photographic techniques disclosed herein, a primary or specialist care physician may simply be able to take both frontal and profile photographic images of the patient's head and neck (including the sternal notch) from which a variety of craniofacial landmarks may be identified. The photographs are either taken directly in a digital format using a digital camera, or if a digital camera is not available, the photographs would be converted into a digital format (i.e. scanned) such that the landmarks may be identified with reference to a pixel location (x, y) on the image. The landmarks may include those points described in Tables 2 and 3 below.

[ 0055 ] Selected measurements are then subsequently computed with respect to those landmarks. In essence, the measurements represent various dimensions of the craniofacial soft tissues compartments, bony compartments and a combination of both. The interaction between the relative sizes of these compartments is important in the pathogenesis of the condition. The selected measurements may comprise lineal or angular measurements between selected landmarks, or alternatively may comprise circumferential (eg. neck circumference) areal (eg. triangular) or volumetric (eg. polyhedral) measurements defined by three, four, five or more selected landmarks. For examples of typical lineal and angular measurements, see below in Tables 4 and 5 respectively. For examples of typical areal and volumetric measurements, see below in Tables 6 and 7 respectively.

[ 0056 ] In some arrangements described below, the measurements relied on for the risk assessment or diagnosis are absolute measurements which are required to be expressed in measurement units. In this case the photographs need to be calibrated in a standardised manner such that the measurements are accurate. In some alternate arrangements, however, the measurements required do not need to be in absolute terms, such as certain angular measurements or those that may simply be expressed in terms of one or more ratios between particular measurements derived from the landmark locations. In this instance, calibration of the photographs is not required since the relevant measurements in the risk assessment calculation are only required to be expressed in relative terms.

[ 0057 ] The landmarks identified may comprise a large number of points on the patient's craniofacial structure from which a large number of measurements may be computed. Alternatively, only a small selected sample of the landmarks may need to be identified from which a selected few measurements, potentially comprising a mixture of one or more of each of the potential lineal, angular, areal or

volumetric measurements (see for instance the selected measurements used in Example 5 below) from which either a diagnosis of the presence of the condition, or a risk assessment of the patient's susceptibility to the condition may be determined.

[ 0058 ] The risk assessment of the susceptibility of the patient to a particular condition arrived at via the photographic techniques described herein may form the basis for identifying patients which warrant a more stringent testing or observation, for example an overnight sleep assessment in an existing sleep laboratory, prior to diagnosis of the patient of possessing the condition. Alternatively, the risk assessment obtained from the photographic technique in a particular patient may be useful in identifying a treatment regime which may be selected from a variety of such treatments. The treatment regime may be recommended on the basis of the potential suitability of the patient to that particular treatment as a direct correlation with the measurements obtained and the risk prediction. Furthermore, in addition to identifying the most suitable treatment regime, the measurements obtained may assist in the clinical application of such treatment. For example, in the case of Continuous Positive Airway Pressure (CPAP) treatment for OSA, such measurement may assist in identifying the correct mask interface for the patient, as well as predicting the required therapeutic pressure to be delivered by the CPAP device. In a further example, in cases where an oral appliance is determined to be the most appropriate treatment, the measurements may assist in predicting the correct degree of mandibular advancement required to treat OSA. In a further example, in cases where surgery is determined to be most appropriate, the measurements may assist in predicting the response to surgical treatment. [ 0059 ] There are a number of operational models in which the photographic techniques described herein may be applied in the primary/specialist care environment:

[ 0060 ] In one arrangement, the primary/specialist care physician may take the frontal and profile photographs of the patient, and enter the pixel coordinates of selected landmark locations into an appropriate computer software package. The software package then computes relevant measurements from the landmark locations, and provides a risk prediction or diagnosis of the condition in the patient.

[ 0061 ] In another arrangement, the primary/specialist care physician may take the frontal and profile photographs of the patient, and forward the photographs to a centralised assessment facility. The photographs may for example be forwarded to the assessment facility via electronic means such as by email or over a local-area or wide-area computer network (LAN or WAN) or via the internet. In other arrangements, the photographs may exist in a physical media format (eg. printed) and be forwarded to the assessment facility via regular postal mail, where they may be subsequently digitised by the assessment facility for further analysis. The centralised assessment facility would then perform the identification of particular landmark locations of the patient from the submitted photographs, compute relevant measurements and provide a risk assessment prediction back to the primary/specialist care physician.

[ 0062 ] In a further arrangement, there may be provided a dedicated apparatus incorporating the risk assessment method described herein. For example, the method or risk assessment technique may be implemented in a dedicated Craniofacial Photographic Analysis Tool (CPAT) which may be provided to the primary/specialist care physician. The CPAT incorporates a digital camera so that the frontal and profile images of the patient may be taken in the primary/specialist care environment. The CPAT may provide either manual or automatic (which may be implemented with the use of facial recognition software or algorithms currently being developed and used in high level security systems and made possible due to advances in computer technology) capability for landmark identification. The CPAT would then compute the relevant measurements as required for an assessment of the patient's risk or susceptibility to the condition, or may provide a diagnosis directly.

[ 0063 ] In still a further arrangement, a patient (or even simply an interested individual) may be provided with instruction on how to obtain adequate frontal and profile photographs, which they may be able to subsequently forward to a centralised assessment facility, which may for example be an automated facility, which performs the landmark identification and relevant measurement computations, and then provide a risk assessment, diagnosis or even probability assessment for existence of the condition in the patient. The risk assessment may be provided directly to the patient or individual, or alternatively may be provided to the individual's primary/specialist care physician for assessment and/or integration with other test results to arrive at a diagnosis and recommended treatment strategy. This arrangement may for example be implemented over either a dedicated network or a publicly accessible network such as the internet.

[ 0064 ] The above arrangements may be summarised by referring to Figures IA and IB. Figure IA is a simplified schematic of the process for obtaining 10 at least one photograph/image of the craniofacial features of a patient (for example frontal and profile photographs) and analysing 20 the photograph(s)/image(s) to determine a risk assessment for the patient's susceptibility or predisposition to a condition. Optionally, the risk assessment may then be applied to determination 30 of a treatment regime for future management of the condition. The photograph(s)/image(s) may be taken using the calibrated photographic techniques described herein, or using a non-calibrated technique. Where a non calibrated technique is used for obtaining the photograph, the prediction of the risk assessment for the condition will be obtained using angular measurements and ratios of one or more measurements calculated from selected landmarks visible in the photograph.

[ 0065 ] Figure IB shows a simplified schematic of the analysis step 20 of Figure IA, generally comprising the steps of identifying 22 selected and/or relevant craniofacial landmarks from the digitised photograph(s)/image(s) (for example frontal and profile photographs/images); computing/calculating/determining 24 selected and/or relevant measurements from the pixel coordinates of the landmarks identified; and analysis 26 of the calculated measurements to determine a risk prediction

factor. Each of the measurements may be any combination of lineal, angular, circumferential, areal or volumetric measurements obtained from two, three, four, five, or more landmarks, and may be expressed in absolute terms (eg. in metric or S.I. units) or relative terms in the form of ratios between two or more measurements. [ 0066 ] In a further arrangement still, a three dimensional photograph or image of the patient may be obtained using appropriate image acquisition devices. This could be obtained with dedicated three dimensional camera systems and computer software workstation or portable stereo camera devices. The three dimensional image may be calibrated using one of the calibrated capture techniques described below and used for calculating absolute measurements from the image of the patient's craniofacial features, or alternatively may be an uncalibrated image used for calculating relative or angular measurements. The three dimensional image, when available, may have advantages over one, two or more two dimensional images obtained with a standard camera such as improved precision and allowing assessment of non-linear craniofacial features.

[ 0067 ] In still further arrangements, the measurements obtained of the patient's craniofacial morphology derived from the photographs may be combined with other data from the patient which may provide a further indication of the presence of or susceptibility to the condition in question. For example, non-craniofacial measurements such as the patient's body mass index (BMI), neck circumference (NC), waist circumference (WC), or even intra-oral measurements may also be obtained and comparing with the craniofacial measurements to provide an assessment of either the presence of the condition in the patient or the patient's susceptibility to the condition.

Advantages of Photogrammetry and Photography

[ 0068 ] Photogrammetry has a number of advantages over traditional anthropometric methods for craniofacial assessment. A significant advantage is the ability to capture an image quickly thus minimising subject discomfort and movements artefacts. Another advantage is the possibility of performing more complex measurements that are not possible with simple calipers. Soft tissue measurements are also obtained more easily compared to using calipers directly on the subject, which usually causes deformation of tissues. While there is some image processing time required with photogrammetry, it remains significantly quicker than anthropometry, especially using the landmark digitisation methods described and automated computation. The time taken for landmark digitisation by an operator including automated measurement computation is approximately 5 minutes.

[ 0069 ] Craniofacial photography in the assessment of subjects also has a number of benefits over cephalometry which are important attributes in ensuring such a tool is valuable in the clinical setting, for example:

• it does not expose subjects to radiation.

• it is readily accessible and relatively inexpensive.

• it is portable and simple to use and implement clinically.

• it provides composite information regarding skeletal and soft tissue aspects, rather than skeletal only. Limitations ofPhotogrammetry and Photographic Techniques

[ 0070 ] There are a number of limitations in regard to both photogrammetry and the photographic techniques. Photographic techniques limitations include patient alignment errors, head positioning errors and intrinsic camera system limitations (e.g. lens distortion). While these errors are not completely avoidable, they are minimised if the photographic techniques are standardised. Ideally, all technical aspects need to be consistent to maximise reproducibility. However, the consistency of both the calibrated and uncalibrated photographic techniques described below suggests that these technical limitations only makes a minor contribution to the errors.

[ 0071 ] Two-dimensional photographs captured from 3-dimensional craniofacial structures can also lead to projection errors. Errors in projection were shown to be in excess of 20% in a simulated clinical environment. Comparison between anthropometry and photogrammetry suggests that a significant number of measurements are different, although it is likely that there is a systematic difference which can be made compatible with a correction factor. These errors can be significantly minimised using measurements obtained from photographs from two perpendicular views and applying the mathematical techniques described herein. [ 0072 ] Despite the ability to measure 3-dimensional polyhedral volumes, these remain derived measurements from a number of important landmarks. The non-linear nature of the craniofacial anatomy cannot be captured in these measurements. In addition, all measurements relate only to sizes rather than shapes. Shape analysis may provide additional information relevant in OSA.

[ 0073 ] Soft tissues measurements also tend to be more amendable to photogrammetry, while bony dimensions can be more difficult to measure. However, prior surface marking of bony landmarks add to the precision of bony measurements derived from the photographs.

[ 0074 ] Finally, inter-observer variation in obtaining the photographs and landmark digitisation may result in a degree of random errors.

[ 0075 ] However, even in the light of these potential errors, the inventors have surprisingly found that the application of mathematical measurement computations on a variety of landmark locations provides a significantly improved prediction method for assessing the risk, predisposition or diagnosis of a condition related to craniofacial morphology (eg. OSA) over currently employed techniques, even in the case where un-calibrated photographs are used.

Calibrated Craniofacial Photographic Techniques

[ 0076 ] Described below are two methods for obtaining calibrated craniofacial photographs for assessment of risk to a condition such as, for example, OSA.

Standardised Photographic Technique (SPT)

[ 0077 ] In this method, photographs of a subject undergoing assessment for OSA were obtained in a well-lit office room. A tripod (190CL, Manfrotto, Italy) was setup with a detachable head plate (141RC, Manfrotto, Italy) on which the camera (D70 SLR, Nikon Corp., Japan) was mounted. A true vertical pole was setup at a horizontal distance of 160cm away from the digital sensor plane of the camera. The camera was aligned so that the horizontal axis is perpendicular to the true vertical line. A vertical line was marked on the lateral wall which is at a right angle to the plane between the camera and the subject.

[ 0078 ] Using the Nikon 18-70mm variable zoom lens, a focal length of 70mm (effective focal length of 105mm) was chosen to maximise the size of the subject within the framing of the camera. This focal length also produced less subject distortion compared to the wider angle setting. The large JPEG option was used which yielded a horizontal picture resolution of 3008 pixels and a vertical resolution of 2000 pixels. The following camera settings were used: manual mode, f-stop (aperture size) of 7.1, shutter speed of 1/100th of a second and an ISO of 400. An external ring flash unit (SB-29s, Nikon Corporation, Japan) was attached to the camera body. Flash unit setting was in M mode. A piece of white paper was used to cover the flash unit to produce diffuse lighting and minimise subject shadows.

[ 0079 ] The subject was initially asked to sit down and assume a comfortable head posture. Various facial landmarks were identified by palpation and marked with strips of 35mm by 4mm white adhesive tape. The edges or tips of the tapes were used to indicate landmark points of interests. The landmarks identified by palpation are listed on Table 1.

Table 1: Landmarks Identification by Palpation for Marking

[ 0080 ] For the frontal photograph, the setup for which is depicted in Figure 2A, the subject was adequately exposed above the level of the sternal notch. The subjects with long hair had it tied back to expose both ears and the back of the neck. Accessories such as glasses and necklaces were removed.

[ 0081 ] The subject was aligned next to the true vertical pole in the standing position with their head in the neutral head posture. This was achieved by asking the subject to rock his or her head back and forth, aided by looking into a mirror until a comfortable head posture was assumed. The operator ensured the subject landmark nasion is aligned along the pole-to-wall plane. The height of the tripod was adjusted to ensure the subject's head is within the centre grid of the camera viewfmder. The operator also aligned the head so that the frontal view was symmetrical by ensuring both ears are equally seen. Instructions were given to the patient to remain stationary, to maintain a neutral resting facial expression and breathe quietly with mouth closed and lips lightly touching. The frontal photograph was then taken. The patient was asked to remain stationary after the photograph was taken and a head clip with a mounted laser pointer device was place over the subject's head. The operator aligned the laser pointer so it pointed at the centre of the camera lens whilst the subject remained stationary.

[ 0082 ] The patient was then asked to turn his or her body 90 degrees to face the lateral wall for the profile photograph. The operator ensured the subject's mid-sagittal plane was aligned with the pole-to- wall plane. The subject was then asked to adjust his or her head position so the laser pointer is aligned with a vertical line on the wall to ensure a precise profile view of the subject's head, i.e. exactly half of the subject's face is on view. The neutral head posture was assumed, again aided by looking into a handheld mirror.

[ 0083 ] The laser pointer mounted head clip was then removed and instructions similar to those for the frontal photographs were again given to the patient before the profile photograph was taken, the setup for which is depicted in Figure 2B.

[ 0084 ] As can be seen from the data in the Examples below, the approach developed for the Standardised Photographic Technique was systematic. Control for the subject-camera distance ensured consistent subject magnification. Head posture was achieved with an accepted method with good reproducibility. Profile view was captured by careful subject alignment with a laser pointer. These systemic methodologies used were much more rigorous than those seen in other studies examining craniofacial phenotyping in other diseases. The good test-retest reliability (accuracy) and agreement (precision) with anthropometry is a reflection of the systematic approach, although the measurements are not exactly the same as they are obtained with different techniques. Internal consistency of the technique is excellent as demonstrated by the high test-retest reliability. The choice of equipment is important in producing images with high clarity and resolution. A consistent focal length of 70mm was chosen as this minimises subject distortion and maximises the subject size within the frame of the image.

Laser-Calibrated Digicam (LCD)

[ 0085 ] Figure 3 shows a photograph of a prototype laser-calibrated digital camera device used to make the process of obtaining calibrated photographs much simpler to use in practice. Despite this, the

test-retest reliability (accuracy) was comparable to the Standardised Photographic Technique as can be seen from the data in the Examples below.

[ 0086 ] The prototype of the LCD camera system was developed using a consumer digital camera (IXUS 60, Canon Inc., Japan) mounted onto a custom made bracket attached to 2 parallel beam laser pointers. The distance between the laser beams were calibrated with precision to 40.0 mm, and served as a calibrated scale in the photographs.

[ 0087 ] Again, prior to taking the photographs, a number of facial landmarks on the subjects were identified by palpation and marked with strips of white adhesive tape. Subjects were adequately exposed above the level of the sternal notch. Both frontal and profile photographs were obtained with the subject in the standing position assuming the neutral head posture. The latter was achieved by asking the subject to rock his or her head back and forth until a comfortable head posture is assumed. Instructions given to the subjects during the photographs were to remain stationary, to maintain a neutral resting facial expression and breathe quietly. The mouth was closed with lips lightly touching. For the frontal photograph, the operator ensured the frontal view is symmetrical. This is achieved by ensuring both ears are equally seen. The face was lined up in the centre grid of the camera with the laser pointers projecting on the front of the face. Subjects were then asked to turn to the left side while maintaining the neutral head posture. The profile photograph was aligned by ensuring the right-sided half of the face was within the camera grid.

[ 0088 ] Images obtained with the LCD were of similar resolution but lower quality. While the consistency between the SPT and LCD is not as high as their individual test-retest reliability, the two methods are in reasonably good agreement with each other. Furthermore, the comparison between these two photographic techniques and a 3D digitiser was similar, suggesting the simplified methodology of the LCD could provide an accurate craniofacial assessment.

Craniofacial Photogrammetry Analysis [ 0089 ] The digital photographs were examined using image analysis software (Image J vl.36, NIH, Bethesda, MD) for landmarks digitisation. Using the "point tool" function, the photographic landmarks of interest (Figures 4A and 4B) were identified. The sequence of landmark pixel coordinates (x, y) of the image captured were entered into a spreadsheet application (for example Excel 2003, Microsoft Corp., US) containing mathematical formulae for computation of linear and angular dimensions, as well as area and volume measurements relevant in OSA as described below. The measurements output were in the metric scale.

Landmark Digitisation

[ 0090 ] The firontal (Figure 4A) and profile (Figure 4B) photographs were examined at full resolution using image analysis software (Image J vl.36, NIH, Bethesda, MD) for landmark digitisation. Using the "point tool" option, landmarks of interest on the patient's face were identified in the photographs, each landmark thus being described in pixel coordinates (x, y) with respect to the captured image. The pixel coordinates are then entered into a custom-designed spreadsheet (Excel 2003, Microsoft Corp., US) containing the necessary formulae for automated computation of linear and angular dimensions in the craniofacial structure, as well as area and volume measurements relevant in OSA as described below. The measurements output were in the metric scale. The landmarks of interest are shown in Figures 4A and 4B, respectively being frontal and profile photographs of the patient, the particular landmarks being identified in Tables 2 and 3, relating to the frontal and profile images respectively. These landmarks were chosen because of their relative ease of identification and their potential relevance in the context of OSA.

Table 2: Description of Example Photographic Landmarks - Profile View

Table 3: Description of Example Photographic Landmarks — Frontal View

L: Left side on the photograph; R: Right side on the photograph

Computation of Measurements

[ 0091 ] To enable calibration of the photographic images and conversion of measurements taken on the images into metric dimensions, a ruler (precision ± 0.05 cm) placed along the subject alignment plane (160 cm from the camera) was photographed. The pixel count for a length of 15.0 cm was found to be 780 pixels (i.e. 52.0 pixels/cm). AU pixel dimensions and measurements may be converted to metric measurements using this calibrated scale. Using the same ruler alignment method, the conversion scales were 55.2 pixels/cm and 49.3 pixels/cm for objects at a distance 150cm and 170cm from the camera respectively. These conversion scales were used to correct for craniofacial measurements that were positioned in front of or behind the subject alignment plane. [ 0092 ] Figures 5A and 5B show the range of linear measurements calculated from the frontal and profile photographs Figures 4A and 4B.

Linear Measurements

[ 0093 ] A number of linear dimensions may be calculated with mathematical functions using the coordinates of various landmark across both the frontal and profile, and examples of the types of linear measurements that may be calculated are disclosed in Table 4.

[ 0094 ] The formula used for calculation of the direct distance between two landmark coordinates (x _h y _λ ) and (x ₂ , y ₂ ) is:

Distance in pixels = J( _^ x ₁ - X ₂ ) — {y _\ - y ₂ ) (1)

[ 0095 ] The true horizontal (TH) measurements represent the horizontal distances between 2 landmarks along the x-axis. The formula used for their calculation is:

Distance in pixels = ^x ₁ -X ₂ ) (2)

[ 0096 ] The true vertical (TV) measurements represent the vertical distances between 2 landmarks along the y-axis. The formula used for their calculation is:

Distance in pixels = J( _^ y ₁ - y ₂ ) (3)

[ 0097 ] The diagonal (Diag) measurements represent the 3-dimensional linear distances between 2 landmarks. These can be calculated mathematically as the profile and frontal photographs are perpendicular images. The formula used for their calculation is:

Distance in pixels = ^J a ² - (b 12) (4)

[ 0098 ] where a = distance between 2 profile landmarks, and b = distance between 2 frontal landmarks forming a base of the triangle. As an example, to calculate the upper face depth (t-n Diag), Equation (4) is applied by using the distance between t-n from the profile photograph (Figure 4B) and distance between tl-tr from the frontal photograph (Figure 4A).

[ 0099 ] The neck perimeter was calculated using the formula for an eclipse perimeter, i.e.:

Distance in pixels = J2r(c/2) ² -{dllfλ (5)

[ 00100 ] where c is the neck depth and d the neck width.

[ 0100 ] The cricomental space distance (line 100 of Figure 6) is derived from the coordinates for the cervical point (x _cer , y _cer ), the mentum (x _me , y _me ); cricoid = (x _cr , y _cr ) and is calculated using the following formula:

e ² +f ² + g ² ₊ h ² -i ² -j ²

Cricomental space distance = sin cos (6)

[ 0101 ] where e = xcr - xme ; /= ycr - yme ;g = xcer - xcr ; h = ycer - ycr ; i = xcer - xme ; and j ~ ycer — yme. The cricomental space distance could be of a negative value if the landmark cervical point (per) is to the right of the line joining the mentum {me) and cricoid (cr).

[ 0102 ] Frontal photographic measurements such as the face width, mandible width, maximum cranial width and neck width are calculated using the appropriate conversion scale to obtain their true metric dimensions. This is necessary as the landmarks for these measurements are positioned at variable distances behind the subject alignment plane.

Table 4: Example Linear Measurements

Table 4: Example Linear Measurements

TV: True vertical; HT: True Horizontal; Diag.: Diagonal

Angular Measurements

[ 0103 ] All angular measurements were calculated by firstly calculating the 3 sides of the triangle formed by the 3 landmarks of interest (eg. sides x, y and z in Figure 7A. Using the following formula, an angle of interest (Angle A) is calculated by:

Angle A (degrees) = cos -1 y' + z' -x" 2yz O)

[ 0104 ] where x, y and z are the 3 sides of the triangle. Angle A is the angle between sides x and y. Angles which are formed in relation to the true horizontal (e.g. natural head position angle, head base inclination angle) are calculated using established trigonometry methods (i.e. tangent rules). The mandibular width-length angle, face width-mid face depth angle and face width-lower face depth angle are calculated using measurements obtained from both the frontal and profile photographs (Figures 4A and 4B respectively). A sample of the types of angular measurements that may be calculated is disclosed in Table 5 and shown schematically in Figure 7B.

Table 5: Example Angular Measurements

Lip Measurements

[ 0105 ] A number of lineal and angular measurements in relation to lip morphology can also be performed with the photographic analysis. These include the upper lip height (using distance between landmarks subnasale (sn) and stomion (sto)), lower lip height (distance between landmarks sto and sublabiale (si)), lateral lip height (distance between landmarks sn and labiale superius (Is)), upper vermilion (distance between landmarks Is and sto), lower vermilion (distance between landmarks sto and labiale inferius (Ii)), nasolabial angle (angle between columella of nose (en), sn and Is) and mouth breadth (distance between landmarks cheilion (L) (chel) and cheilion (R) (cher)).

Area Measurements [ 0106 ] A number of triangular area measurements may be calculated using:

Area of triangle = yjs(s - x)(s - y)(s -z) (8)

[ 0107 ] where x, y and z are the three sides of the triangle and the semi-perimeter, s, is given by (x + y + z)l2. A sample of the triangular area measurements that may be calculated is disclosed in Table 6 and shown schematically in Figure 8A to 8R. Certain area measurements (such as the total anterior neck soft tissue area shown in Figure 8F) are calculated by the summation of a number of triangular area measurements. The anterior neck space area (Figure 8C) may also be calculated by subtracting the total area between landmarks go, me, cer, thy, cr and ste from the triangular area formed by landmarks go-me- ste. The anterior neck space area can be of a negative value if the total area of the former is larger than the one formed by landmarks go-me-ste. [ 0108 ] The thyromental and cricomental space areas (Figures 8A and 8B respectively) can also be of a negative value if the landmark cer is to the right of the line joining the mentum (me) and thyroid (thy) or cricoid (cr) respectively.

[ 0109 ] The neck cross-sectional area (shown in Figure 81) is calculated using:

Neck cross-sectional area = π (9) [ 0110 ] where c is the patient's neck depth and d is the neck width.

Table 6: Example Areal Measurements

TV: True vertical; HT: True Horizontal

Polyhedral Volume Measurements

[ 0111 ] Polyhedral volume measurements may also be calculated using the digitised landmarks from the perpendicular frontal and profile photographs (Figures 4A and 4B). Polyhedral volume measurements may add further information as they take into account measurements obtained from the two perpendicular photographs. These measurements give an estimate of the volume of tissue of interest bounded by the chosen landmarks. An assumption for these measurements is that the frontal and profile photographs are perfectly perpendicular; otherwise errors in calculation can be introduced. The excellent test-retest reliability for both the Standardised Photographic Technique and LCD suggests patient alignment error is generally minimal. [ 0112 ] These measurements represent estimates of the size of various craniofacial anatomy using polyhedron shapes. The building blocks for all polyhedron shapes are based on tetrahedrons, the most

basic form of which has four planer triangular faces and six edges. Therefore, all polyhedral shapes volume can be calculated by dividing the shapes into tetrahedrons and calculating their respective volumes.

[ 0113 ] The volume of a tetrahedron (regular or irregular) may be calculated using:

(10)

[ 0114 ] where det(M) is the determinant of the 5x5 matrix:

[ 0115 ] with a, b, c, d, e and f being the 6 edges of the tetrahedron as shown in Figure 9. A sample of the polyhedral volume measurements that may be calculated is disclosed in Table 7 and shown schematically in Figure 1OA to 1OG. As an example, the polyhedron mandibular volume (Figure 10B) was determined by the summation of the volume between tetrahedron landmarks tl-tr-me-gor and tetrahedron landmarks tl-tr-me-gol.

[ 0116 ] The anterior neck space volume (Figure 10F) was calculated by subtracting the total anterior neck soft tissue volume (Figure 10E) from the tetrahedron volume formed by landmarks gol-gor-me-cr. The anterior neck space volume can be of a negative value if the anterior neck soft tissue volume is larger than that formed by landmarks gol-gor-me-cr.

Table 7: Polyhedral Volumetric Measurements

EXAMPLES

[ 0117 ] As discussed above, craniofacial phenotypic abnormalities have been identified as important anatomical risk factors for obstructive sleep apnoea (OSA). These abnormalities can be quantified with clinical anthropometry and cephalometry; however, these techniques have limitations which preclude their routine use in the clinical assessment of patients with OSA.

[ 0118 ] The studies in the Examples 1 to 4 below examine the role of a quantitative photographic technique in the identification of craniofacial risk factors in patients with OSA by quantifying craniofacial structure. It is found that facial phenotype is able to reflect the underlying upper airway anatomy and be significantly correlated with OSA severity.

[ 0119 ] Example 5 demonstrates the application of a more extensive statistical analysis (by logistic regression, although other statistical techniques may be used) on the available landmarks and measurements available from the photographic technique to develop an algorithm for determination of a risk assessment to OSA.

[ 0120 ] Finally, Example 6 demonstrates an alternate statistical method based on Classification and Regression Tree (CART) analysis of the available landmarks and measurements available from the photographic technique for determination of an OSA risk assessment.

Example 1: Relationship between Surface Facial Dimensions on MRI and Obstructive Sleep Apnoea Severity

Methods

[ 0121 ] Subjects were recruited as part of a study using MRI to assess the upper airway in OSA patients (AHI>10/hr) undergoing oral appliance treatment. Body mass index (BMI), neck and waist circumference (NC & WC respectively) were measured at baseline. Measurements of surface facial dimensions and upper airway soft tissue structures were made on the MR images using image analysis software.

Results [ 0122 ] Fifty patients with mean AHI (±SD) of 26.9±13.6/hr were recruited. The severity of OSA (AHI[IOg]) did not correlate with anthropometric measurements, upper airway volume, lateral pharyngeal wall thickness or parapharyngeal fat pad volume. However, there was a moderate correlation between AHI[log] and certain surface facial dimensions, such as face width (r=0.42, p=0.002), face length (r=0.28, p=0.068) and jaw width (r=0A0, p=0.005). [ 0123 ] After controlling for age, BMI and neck circumference, a significant correlation remained between AHI[log] and the face width (r=036, p=0.013) and jaw width (r=0.31, p=0.036). Face width correlated with the neck circumference (r=0.80, p<0.001), tongue mid-sagittal area (r=0.74, p<0.001) and uvula volume (r=0.34, p=0.034).

Discussion [ 0124 ] This example demonstrates that surface facial dimensions may have a stronger relationship with OSA severity than traditional anthropometric and upper airway soft tissues measurements. The patient's face width is particularly identified as a clinically useful measurement in the risk assessment of OSA.

Example 2: Craniofacial Differences in Obstructive Sleep Apnoea: A Quantitative Photographic Analysis

Methods

[ 0125 ] Cases of OSA (AHI 10/hour) were compared to controls (AHI<10/hour) from a population referred to a sleep laboratory for assessment of OSA. All patients had frontal-profile craniofacial photographic imaging with standardized techniques. Mathematical functions as described above were used to compute lengths, angles, areas and polyhedral volumes of the craniofacial geometry. Student s t- test and regression were used for analysis.

Results

[ 0126 ] The photographic assessment was performed in 62 patients with OSA and 33 controls. The mandibular length (ό.O±O.l vs 6.4±0.1 cm; p=0.006) and sterno-mandibular distance (10.3±0.2 vs 11.4±0.2 cm; p<0.001) were shorter in the OSA group; whereas the face width was longer (15.8-fcO.l vs 14.9±0.1 cm; p<0.001).

[ 0127 ] In the OSA group, the mandibular-nasion angle (34.0±0.4 vs 36.7 0.5 degrees; pO.OOl), and crico-mental space area (0.83±0.2 vs 2.2±0.3 cm ² ; p<0.001) were smaller, while the cervico-mental angle (168±2.2 vs 154±2.9 degrees; p<0.001) and neck cross-sectional area (143±3.7 vs 118±4.1 cm ² ; p<0.001) were larger. Volumetric measurements showed a larger tragion-neck soft tissue volume (255±6.3 vs 226±6.2 cm ³ ; p=0.002).

[ 0128 ] Multiple linear regression analysis showed certain photographic measurements (r ² = 0.44) were better predictors for the AHI than BMI (r ² = 0.22) and neck circumference (r ² = 0.28).

Discussion

[ 0129 ] This example reveals that craniofacial differences in OSA can be quantified using a photographic technique to provide a better predictive outcome than simply BMI or neck circumference.

Example 3: Quantitative Photographic Technique for Craniofacial Phenotyping in Obstructive Sleep Apnoea

Methods

[ 0130 ] Subjects recruited from a sleep laboratory population had both clinical craniofacial anthropometric measurements with calipers and photographic imaging. Frontal and profile craniofacial photographic images were obtained with a standardised technique as described above using the laser calibrated device (LCD) system. The photographic craniofacial landmarks were then manually digitised with image analysis software.

[ 0131 ] Mathematical functions as described above were used to compute linear dimensions, angular relationships, areas and polygonal volumes of the craniofacial and soft tissue geometry. Pearson correlation was used to examine the relationships between the photographic and clinical measurements.

[ 0132 ] Test-retest reliability of the photographic imaging technique and intra-observer reliability of the photographic landmark identification were also assessed.

Results [ 0133 ] Fifty-eight subjects were recruited. Strong correlations between photographic dimensions and a number of clinical anthropometric measurements were shown. Some of these correlations include the

total facial height (r=0.859, p<0.00\), mid-face width (r=0.824, pO.OOl) and neck circumference

[ 0134 ] Test-retest reliability was assessed in 10 subjects with a mean coefficient of variation (CV) of 1.24%, 1.04% and 0.79% for selected frontal lengths, profile lengths and profile angular measurements respectively.

[ 0135 ] Intra-observer reliability in 10 subjects showed an overall mean CV of 0.57% for lengths, 1.24% for angular relationships, 1.11% for areas and 1.74% for volumes measurements.

[ 0136 ] Furthermore, the LCD test-retest reliability was further assessed on twenty subjects referred to a sleep laboratory for the investigation of OSA. All subjects completed the photographic imaging with the LCD on two separate occasions five minutes apart. Craniofacial photogrammetry was performed on the two sets of photographs the following day. The mean coefficients of variation (CV) were 2.07%, 3.77%, 3.74% and 4.65% for linear, angular, area and polyhedral volume measurements, respectively. The mean intraclass correlation coefficients (ICCs) (using the 2-way mixed model for absolute agreement) were 0.95 for the linear, angular and area measurements and 0.97 for the polyhedral volume measurements.

[ 0137 ] Agreement between the LCD was compared to the highly standardised method of craniofacial photography using a SLR camera setup (D70 SLR, Nikon Corp., Japan) as described above using the Standardised Photographic Technique (SPT). In the 20 subjects, the mean CV were 3.32%, 5.98%, 5.82% and 6.66% for linear, angular, area and polyhedral volume measurements, respectively. The mean ICCs (using the 2-way mixed model for consistency) were 0.89, 0.90, 0.90 and 0.93 for the linear, angular, area and polyhedral volume measurements, respectively.

[ 0138 ] Agreement between the LCD was also compared to a 3D digitisation method (MicroScribe 3DX, Immersion Corp., U.S.) for obtaining craniofacial measurements. In the 20 subjects, the mean CV were 3.48%, 11.26%, 10.36% and 11.98% for linear, angular, area and polyhedral volume measurements, respectively. The mean ICCs (using the 2-way mixed model for consistency) were 0.79, 0.68, 0.80 and 0.82 for the linear, angular, area and polyhedral volume measurements, respectively.

Discussion

[ 0139 ] Detailed craniofacial analyses can be performed using a quantitative photographic technique. It is highly reproducible, reliable and simple to perform.

Example 4: Techniques for Craniofacial Assessment in Obstructive Sleep Apnoea Methods

[ 0140 ] Subjects were recruited from a population referred to a sleep laboratory for assessment of OSA. Craniofacial assessment was performed using three standardised techniques: (1) standardised photographic technique (SPT); (2) laser-calibrated digicam (LCD); (3) 3D digitisation (3DD). These techniques, in combination with computer software analyses, provided detailed quantification of craniofacial geometry. Test-retest reliability and agreement between the techniques were assessed.

Results

[ 0141 ] Test-retest reliability was assessed on two separate occasions in 20 subjects for each technique. The mean intraclass correlation coefficients (ICC) of the craniofacial geometric measurements using the SPT, LCD and 3DD were 0.96, 0.96 and 0.92, respectively. The mean ICC was 0.79 when comparing measurements obtained with the SPT and 3DD. The mean ICC was 0.77 when comparing measurements obtained with the LCD and 3DD. The mean ICC was 0.91 when comparing measurements obtained with the SPT and LCD. Discussion

[ 0142 ] A quantitative craniofacial assessment can be obtained using these techniques. They have high precision and accuracy, and are relatively simple to perform. These techniques may be useful in the research setting or in the clinical assessment of patients with OSA.

Example 5: Logistic Regression Analysis [ 0143 ] In the present example, the Apnoea-Hypopnoea Index (AHI) was used to determine whether a patient is classified as having obstructive sleep apnoea (OSA). As before, subjects were classified as not having sleep apnoea if AHI <10 and as having sleep apnoea if AHI >10. The sample size of the study was comprised of 180 subjects and 133 photographic measurements were considered (70 linear measurements, 21 angle measurements, 23 area measurements, 19 volume measurements) from each subject. Multicolinearity reduced the number of linear measurements to 56, angle measurements to 17, area measurements to 19, and volume measurements to 13. These 105 measurements were further reduced using stepwise regression of the log transformed (AHI+1) for each group (linear, angle, area, volume). This approach led to the reduced set of variables neck depth (L61), mandibular length 1 (L27), face width (L62), eye width (L65), mandibular width-length angle (ANl 9), cervico-mental angle (ANl 8), neck Circumference area (AR9), mandibular pharyngeal triangle area (sag) (ARl 4), cranial base area 1 (ax) (AR20), anterior neck space area (sag) (AR3), total neck soft tissue volume (Vl 9), total anterior neck space volume 1 (V 13) and maxillary volume (V2). Backward LR logistic regression on the above 13

variables identified L62 (face width), L65 (eye width), ANl 8 (cervico-mental angle) and L27 (mandibular length 1) as significant independent predictors for OSA.

Using Photographs Obtained with the LCD

[ 0144 ] Probability of OSA (AHI > 10) is calculated by the formula:

1 l AHI>W ^■ Hi

[ 0145 ] where z is given by the relation: z -A+B x (face width) + Cx (eye width) + D x (cervico-mental angle) + Ex (mandibular length 1)

[ 0146 ] with A, B, C, D and E constants derived from the analysis and the measurements of thence width, eye width, and mandibular length 1 are each expressed in centimetres and the cervico-mental angle is expressed in degrees.

[ 0147 ] In the present example, the constants A, B, C, D and E have been determined and found to be equal to A = - 9.235, B = 1.442, C = - 2.872, D = 0.02, and E = - 1.224. The classification table below (Table 8) and the receiver operating characteristics (ROC) curve of Figure 11 (where the area under the ROC curve is 0.822) demonstrates that 76.1% of the subjects are able to be correctly classified as having OSA with this model with the above values for constants A -E.

[ 0148 ] It will, of course, be appreciated by the skilled addressee that the values of the constants A - E may vary for each application of the regression analysis, and these may vary in a range of between ±0.5% to ±10%. Also, different values of the constants A - E may be found depending on the particular data set used to develop the model as would be appreciated by the skilled addressee, and that the prediction efficiency may be further improved with the use of a more rigorous analysis, which may also include further terms in the expression of the constant z, each relating to one or more further measurements of the patient's craniofacial features selected from those available, for example in any one of Tables 4 to 7.

Table 8: OSA Prediction Accuracy using LCD device Classification Table ^a a- The cut value is .500

Using Uncalibrated Digital Photographs

[ 0149 ] In order to further simplify the model to allow any (i.e. not calibrated) photographs to be analysed, a model was developed using only relative or angular measurement, for example, using the ratio of L62/L65 (Face width-eye width ratio), ANl 8 (Cervico-mental angle) and AN9 (Mandibular-nasion angle).

[ 0150 ] Again, the relation used to determine the probability of OSA (AHI > 10) is calculated by the formula:

1

°AHI>\0

(I ₊ .-)

[ 0151 ] however, in this model the constant z is given by the relation: z — A + B X (face width /eye width) + C X (cervico-mental angle) + D x (mandibular-nasion angle)

[ 0152 ] where A, B, C and D are constants derived from the analysis and the measurements of the cervico-mental angle and the mandibular-nasion angle are each expressed in degrees. [ 0153 ] In the present example, the constants A -D were found to be _^ 4 = - 4.516, B = 1.528, C = O.025 and D = — 0.262. The classification table below (Table 9) and the receiver operating characteristics (ROC) curve of Figure 12 (where the area under the ROC curve is 0.804) derived using these constants demonstrates that 71.1% of patients can be classified correctly as having OSA with this model with the above values for constants A -D. [ 0154 ] It will, of course, again be appreciated by the skilled addressee that the values of the constants A - D may vary for each application of the regression analysis, and these may vary in a range of between ±1% to ±10%. Also, different values of the constants A - D may be found depending on the particular data set used to develop the model as would be appreciated by the skilled addressee, and that the prediction efficiency may be further improved with the use of a more rigorous analysis, which may also include further terms in the expression of the constant z, each relating to one or more further measurements of the patient's craniofacial features selected from those available, for example in any one of Tab!es 4 to 7.

Table 9: OSA Prediction Accuracy using Uncalibrated Photographs Classification Table ¹

3- The cut value is .500

Example 6: Classification and Regression Tree (CART) Analysis [ 0155 ] CART analysis is a predictive model that uses nonparametric techniques to evaluate data, account for complex relationships, and present the results in a clinically useful form. In this type of analysis, there is progressive splitting of the population into subgroups that are based on the predictive independent variables. The variables that are chosen, the discriminatory values of the variable, and the order in which the splitting occurs are all produced by the underlying mathematic algorithm to maximize predictive accuracy.

[ 0156 ] This type of model is relatively easy to use for the clinician. First, in contrast to many logistic regression models, there are no complicated equations to remember or use. The structure of the tree is one that is appealing intuitively and congruent with methods of decision-making that a physician already uses on many occasions. For example, in trying to understand the best diagnostic test or treatment for a given patient, clinicians will use specific patient characteristics to determine progressively which modalities are most appropriate or which outcomes are most likely. The CART not only uses this type of logic but also provides a formal structure and quantitative outcome assessment that can optimize the actual clinical decision.

[ 0157 ] A number of potential CART analyses are described with reference to assessment of a sample size of 180 patients for susceptibility or risk of OSA. The 180 patients were divided into a learning sample for model derivation and a test sample for validation of the model. The various models used in this study and their predictive capabilities are:

• Model 1: Simplest model using a single photographic measurement {Mandibular width- length angle). The prediction accuracy for overall correct diagnosis of patients with OSA was 77% in the learn sample, and 61% in the test sample. This model is depicted schematically in Figure 13A.

• Model 2: CART model using four photographic measurements (ANl 9 Mandibular width- length angle, L61 Neck depth, L63 Mandible width and AN21 Face width-lower face depth angle). The prediction accuracy for overall correct diagnosis of patients with OSA was 64% in the learn sample, and 63% in the test sample. This model is depicted schematically in Figure 13B.

• Model 3: CART model using seven photographic measurements (ANl 9 Mandibular width-length angle, L61 Neck depth, L65 Eye width, ARl 4 Mandibular pharyngeal triangle area (sag), AR9 Neck Circumference area (ax), AR3 Anterior neck space area (sag), ANl 8 Cervico-mental angle). The prediction accuracy for overall correct diagnosis of patients with OSA was 64% in the learn sample, and 63% in the test sample. This model is depicted schematically in Figure 13C.

• Model 4: This model uses four photographic measurements (FEV Face width-Eye width ratio, AN9 Mandibular-nasion angle 2, ANl 8 Cervico-mental angle). The prediction accuracy for overall correct diagnosis of patients with OSA was 77% in the learn sample, and 73% in the test sample. This model is depicted schematically in Figure 13D.

• Model 5: This model describes the use of a combination of five photographic measurements (ANl 9 Mandibular width-length angle, ANl 8 Cervico-mental angle, Vl 3 Total anterior neck space volume 2, ARl 4 Mandibular pharyngeal triangle area (sag), L65 Eye width) and anthropometric measurements (waist circumference and body mass index). The prediction accuracy for overall correct diagnosis of patients with OSA was

84% in the learn sample, and 69% in the test sample. This model is depicted schematically in Figure 13E.

[ 0158 ] In any one of the arrangements and/or examples disclosed above, the method of providing an assessment of the risk or susceptibility or the presence or diagnosis of a condition from craniofacial photographs may be implemented using a computer system 1400, such as that shown in Figure 14 wherein the processes of Figures IA and IB and Figures 13A to 13E may be implemented as software, such as one or more application programs executable within the computer system 1400. In particular, the steps of method of providing an assessment of the risk or susceptibility or the presence or diagnosis of a condition from craniofacial photographs are effected by instructions in the software that are carried out within the computer system 1400. The instructions may be formed as one or more code modules, each for performing one or more particular tasks. The software may also be divided into two separate parts, in which a first part and the corresponding code modules performs the methods and a second part and the corresponding code modules manage a user interface between the first part and the user.

[ 0159 ] The software may be stored in a computer readable medium, including the storage devices described below, for example. The software is loaded into the computer system 1400 from the computer readable medium, and then executed by the computer system 1400. A computer readable medium having such software or computer program recorded on it is a computer program product. The use of the computer program product in the computer system 1400 preferably effects an advantageous apparatus for providing an assessment of the risk or susceptibility or the presence or diagnosis of a condition from craniofacial photographs.

[ 0160 ] As seen in Figure 14 the computer system 1400 is formed by a computer module 1401, input devices such as a keyboard 1402 and a mouse pointer device 1403, and output devices including a printer 1415, a display device 1414 and loudspeakers 1417. An external Modulator-Demodulator (Modem) transceiver device 1416 may be used by the computer module 1401 for communicating to and from a communications network 1420 via a connection 1421. The network 1420 may be a wide-area network (WAN), such as the Internet or a private WAN. Where the connection 1421 is a telephone line, the modem 1416 may be a traditional "dial-up" modem. Alternatively, where the connection 1421 is a high capacity (eg: cable) connection, the modem 1416 may be a broadband modem. A wireless modem may also be used for wireless connection to the network 1420.

[ 0161 ] The computer module 1401 typically includes at least one processor unit 1405, and a memory unit 1406 for example formed from semiconductor random access memory (RAM) and read only memory (ROM). The module 1401 also includes an number of input/output (I/O) interfaces including an audio- video interface 1407 that couples to the video display 1414 and loudspeakers 1417, an I/O interface 1413 for the keyboard 1402 and mouse 1403 and optionally a joystick (not illustrated), and an interface 1408 for the external modem 1416 and printer 1415. In some implementations, the modem 1416 may be incorporated within the computer module 1401, for example within the interface 1408. The computer module 1401 also has a local network interface 1411 which, via a connection 1423, permits coupling of the computer system 1400 to a local computer network 1422, known as a Local Area Network (LAN). As also illustrated, the local network 1422 may also couple to the wide network 1420 via a connection 1424, which would typically include a so-called "firewall" device or similar functionality. The interface 1411 may be formed by an Ethernet™ circuit card, a wireless Bluetooth™ or an IEEE 802.21 wireless arrangement. [ 0162 ] The interfaces 1408 and 1413 may afford both serial and parallel connectivity, the former typically being implemented according to the Universal Serial Bus (USB) standards and having corresponding USB connectors (not illustrated). Storage devices 1409 are provided and typically include a hard disk drive (HDD) 1410. Other devices such as a floppy disk drive and a magnetic tape drive (not illustrated) may also be used. An optical disk drive 1412 is typically provided to act as a non-volatile source of data. Portable memory devices, such optical disks (eg: CD-ROM, DVD), USB-RAM, and

floppy disks for example may then be used as appropriate sources of data to the system 14OO.The components 1405, to 1413 of the computer module 1401 typically communicate via an interconnected bus 1404 and in a manner which results in a conventional mode of operation of the computer system 1400 known to those in the relevant art. Examples of computers on which the described arrangements can be practised include IBM-PC's and compatibles, Sun Sparcstations, Apple Mac™ or alike computer systems evolved therefrom.

[ 0163 ] Typically, the application programs discussed above are resident on the hard disk drive 1410 and read and controlled in execution by the processor 1405. Intermediate storage of such programs and any data fetched from the networks 1420 and 1422 may be accomplished using the semiconductor memory 1406, possibly in concert with the hard disk drive 1410. In some instances, the application programs may be supplied to the user encoded on one or more CD-ROM and read via the corresponding drive 1412, or alternatively may be read by the user from the networks 1420 or 1422.

[ 0164 ] Still further, the software can also be loaded into the computer system 1400 from other computer readable media. Computer readable media refers to any storage medium that participates in providing instructions and/or data to the computer system 1400 for execution and/or processing. Examples of such media include floppy disks, magnetic tape, CD-ROM, a hard disk drive, a ROM or integrated circuit, a magneto-optical disk, or a computer readable card such as a PCMCIA card and the like, whether or not such devices are internal or external of the computer module 1401. Examples of computer readable transmission media that may also participate in the provision of instructions and/or data include radio or infra-red transmission channels as well as a network connection to another computer or networked device, and the Internet or Intranets including e-mail transmissions and information recorded on Websites and the like. The second part of the application programs and the corresponding code modules mentioned above may be executed to implement one or more graphical user interfaces (GUIs) to be rendered or otherwise represented upon the display 1414. Through manipulation of the keyboard 1402 and the mouse 1403, a user of the computer system 1400 and the application may manipulate the interface to provide controlling commands and/or input to the applications associated with the GUI(s).

[ 0165 ] The method of providing an assessment of the risk or susceptibility or the presence or diagnosis of a condition from craniofacial photographs may alternatively be implemented in dedicated hardware such as one or more integrated circuits performing the functions or sub functions of identifying landmarks in the photographs, performing the calculations of the measurements, or analysing the measurements to provide the risk assessment or diagnosis for the condition. Such dedicated hardware may include graphic processors, digital signal processors, or one or more microprocessors and associated memories.

[ 0166 ] It will be appreciated that the methods, apparatus, devices and systems described and/or illustrated above at least substantially provide methods and apparatus for assessment of susceptibility of a patient to a condition using craniofacial photogrammetry.

[ 0167 ] The methods, apparatus, devices and systems described herein, and/or illustrated in the drawings, are presented by way of example only and are not limiting as to the scope of the invention.

Unless otherwise specifically stated, individual aspects and components of the methods, apparatus, devices or systems may be modified, or may have been substituted therefore known equivalents, or as yet unknown substitutes such as may be developed in the future or such as may be found to be acceptable substitutes in the future. The methods, apparatus, devices or systems may also be modified for a variety of applications while remaining within the scope and spirit of the claimed invention, since the range of potential applications is great, 'and since it is intended that the present methods, apparatus, devices or systems be adaptable to many such variations.