an inter-center comparison of dental arch relationships ... · born with a cleft. in fact, there is...

An Inter-Center Comparison of Dental Arch Relationships, Craniofacial Form, and Nasolabial Esthetics in Patients with

Complete Unilateral Cleft Lip and Palate Treated with Different Pre-Surgical Infant Protocols

by

Michelle Kornbluth D.M.D

A thesis submitted in conformity with the requirements for the degree of Master of Science (orthodontics), Graduate Department of Dentistry,

University of Toronto

© Copyright by Michelle Kornbluth 2016

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An Inter-Center Comparison of Dental Arch Relationships, craniofacial form and

Nasolabial Esthetics in Patients with Complete Unilateral Cleft Lip and Palate

Treated with Different Pre-Surgical Infant Protocols

Michelle Kornbluth

Master of Science Degree, 2016

Discipline of Orthodontics, Faculty of Dentistry, University of Toronto

Toronto, Ontario, Canada

Abstract

The purpose of this study was to compare the dental arch relationships nasolabial esthetics, and craniofacial form of mixed dentition patients with complete unilateral CLP originally treated with distinct infant orthopedic (IO) approaches (Latham, modified McNeil, nasoalveolar molding (NAM), and no IO). A total of 138 study models, 180 photographs and 124 cephalograms were assembled from existing records at five different North American cleft centers. Six trained, calibrated judges blindly rated dental arch relationships using the Goslon yardstick, and the nasolabial esthetics using the method of Asher-McDade. The radiographs were analyzed using hard and soft tissue landmarks on Dolphin Imaging software. The most favorable occlusal relationships and skeletal relationships were achieved at the center using no IO (p<0.001). The most favorable nasolabial esthetics were obtained at centers using Latham or NAM (p=0.01). Overall, some aspects of CLP treatment may be enhanced, and others worsened by the use of IO.

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Acknowledgments I would like to express my gratitude to the following people for their dedication and support during this investigation:

Dr. John Daskalogiannakis, University of Toronto, Faculty of Dentistry, Department of Graduate Orthodontics; thank you for your encouragement, guidance and patience over the past three years. It was an absolute pleasure to work with you and to be included in your Americleft family.

Dr. Bryan Tompson, University of Toronto, Faculty of Dentistry, Department of Graduate Orthodontics; thank you for your guidance and support throughout this research project and over the past three years in the Orthodontics program – I really appreciated it.

Dr. Thomas Sitzman, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; thank you for taking the time out of your busy schedule to serve on my committee. Your expertise and guidance were invaluable and very much appreciated.

Dr. Ross E. Long Jr, Chief of Orthodontics and Director of Research, Lancaster Cleft Palate Clinic, Lancaster, PA; thank you for making me feel so welcome among the Americleft clan and for all your help with this project. You really went above and beyond!

The Americleft Group; thank you all for your advice and encouragement and for taking the time to rate photo after photo and of course those Wilbur buds. I couldn’t have done it without all of you!

The staff in the Orthodontic, Media Services and Health Records Departments at SickKids Hospital, Toronto, Ontario; thank you for all your help in pouring through records to collect my sample and letting me “set up shop” in your space.

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Table of Contents Acknowledgments ............................................................................................................................... iii

Table of Contents .................................................................................................................................. iv

List of Tables .......................................................................................................................................... vi

List of Figures ........................................................................................................................................vii

List of Appendices................................................................................................................................. ix

Introduction, Definitions and Statement of the Problem ........................................................ 1

1 Review of the Literature ............................................................................................................. 4 1.1 Embryogenesis of Cleft Lip and Palate ........................................................................................ 4 1.2 Classification of Cleft Lip and Palate............................................................................................ 6 1.3 Nasolabial Morphology in Infants with CUCLP ........................................................................ 8 1.4 Primary Surgical Repair of Patients with CUCLP .................................................................... 9 1.5 Gingivoperiosteoplasty and Alveolar Bone Grafting in Patients with CUCLP ............ 12 1.6 Development of presurgical Infant Orthopedics (IO) ......................................................... 16 1.7 Outcome Assessment: The Americleft Project ....................................................................... 19

2 Objectives of the Study ............................................................................................................. 21

3 Hypotheses ................................................................................................................................... 22

4 Samples .......................................................................................................................................... 23 4.1 Inclusion/Exclusion Criteria ........................................................................................................ 24 4.2 Descriptive Data/Sample Sizes .................................................................................................... 25

5 Methods ......................................................................................................................................... 29 5.1 Evaluation of Dental Arch Relationship ................................................................................... 29 5.2 Evaluation of Craniofacial Form (Cephalometrics).............................................................. 32 5.3 Evaluation of Nasolabial Esthetics ............................................................................................. 36

5.3.1 Americleft “Q-Sort” Modification of Asher-McDade Method ..................................................... 38 5.4 Statistical Analysis ........................................................................................................................... 39

6 Results ............................................................................................................................................ 40 6.1 Dental Arch Relationship (Goslon Yardstick) ........................................................................ 40

6.1.1 Intra-Rater and Inter-Rater Reliabilities ........................................................................................... 40

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6.1.2 Goslon Scores ................................................................................................................................................ 41 6.2 Craniofacial form .............................................................................................................................. 44

6.2.1 Intra-Rater Reliability ............................................................................................................................... 44 6.2.2 Craniofacial Form Scores ......................................................................................................................... 44

6.3 Nasolabial Esthetics ......................................................................................................................... 49 6.3.1 Intra-Rater and Inter-Rater Reliabilities ........................................................................................... 49 6.2.3 Nasolabial Esthetics Scores .......................................................................................................................... 50

7 Discussion ..................................................................................................................................... 55 7.1 Interpretation of Results ............................................................................................................... 55 7.2 Limitations of the Study ................................................................................................................. 59

8 Conclusions .................................................................................................................................. 63

9 Clinical Significance and Future Directions ...................................................................... 64

10 References .................................................................................................................................... 65

11 Appendix 1: Abbreviations/Acronyms ............................................................................... 80

12 Appendix 2: Goslon Kruskal-Wallis Results: Multiple Comparisons ....................... 81

13 Appendix 3: Hard Tissue Cephalometric Landmark Definitions .............................. 85

14 Appendix 4: Soft- Tissue Cephalometric Landmark Definitions ............................... 87

15 Appendix 5: ANOVA and Tukey Pairwise Comparison for Cephalometric

Measurements ..................................................................................................................................... 88

16 Appendix 6: Nasolabial Kruskal-Wallis Results: Multiple Comparisons .............. 116 16.1 Nasofrontal Ratings ...................................................................................................................... 116 16.2 Vermillion Border ratings .......................................................................................................... 119 16.3 Nasal Profile Ratings .................................................................................................................... 123

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List of Tables Table 1: Demographics of Centers ............................................................................................... 28

Table 2: Treatment protocols of centers ....................................................................................... 28

Table 3: Hard-issue landmarks used in this study ........................................................................ 34

Table 4: Soft-tissue landmarks in this study ................................................................................. 35

Table 5: Intra- and Inter- Rater Reliability Scores for the Dental Arch Relationship Evaluation 40

Table 6: Agreement Categories (Landis and Koch, 1977) ........................................................... 41

Table 7: Sample Sizes and Mean Goslon Scores by Center ......................................................... 43

Table 8: Averaged Intra-Class Correlation Coefficients for Hard and Soft Tissue Cephalometric

Measurements ............................................................................................................................... 44

Table 9: Kappa values by Rater for the Cumulative Nasolabial Scores ....................................... 49

Table 10: Median Values of Nasolabial Esthetic Ratings Using the Modified Asher-McDade

Method .......................................................................................................................................... 54

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List of Figures Figure 1: Latham appliance displaying crossbar ............................................................................ 2

Figure 2: Illustrative drawings of different types of CLP. .............................................................. 7

Figure 3: Typical nasolabial morphology in patients with unrepaired CUCLP ............................. 8

Figure 4: LeMesurier Quadrilateral Repair ................................................................................... 10

Figure 5 Rose-Thompson and Mirault - Blair-Brown-McDowell Repair .................................... 10

Figure 6: Millard Repair ............................................................................................................... 11

Figure 7: Tennison-Randall Triangular Repair ............................................................................. 11

Figure 8: Gingivoperiosteoplasty technique ................................................................................. 15

Figure 9: Goslon Yardstick Reference Chart ................................................................................ 30

Figure 10: Cephalometric Hard and Soft Tissue Landmarks Used in this Study ......................... 33

Figure 11: Example of Coded Nasolabial (Vermillion Border) Yardstick ................................... 37

Figure 12: Inter- and Intra- Rater Reliability Scores for the Dental Arch Relationship Evaluation

....................................................................................................................................................... 40

Figure 13: Goslon Rating Percentages .......................................................................................... 42

Figure 14: Kruskal-Wallis Goslon Distribution ............................................................................ 42

Figure 15: Tukey Pairwise Comparison for SNA (left) and Ba-N-A (right) measurements ........ 45

Figure 16: Tukey Pairwise Comparison Graph for Ba-N-ANS (left) and ANB (right) ............... 45

Figure 17: Tukey Pairwise Comparison Graph for Na-Pg (left) and Wits (right) ........................ 46

Figure 18: Tukey Pairwise Comparison Graph for G-Sn-Po (left) and Co-Gn (right) ................. 46

Figure 19: Tukey Pairwise Comparison Graph for N-ANS (left) and ANS-Me (right) ............... 47

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Figure 20: Tukey Pairwise Comparison Graph for N-Me (left) and Sn-Me (right) ..................... 47

Figure 21: Tukey Pairwise Comparison Graph for ANB' (left) and Nasolabial Angle (right) ..... 48

Figure 22: Tukey Pairwise Comparison Graph for N’-Pn-Sn ...................................................... 48

Figure 23: Inter- and Intra- Rater Reliability Scores for the Cumulative Nasolabial Scores ....... 49

Figure 24: Nasofrontal Score Distribution .................................................................................... 50

Figure 25: Kruskal-Wallis Nasofrontal Graph .............................................................................. 51

Figure 26: Nasal Profile Score Distribution .................................................................................. 52

Figure 27: Kruskal-Wallis Nasal Profile Graph ............................................................................ 52

Figure 28: Vermillion Border Score Distribution ......................................................................... 53

Figure 29: Kruskal-Wallis Vermillion Border Graph ................................................................... 54

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List of Appendices Appendix 1: Abbreviations/Acronyms ………………………………………………………… 79

Appendix 2: Goslon Kruskal-Wallis Results: Multiple Comparisons …………………………. 80

Appendix 3: Hard Tissue Cephalometric Landmark Definitions …………………………….... 84

Appendix 4: Soft Tissue Cephalometric Landmark Definitions ………………………………. 86

Appendix 5: ANOVA and Tukey Pairwise Comparison for Cephalometric Measurements ..… 87

Appendix 6: Nasolabial Kruskal-Wallis Results: Multiple Comparisons …………………..... 115

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Introduction, Definitions and Statement of the Problem Children born with complete unilateral cleft lip and palate often present with significant nasolabial and skeletal deformities. These deformities involve skeletal and soft-tissue elements of the naso-maxillary complex, which in turn affect facial symmetry and esthetics. It is safe to say that there is no consensus on the best approach to treatment of an infant born with a cleft. In fact, there is a surprising degree of variability in treatment protocols of infant management and surgical intervention among cleft centers worldwide (Shaw et al., 2001).

Any manipulation of the infant’s cleft alveolar segments prior to lip and nasal repair is referred to by the umbrella term Infant Orthopedics (IO). This may involve some form of taping or strapping, or other various designs of intraoral removable or fixed appliances (plates) that apply different forces to the segments of the cleft maxilla or lips. Infant orthopedics has been used in the treatment of cleft lip and palate for centuries. Its objectives are to reposition the alveolar segments thereby establishing a better arch form, and to reduce the width and severity of the cleft before primary surgery.

One of the original approaches of IO was that by McNeil in the 1950’s (McNeil, 1950). In his technique, a maxillary impression was taken of the newborn and an acrylic appliance was formed from a plaster model that was cut and modified with the cleft gap slightly closed. By repeating this step and frequently modifying the appliance, McNeil claimed to be able to close not only the alveolar gap, but also the hard palatal cleft by influencing the direction of bone growth (McNeil 1950). This type of technique is known as active IO as opposed to the alternative approach of a passive plate that was molded to the maxilla of an infant and was able to constrict the alveolar cleft by merely keeping the tongue away from it.

One of the more popular approaches for active IO was that developed by Latham in 1980. The design of the appliance includes a screw of 25mm in length embedded in an anteroposterior direction in an intra-oral appliance made of acrylic. The lateral bases pivot freely on hinges at the ends of a transverse crossbar (figure 1) allowing them to move in the anteroposterior direction with respect to each other. By turning the screw, the lesser

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alveolar segment is forced to move forward and outward, and the greater segment is rotated toward the cleft. There is also a bilateral design that forces the protrusive premaxilla back through daily screw activation (Chan et al., 2003 Latham and Scott, 1970 Latham, 1980).

In 1993, Grayson et al., described the nasoalveolar molding (NAM) technique as a means to reduce the severity of the initial alveolar and nasal cleft deformity (Grayson, 2009, Jaeger et

al., 2007). The advantage of this technique is that it allows re-shaping ("molding") of the deformed and stretched immature alar cartilage, to a great degree restoring the nasal anatomy, in addition to the alveolar arch improvement and alveolar cleft width reduction prior to cleft repair.

NAM was incorporated in the infant management protocol at Toronto’s SickKids Hospital in the year 2001. Prior to that time, this center performed IO with the use of an active/passive intraoral acrylic appliance usually combined with extraoral “outrigger wires” that were taped on the infant's cheek to aid in retention of the appliance. This served to mold the alveolar process and reduce the width of the cleft deformity prior to surgery. For the purposes of this thesis, the technique of presurgical molding used prior to the introduction of NAM at SickKids Hospital will be termed traditional infant orthopedics (TIO). Infant orthopedics (IO) will be used as a generic term encompassing any type of presurgical

Transverse

crossbar

Figure 1: Latham appliance displaying crossbar

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manipulation of the cleft segments, alveolar or otherwise, which includes traditional infant orthopedics (TIO), Latham and nasoalveolar molding (NAM) techniques.

To date, there is a lack of standardized studies focusing on the various dental, skeletal and esthetic effects of different types or methods of IO in patients with CLP. The goal is obviously obtaining pleasing facial esthetics while minimizing the possible growth restriction of the maxilla and facial skeleton. Good facial growth may result in dental arch relationships that can be treated using conventional orthodontics, avoiding surgical correction of the skeletal bases and associated morbidity.

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1 Review of the Literature 1.1 Embryogenesis of Cleft Lip and Palate Development of the human craniofacial region involves a complicated set of events that begins in the early stages of fetal life. Understanding the embryology of lip and palate development will provide insights into the multifactorial causes of clefting and possible prognostic, preventive, and treatment regimens (Eberlin et al., 2013).

The craniofacial morphogenesis of the face, lip, and palate is best understood by information drawn from the multidisciplinary worlds of classical embryology, developmental biology, and, today, from the exciting world of molecular biology. One of the most important cell types in understanding normal and abnormal craniofacial morphogenesis is the neural crest cell. These important “building-block” cells arise from the final stages in formation of the embryonic neural tube (Bernheim et al., 2006). Following embryo gastrulation in the third week of development, neural crest cells are specified at the border of the neural plate and the non-neural ectoderm. During the process of neurulation, the borders of the neural plate, the neural folds, converge at the dorsal midline to form the neural tube. Neural crest cells from the roof plate of the neural tube then undergo an epithelial-to-mesenchymal transition and begin to migrate through the periphery where they differentiate into varied cell types. These neural crest cells contribute largely to the formation of the mesenchyme of the craniofacial complex (Kirschner and LaRossa, 2000).

The neural crest cells aid in establishing the five facial primordia including the frontonasal prominence and the paired maxillary and mandibular prominences that will later contribute to the formation of the lips, nose and palate (Melnick, 2003). The early oral pit, or stoma, is apparent at approximately 4 weeks of age. The facial structures continue to rapidly develop in the ensuing weeks. The nasal placodes are present laterally with the development of medial and lateral nasal prominences during the fifth week of development. During the sixth week, the medial nasal processes join in the midline to form the nasal tip, columella, prolabial segment, and primary palate. The maxillary prominences join with the lateral aspect of each medial nasal process to form the lateral components of

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the upper lip. Failure of fusion of one or both medial nasal and maxillary prominences results in unilateral or bilateral cleft lip, respectively. During this time, the secondary palate begins to form (Pearson and Kirschner, 2014). It forms as bilateral outgrowths from the maxillary processes, which grow vertically down the side of the tongue (Rohrich et al., 2004). Subsequently, the palatal shelves elevate to a horizontal position above the tongue, contact one another and commence fusion. Fusion of the palatal shelves ultimately divides the oronasal space into separate oral and nasal cavities. Once fusion of the shelves of the secondary palate occurs, the mesenchymal cells differentiate and become osteogenic cells contributing to the bony development of the premaxillary, maxillary and palatine portions of the palate (Berkowitz, 1996). Cleft palate results from the failure of fusion of these paired lateral palatine processes as a result of a defect in any of the three major stages of palatal formation – palatal shelf outgrowth, elevation, or fusion (Kaartinen et al., 1995).

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1.2 Classification of Cleft Lip and Palate Numerous methods have been proposed for the classification and recording of cleft lip and palate (CLP) deformities, however, the development of a comprehensive and universally accepted scheme for classifying CLP deformities remains elusive. In the United States, Davis and Ritchie introduced a classification system in 1922 (Davis and Ritchie, 1992). The European response was presented by Veau in 1931 (Veau, 1931). Both of these classifications omitted some of the common variations of oral clefts. For example, Veau's classification did not account for clefts of the lip, or of the lip and alveolus alone. The first most commonly accepted classification was presented by Kernahan and Stark in 1958, who described all common types of cleft lip/palate, complete unilateral cleft lip/palate and the isolated posterior cleft palate in a symbolic classification system. To describe the unusual types of cleft deformities, Kernahan modified his classification into symbolic striped ‘Y’ classification in 1971, which still had many shortcomings. The striped ‘Y’ classification was further modified by Millard in 1977 (Liu, 2007; Khan, 2013).

In 1989, Kriens proposed a simple palindromic system for cleft classification. Kriens’s system utilized the letters LAHSHAL to represent the two sides of the lip (L), alveolus (A), hard palate (H), and soft palate (S) (Kriens, 1989). In addition, upper and lower case letters were used to signify complete versus incomplete clefts, respectively. This method of classification proved to be very comprehensive as it could be used to describe various different combinations of CLP.

A more simplified approach focuses on the distinction between clefts involving the lip, palate or a combination thereof, with reference to the extent of the cleft (complete or incomplete), between unilateral or bilateral clefts, and between those occurring in conjunction with or in the absence of an associated syndrome. Non-syndromic CUCLP may therefore be defined as a continuous cleft extending from the nasal sill through the upper lip and alveolar process on one side up to the incisive foramen and posteriorly from the incisive foramen to include both the hard and soft palates. This sequence would be in conjunction with a n individual who was not diagnosed with a syndrome.

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Figure 2: Illustrative drawings of different types of CLP. a and e show unilateral and

bilateral clefts of the soft palate; b, c and d show degrees of unilateral CLP; f, g and h show degrees of bilateral CLP (Dixon et al., 2011)

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1.3 Nasolabial Morphology in Infants with CUCLP For children with CUCLP, external facial appearance is a critical aspect of treatment outcome and it substantially improves psychosocial development (Asher-McDade, 1992). It often negatively affects perceptions of others, which in turn may influence relationship with peers, social adjustment, and success in school (Broder et al., 1994).

Children with repaired CLP frequently demonstrate some degree of deformation of the nose and upper lip, such as nasal asymmetry, a relatively retrusive upper lip, or an uneven vermillion border (Adeola and Oladimeji, 2015). The abnormal morphology of the hard tissues supporting the nose, lips and cheeks may be largely associated with poor nasolabial esthetics. In patients with CUCLP the deviation of the facial skeleton may be particularly significant due to the extent of the cleft and its asymmetric location (Urbanova et al., 2013). Deviation of the nasolabial regions towards the non-cleft side occurs as aberrant muscle insertions and tongue protrusion cause the non-cleft side of the maxilla to rotate away from the cleft. The perioral musculature overpowers the inadequately supported bone and pulls the nose and nasal septum to the non-cleft side, yet the alar base on the side of the cleft remains fixed. As a result, the cleft side nostril becomes stretched and flattened (Ross, 2002). The columella on the cleft side is shortened significantly, as compared with the non-cleft side and is oriented obliquely, with its base deviated toward the non- cleft side, away from the midline. The alar bases are asymmetric, with the cleft side alar base displaced inferiorly and posteriorly (Lo, 2006).

Figure 3: Typical nasolabial morphology

in patients with unrepaired CUCLP

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1.4 Primary Surgical Repair of Patients with CUCLP The main goals of surgical cleft repair are functional restoration of the oro-nasal sphincter and oro-nasal soft tissues; re-establishment of the complex relationship between perioral and perinasal muscle rings; and the unhindered promotion of midfacial growth and development (Anastassov and Joos, 2001). Many controversies still surround the optimal timing and sequence of the interventions necessary for the correction of cleft lip and palate deformity and no single universally accepted protocol exists (Dorf and Curtin, 1982). Historically the ‘rule of 10s’ was applied for the timing of cleft lip repair – an age of at least 10 weeks, with a weight of 10 lbs and haemoglobin level of 10 g/dl. In most centers, cleft lip repair is carried out at 3–6 months of age (Rohrich et al., 2000). By this time, fetal physiology is replaced by that of an infant and the risks of anaesthesia are significantly reduced.

The issue of timing of surgery for palatal repair has been even more controversial. There are varying schools of thought about the timing and staging of palatal repair and their implications on speech and facial growth and development. The main aim of palate repair is restoration of soft palate function, especially with regard to normal speech development, as certain sounds need a build-up of oral air pressure, which relies on a competent velopharyngeal seal. Early surgery has the potential advantage of better speech outcomes whereas delayed surgery is potentially associated with less impairment of midfacial growth, but arguably less favorable speech outcomes (Rohrich et al., 2000). Many surgeons continue to advocate two-stage repair of the cleft palate. Advocates of two-stage palatal repair perform repair of the soft palate between 3 and 8 months of age to help minimize the speech pathology associated with velopharyngeal dysfunction (VPD) – namely hypernasal resonance and nasal air escape (Arosarena, 2007). Hard palate repair is subsequently delayed until 12 months to 12 years of age to minimize midfacial growth restriction (Arosarena, 2007).

Dorf and Curtain (1982, 1990) examined the articulation of children who underwent cleft palate repair before and after 12 months of age. In each of their reports, significantly better results were noted in the former group of patients. Data from the Cleft Lip and Palate Center at the Children’s Hospital of Philadelphia, however, have demonstrated no

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significant differences in velopharyngeal function among children who underwent palatoplasty before 24 months of age (Kirschner et al., 1999). Also, no significant differences in craniofacial morphology have been identified in children who had palatal clefts repaired between 8 months and 8 years (Utreja et al., 2000; Rohrich et al., 2000; de Silva Filho et al., 2001). Consequently, most craniofacial surgeons advocate complete repair of palatal clefts between 9 and 12 months to prevent the detrimental effects of delayed repair on speech and language development (Nguyen and Sullivan, 1993; Kirschner and LaRossa, 2000; Salyer, 2001; Van Lierde et al., 2004).

Early methods of cleft lip repair were straight-line closure techniques as described by Rose in 1891 and then by Thompson in 1912. In the 1940s and 1950s, techniques based on triangular flap modification were proposed by Blair and Brown, and Brown and McDowell (1945). Le Mesurier’s quadrilateral flap technique (1949) and Tennison-Randall’s triangular flap technique (1952) both introduced tissue into the lower part of the lip and produced an aesthetically pleasing cupid’s bow and pouting of the tubercle. In 1955, Millard pioneered the principle of downward rotation of the medial segment and the lateral flap advancement into the upper lip. In the 1970s, Delaire emphasized the importance of a functional muscle repair. His procedure respected the anatomical boundaries between the lip and the nose with the goal to avoid scars crossing the alar rim and columellar base. Wide sub-periosteal undermining of the cleft-sided anterior maxilla to release the peri-oral muscles, careful muscle dissection and anatomical repositioning of not only the peri-oral but also the peri-nasal muscles contribute towards achieving lip length and aesthetics with this technique.

Figure 4: LeMesurier Quadrilateral Repair Figure 5 Rose-Thompson and Mirault - Blair-

Brown-McDowell Repair

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Cleft palate surgical repair began when Wardill (1928) and Kilner (1937) developed a ‘push-back’ procedure in the 1920s and early 1930s. This technique has the disadvantages of leaving denuded areas on the palate antero-laterally, with associated scar contracture, growth impairment and fistula formation. Another technique is a three-layer closure of the soft palate, dissection of the nasal mucosa and posterior based unipedicled flaps for velum lengthening by V-Y closure developed by Victor Veau in the 1930s. In 1962, Bernhard von Langenbeck (1972) suggested palatal closure with two bi-pedicled muco-periosteal palatal flaps mobilized medially. This technique is still in use today. There is also uncertainty about long-term stability of the gained palatal length. The technique of a double opposing Z-plasty for simultaneous velar closure and lengthening was introduced by Furlow in 1978. This technique has the advantage of reorienting and retro-positioning the levator muscles more anatomically with less muscle dissection, thus minimizing scarring around the muscles. Lengthening of the velum and narrowing of the naso-pharyngeal orifice are also useful outcomes of this method, which has gained popularity and is used in many centers around the world.

Figure 6: Millard Repair Figure 7: Tennison-Randall Triangular Repair

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1.5 Gingivoperiosteoplasty and Alveolar Bone Grafting in Patients with CUCLP

Restoration of dentoalveolar continuity is essential for stabilization of the maxillary arch, support of dental roots on either side of the cleft, and ultimate eruption of the permanent lateral incisor and canine teeth. In addition, restoration of the maxillary arch is important to provide a stable platform for the alar base of the nose (Dado et al., 1997). Over the years, there have been different surgical techniques such as secondary bone grafting, primary bone grafting and gingivoperiosteoplasty (GPP) that were shown to repair the bony defect in the alveolar cleft area.

Alveolar bone grafting has become an integral part of repairing clefts that involve the anterior maxilla. The goals of ABG are to 1) close the oronasal fistula and restore the dimensions of the dental arch and maxilla; 2) stabilize the maxilla during function; 3) improve bone support and periodontal health; 4) facilitate eruption of teeth adjacent to and through the cleft; 5) improve oral hygiene; 6) provide support for the receded alar base, reducing nasal asymmetry; 7) provide appropriate morphology for speech articulation; 8) provide a permanent repair, requiring no further treatment; and 9) enable the orthodontist to achieve an attractive alignment of natural teeth, fully supported by normal bone and periodontal tissues (Boyne and Sands, 1972; Bell and Proffit, 1980; Abyholm et al., 1981; Sullivan, 1981; Braun and Sotereanos, 1981; Bergland et al., 1986; Schultz, 1986; Ross, 1987; Tolman et al., 1988; Kalaaji et al., 1994, 1996; Cameron and Widmer, 1998; Lilja et al., 2000)

Secondary bone grafting was first introduced in Oslo, Norway by the CLP team in 1977 (Bergland et al., 1986). The procedure was based on the preliminary work of Byne and Sands (1972, 1976) and Boyne (1974), who were the first to utilize the osteogenic potential of cells in a fresh autograft to treat cleft anomalies.

According to a survey distributed to all the teams registered with the ACPA across North America, there was outstanding uniformity in the decision to perform secondary ABG procedures (90% of centers), while 78% of centers performed the procedures between the ages of 6 to 9 years (Murthy and Lehman, 2005). Many authors advocate placement of the

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ABG prior to the eruption of the canine, when the roots are between one-fourth and two-thirds formed (Turvey et al., 1984; Bergland et al., 1986; Loh et al., 1988; Newlands, 2000). Radiographic studies have shown that timing of the procedure is an important variable affecting the outcome of ABG (Trindade et al., 2005; Jia et al., 2006). Specifically, the bone grafts that yield the most successful results in terms of alveolar bone height were those performed prior to canine eruption and by an experienced surgeon (Abyholm et al., 1981; Sindet-Pedersen and Enemark, 1985; Bergland et al., 1986; Paulin et al., 1988; Kalaaji, 1994)

On the other hand, one of the supposed advantages of alveolus repair performed in infancy or in primary dentition is the early elimination of oronasal fistulas (Ross, 2002). These fistulas, however, are generally asymptomatic in the primary dentition because the dental arch contraction obliterates them. Also, the quality and quantity of the resulting ABG is frequently less than desirable when placed during infancy (Ross, 2002). Another purported advantage of primary ABG is the avoidance of a separate, additional surgical procedure in the mixed dentition to repair the alveolar cleft (i.e secondary bone grafting). The most significant concern with primary ABG is the long-term maxillary growth inhibition. A number of studies have alluded to such an undesirable effect (Long et al., 1997).

Although bone grafting of the residual alveolar cleft in patients with CUCLP has become a well-established procedure, a review of the literature reveals great variability in timing of ABG placement (Kalaaji et al., 1994). According to Helms et al., (1987), bone grafting is termed “primary” when performed during infancy (age 6 to 12 months); “early secondary” when it is undertaken between ages of 5 and 6 years; “secondary” (mixed-dentition) when performed between ages of 9 and 11 years or before permanent canine eruption; and “late secondary” when it occurs after the eruption of the permanent canine. Grafting at age 5 to 6 years has some proponents, since it establishes bony continuity prior to the eruption of the permanent central incisor or supernumerary tooth on the margin of the cleft (Ross, 2002, Precious, 2009). If bone support is unfavorable and maintenance of this tooth is considered important, grafting will greatly enhance the chances of survival. In contrast, delayed bone grafting is usually reserved for patients who present in the permanent dentition without ABG, either because of negligence, failure of an earlier graft, or because the alveolar defect

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was deemed too large to graft successfully prior to surgical advancement of the lesser segment (Ross, 2002). Studies have also attempted to assess the growth of the maxillofacial region in patients with clefts following secondary ABG. Trotman et al., (1997) conducted a retrospective study analyzing postero-anterior cephalograms taken on 28 subjects with grafted and 58 with ungrafted CUCLP, as well as 60 non-cleft control subjects. This study concluded that secondary ABG procedures had a minimal effect on transverse craniofacial growth long-term. However, it is important to note that several authors have found no appreciable antero-posterior differences between grafted and ungrafted subjects (Semb 1988; Ross, 1995; Daskalogiannakis and Ross, 1997). Another retrospective study also investigated the effects of secondary ABG in patients with CUCLP (Levitt et al., 1999). Cephalometric radiographs were used to assess sagittal and vertical growth changes. No significant differences were noted between the patients that received an ABG and those that did not although the rate of vertical growth of the anterior maxilla was found to be relatively decreased in the grafted group. However, ultimately, the amount of maxillary growth in patients with grafted clefts did not differ significantly from that of patients with ungrafted clefts during the same time period.

An alternative to ABG, gingivoperiosteoplasty (GPP), first introduced by Skoog (1956) and later championed by Millard and Latham (1990), has been used to repair the cleft alveolus as well. Skoog formed a periosteal flap taken from the canine fossa and turned this flap over the alveolar cleft. In 1980, Ralph Millard suggested a new technique. He describes small gingivoperiosteal flaps from both alveolar cleft margins and closing the cleft in a tunnel fashion at the age of 5 months (Henkel and Gundlach, 1997). 1997, Cutting described a modification of Millard’s Gingivoperiosteoplasty (GPP) technique wherein the GPP flaps were limited to the attached gingiva of the dento-alveolus. This technique did not impair midface growth, produced satisfactory bone formation in 60% of unilateral CLP patients, and saved money for the patient by avoiding an unnecessary secondary GPP procedure (Wood et al., 1997).

During GPP, mucoperiosteal flaps are raised and inset across the alveolar cleft, promoting the production of bone in the cleft space. If successful in generating bone across the cleft site, GPP may result in early union of the maxillary dental arch and may eliminate the need

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for secondary alveolar bone grafting (ABG) (Matic and Power, 2008). Controversy exists in the literature as to the efficacy of GPP and its effect on growth of the maxilla. A study by Henkel and Gundlach (1997) demonstrated that patients with UCCLP who were subjected to the Latham appliance in addition to GPP showed a higher frequency of anterior open bites at 10 years of age. The maxillary length was also shorter in the patient group who underwent GPP as compared to the controls. They attributed this result to the unphysiological movement in the premaxillary-vomerine suture of the midface. It was thought that the stress on the premaxillary-vomerine-suture was apparently too strong, therefore damaging to these sutures. Other studies such as that by Dec et al., (2013) appeared to demonstrate that 60% of UCCLP patients treated with the NAM appliance in addition to GPP, produced satisfactory dentoalveolar bone formation and no impairment of maxillary growth was seen when evaluated in a long term follow-up study. In a preliminary study, using bone markers, Spolyar et al., (1992) showed that the Latham method induced profound and complex orthopedic changes but did not appear to harm facial growth. Lukash et al., (1998) reported that children with both unilateral and bilateral complete cleft lip and palate (BCCLP) showed consistently favorable growth patterns following use of the Latham appliance with gingivoperiosteoplasty (GPP). Millard et al., (1999) published a preliminary analysis of serial dental casts of patients with UCCLP who were treated with active presurgical orthopedics, gingivoperiosteoplasty, and lip adhesion (POPLA) and compared the models to those from patients treated with lip adhesion alone. The UCCLP/ POPLA group exhibited less multiple-tooth posterior crossbite and a greater transverse width of the upper dental arch. However, they also found a greater frequency of anterior crossbite in the treated group, but this tended to decrease with age.

Figure 8: Gingivoperiosteoplasty technique

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1.6 Development of presurgical Infant Orthopedics (IO) Cleft lip and palate can present with considerable variation in severity and form. Generally, the wider clefts are associated with more extensive nasolabial deformities (Derek et al., 2013). These clefts, present a significant surgical challenge to achieve a functional and cosmetic outcome. The desire to reduce the surgical challenges of CLP is not a new phenomenon. There have been reports as far back as the 16th century describing retraction of the protrusive premaxilla in BCCLP patients (Grayson and Garfinkle, 2014). This is early evidence of surgeons' attempts to reduce the severity of the deformities before the primary surgical repair in order to achieve a better outcome. As clinicians strived for improved clinical outcomes, the field of IO emerged. Several orthopedic devices for infants with clefts have been described, the most well-known being different designs of active or passive maxillary plates (McNeil, 1956; Hotz, 1969), the Latham appliance (Latham et al., 1976), lip taping (Pool and Farnworth, 1994), and NAM (Grayson et al., 1993). Lip adhesion (Meijer, 1978) is usually reserved as an alternative to IO for the challenging cases when IO is not available/appropriate.

As previously stated, the modern school of infant orthopedic treatment was introduced by McNeil in the 1950’s. This approach used a series of intraoral appliances to actively mold the alveolar segments into the desired position presurgically (McNeil, 1956). The alveolar cleft is thereby narrowed and additional soft and hard tissue is available for surgical repair (Ross and Johnston, 1972). Hotz later described the use of a passive orthopedic appliance made of soft/hard acrylic resin to slowly align the cleft segments (Hotz, 1969). Continued wear of the appliance prevented the tongue from inserting into the cleft, facilitating the approximation of the alveolar segments.

In the 1980’s, Millard and Latham introduced a novel yet controversial method of neonatal maxillary orthopedics. This method consisted of a palatal appliance retained by pins inserted into the alveolar process of the infant, which provided anchorage for the mechanical manipulation of the maxillary segments into close approximation. This was generally followed by gingivoperiosteoplasty and lip adhesion. It was believed that positioning of the alveolar segments, dissection of mucoperiosteum out of the cleft, and union of the mucoperiosteum across the alveolar and anterior hard palate cleft, creating a

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tunnel effect, set up a condition conducive to bone formation (Millard and Latham, 1990). It took several years until the first longer-term studies were published about this procedure. Berkowitz (1996) found that of a group of 32 patients with unilateral complete CLP, 23 had developed an anterior cross bite by the age of 6 years, presumably due to the displacement of the premaxillary portion of the greater alveolar segment and the scar tissue resulting from the periosteoplasty. The proponents of the Latham technique however, claim that it does not hinder maxillary growth and in addition it can create an environment for a more predictable primary surgical repair. Although it is still being used in several cleft centers today, the effects of the Latham appliance with gingivoperiosteoplasty on maxillary growth and overall profile esthetics remains questionable.

After nearly 40 years of neonatal maxillary orthopedics, the focus of the treatment more recently started to shift towards incorporating and improving the esthetics of the nose. In the 1990’s, Grayson and Cutting emphasized the importance of presurgical correction of the nasal cartilage and soft tissue deformity, which can be achieved by combination of nasal and alveolar orthopedic molding (Grayson and Cutting, 2009). Inspired by research on the plasticity of neonatal auricular cartilage (Matsuo et al., 1984), they proposed that active molding and repositioning of the nasal cartilages in patients with CLP may take advantage of the temporary plasticity of the nasal cartilage of the newborn, which is thought to arise from high levels of estrogen circulating for several weeks after birth (Grayson et al., 1993, Cutting et al., 1998, Grayson et al., 1999). The NAM technique combines presurgical alveolar molding with nasal molding through the incorporation of an acrylic nasal stent to the labial vestibular flange of a conventional intraoral molding appliance. The nasal stent and intraoral component are adjusted gradually, usually at weekly intervals over a three-to-four month period, to achieve nasal and alveolar symmetry, nasal tip projection and contact of the cleft alveolar segments just prior to primary repair. According to Grayson, presurgical reduction in the soft tissue and cartilaginous deformities allows for repair under minimal tension, optimizing conditions for scar formation and improving nasal symmetry in the long term (Grayson and Cutting, 2001).

Whether IO is necessary, useful or even harmful in the long term, has been the subject of considerable debate in cleft treatment over the years. The findings of the only prospective

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RCT in patients with CUCLP by Dutchcleft, shows that IO has no effect on early esthetic outcome (at 6 years of age). However, it remains to be investigated further whether differences between groups develop at a later age. It was also concluded that IO only has a temporary effect on maxillary arch dimensions that does not last beyond surgical soft palate closure. This conclusion, although NAM was not evaluated in the study, led to the complete elimination of IO use in the Netherlands (Prahl et al., 2001; Bongaarts et al.,

2006). Conversely, the question remains with respect to the long-term benefits of the nasal component of NAM appliance. The question still remains as to whether NAM provides a benefit to the nose or nasolabial appearance in the long term over not using the NAM at all. This has not been adequately investigated and no consensus exists.

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1.7 Outcome Assessment: The Americleft Project The great variety of infant orthopedic protocols and surgical treatment techniques for patients with CLP documented in the literature is indicative of the lack of scientific evidence on best practices. As a result, clinicians are unable to make rational evidence-based decisions on the most efficient and effective interventions for these patients (Semb and Shaw, 1998). In a survey of 201 European cleft centers, 194 different surgical protocols were reported for the primary correction of CUCLP alone (Williams et al., 2001). This means that two infants born with the same condition on either side of a State line or in different regions of the same country will often have very different treatments. Centers have developed treatment protocols based on preferences of their key operators, or based on tradition, or other regional issues, that generally do not change (Shaw and Semb, 2002). There is a clear need for research on assessment of outcomes of various protocols so as to be able to select the most effective ones and abolish the ones that clearly lead to compromised results.

The landmark Eurocleft project that started in the late 1980s was the first to utilize retrospective analysis of clinical outcome records to detect favorable versus unfavorable approaches to various aspects of cleft care (Semb, 2005 and Shaw et al., 1992). Based on its results, a set of common policy statements were established governing clinical practice for European cleft teams. As well, practice guidelines were developed and minimum record standards were recommended that cleft teams should take and maintain (Shaw et al., 1992). Eurocleft was the first effort that raised the world's awareness of cleft outcomes research. Stemming from this, several other efforts were initiated worldwide. The most important of those is the Scandcleft prospective randomized controlled trial on the influence of surgical technique and staging of repairs on outcome of treatment for patients with complete UCLP, which involves the collaboration of 8 Northern European and 2 UK teams.

Unfortunately, it took almost 20 years from the initial Eurocleft trial until inter-center outcome assessment efforts started in North America. In 2004, WHO issued a report on the global challenges of craniofacial anomalies, identifying the need for inter-center outcomes research so as to begin to discern differences among different protocols (WHO, 2004). As a

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response to this Report, the American Cleft Palate Craniofacial Associaton (ACPA) established the Task Force on Americleft (2006), which was modeled after the original Eurocleft study and originally involved the orthodontists from 6 Cleft/Craniofacial centers in the US and Canada. The original Americleft project only dealt with orthodontically related outcomes of primary infant management protocols for UCLP (dental arch relationship, skeletal morphology, and nasolabial esthetics). One of the first accomplishments of the original Americleft effort was the substantiation of the negative impact of primary bone grafting, which led the center that performed it to subsequently abolish it from its protocol. Since the original meeting (2006), the Americleft Project Orthodontic Group has held annual face-to-face meetings attempting to refine the outcome measures currently available so as to improve reliability and confirm validity; to develop new outcome measures for treatments not assessed in the original Eurocleft study; and to expand the number of participating centers to include centers with protocols that include specific features of interest that were not covered in the original studies. The results of some of these efforts over the past 10 years were published in a 5-part series (Long et al., 2011; Hathaway et al., 2011; Daskalogiannakis et al., 2011; Mercado et al., 2011; Russell et

al., 2011). The project has since expanded to include assessment of speech, psychosocial, and surgical outcomes.

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2 Objectives of the Study • To compare the dental arch relationships of mixed-dentition patients with non-

syndromic CUCLP treated with different neonatal IO protocols (Latham, TIO, naso-alveolar molding (NAM), and no IO).

• To compare the craniofacial form of mixed-dentition patients with non-syndromic CUCLP treated with different neonatal IO protocols (Latham, TIO, naso-alveolar molding (NAM), and no IO).

• To compare the nasolabial esthetics of mixed-dentition patients with non-syndromic CUCLP treated with different neonatal IO protocols (Latham, TIO, naso-alveolar molding (NAM), and no IO).

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3 Hypotheses Hypothesis 1: There exists a significant difference between the dental arch relationship of patients with non-syndromic CUCLP treated with the Latham appliance, and those of patients that received TIO, NAM, or no IO at all.

Null Hypothesis 1: There exists no difference in the dental arch relationship of patients with non-syndromic CUCLP treated with Latham therapy, as compared to that of patients with received TIO, NAM or no IO at all.

Hypothesis 2: There exists a significant difference between the craniofacial form of patients with non-syndromic CUCLP treated with the Latham appliance, and those of patients that received TIO, NAM, or no IO at all.

Null Hypothesis 2: There exists no difference in the craniofacial form of patients with non-syndromic CUCLP treated with Latham therapy, as compared to that of patients with received TIO, NAM or no IO at all.

Hypothesis 3: There exists a significant difference between the nasolabial esthetics of patients with non-syndromic CUCLP treated with the Latham appliance, and those of patients that received TIO, NAM, or no IO at all.

Null Hypothesis 3: There exists no difference in the nasolabial esthetics of patients with non-syndromic CUCLP treated with Latham therapy, as compared to that of patients with received TIO, NAM or no IO at all.

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4 Samples The subjects for the assessment of dental arch relationships and craniofacial form of the various IO protocols, were obtained from four North American centers by a retrospective chart review. A fifth center was included in addition to the other four, for the comparison of nasolabial esthetics. There were two cohorts treated at Sickkids Hospital, Toronto. One sample had undergone TIO as part of its former standard protocol (prior to 2001), and the second one received the current protocol, in which NAM has replaced the previously neonatal approach. The year 2009 was selected as the end point of the experimental period to ensure the presence of photographic, radiographic and dental cast records at ages 6-13 in the latter sample of patients at the time of record evaluation. In addition to the two samples mentioned above, the four other participating centers were: Lancaster Cleft Palate Clinic (Lancaster, PA); Boston Children’s Hospital (Boston, MA); Cincinnati Children’s Hospital (Cincinnati, OH); and Peyton Manning Children’s Hospital (Indianapolis, Indiana). As per the original Americleft participants’ agreement, the center of origin of each sample will remain anonymous in the presentation of the results.

Approval for the use of the clinical records (dental models, cephalometric radiographs and standardized cropped photographs) was obtained from the respective Research Ethics Boards of all participating centers prior to initiating the investigation.

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4.1 Inclusion/Exclusion Criteria a) Only Caucasian patients were included in the investigation to avoid bias introduced

by racial variations in craniofacial form. b) All subjects had been previously diagnosed with a non-syndromic CUCLP. Any

patients with co-existing associated anomalies or syndromes were excluded. c) All primary interventions with respect to the cleft, including orthodontic treatment

for IO and cleft-related surgical procedures, were performed at the institution of record and complete records of all procedures were available.

d) Subjects where appliance use was discontinued or deemed unsuccessful and terminated prematurely as recorded in the chart by the treating orthodontist were excluded (e.g. poor compliance by parent, inability of patient to tolerate appliance).

e) Subjects who underwent any orthodontic intervention including fixed or removable appliances, headgear or face-mask therapy prior to the date of acquisition of the photos were excluded.

f) Photographs of subjects between ages of 6-13 yrs were available for standardization and assessment. These photographs included standard frontal photographs for all subjects, and, when available, cleft-side profile photographs. If the cleft-side photograph was unavailable, the noncleft-side photograph was used and rated to facilitate blinding and uniformity in rating; however, the ratings of the profile view of the noncleft side were excluded from the analysis of the data.

g) Dental models and cephalometric radiographs of subjects in mixed dentition between ages of 6-13 years were available for comparison.

h) Any subjects with photographs, dental models or cephalometric radiographs deemed by the primary investigator or by the consensus of the raters to be of insufficient quality to be reliably rated were excluded.

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4.2 Descriptive Data/Sample Sizes The following descriptive data were recorded for each subject included in the investigation

1 Gender 2 Date of birth 3 Side of cleft 4 Age when photographs, dental models and radiographs were taken

The following information was recorded for each center included in the investigation (Table 2):

1 Type of infant orthopedic appliance (if used) 2 Lip repair technique 3 Primary alveolar repair 4 Hard palate repair 5 Age at secondary bone grafting 6 Age at nose/lip revision 7 Number of surgeons at each center

The first sample (referred to as “Center 1”) comprised 38 patients of which 23 were male, 15 were female. Dental casts used in this study were taken at a mean age of 8.9 years with 23 left-sided clefts and 15 right-sided clefts. This center also contributed 40 cephalometric radiographs (mean age 8.7 years) to analyze the skeletal and soft tissue differences between centers. This center also contributed 38 facial photographs in which 21 were male and 15 were female. The distribution of left-sided to right-sided clefts was 21:15. The mean age at photographs was 8.10 years. No IO was utilized. Surgical repair of the lip (3 months), hard palate (12 months) and soft palate (18 months) were performed by a single surgeon.

The second sample (referred to as “Center 2”) consisted of 17 patients, of which 10 were male, 7 were female. Dental casts used in this study were taken at a mean age of 9.2 years with 11 left-sided clefts and 6 right-sided clefts. This center also contributed 30 cephalometric radiographs (mean age 8.8) to analyze the skeletal and soft tissue differences between centers. This center also contributed 34 facial photographs in which 22 were male and 11 were female. The distribution of left-sided to right-sided clefts was

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24:10. The mean age at photographs was 8.7 years. The Latham appliance was utilized. Surgical repair of the lip (3-4 months), hard palate and soft palate (9-12 months) were performed by 3 surgeons.

The third sample (referred to as “Center 3”) consisted of 19 patients, of which 14 were male, 5 were female. Dental casts used in this study were taken at a mean age of 9 years with 14 left-sided clefts and 5 right-sided clefts. This center also contributed 18 cephalometric radiographs (mean age 10.2) to analyze the skeletal and soft tissue differences between centers. This center also contributed 19 facial photographs in which 14 were male and 5 were female. The distribution of left-sided to right-sided clefts was 14:5. The mean age at photographs was 9.1 years. The Latham appliance was utilized in conjunction with GPP at this center. Surgical repair of the lip (6 months), hard palate and soft palate (10 months) were performed by 2 surgeons.

The fourth sample (referred to as “Center 4”) contributed two cohorts to the study. The first consisted of 28 patients (23 male, 5 female). Dental casts used in this study were taken at a mean age of 7.1 years with 21 left-sided clefts and 7 right-sided clefts. It also contributed 17 cephalometric radiographs (mean age 9) to analyze the skeletal and soft tissue differences between centers. This cohort also contributed 38 facial photographs (30 male, 8 female). The distribution of left-sided to right-sided clefts was 30:8. The mean age at photographs was 7.5 years. The NAM appliance was utilized. Surgical repair of the lip (4-5 months), hard palate and soft palate (18 months) were performed by 3 surgeons. The second cohort of this center consisted of 36 patients (24 male, 12 female). Dental casts used in this study were taken at a mean age of 10.3 years with 22 left-sided clefts and 14 right-sided clefts. This cohort also contributed 19 cephalometric radiographs (mean age 9) to analyze the skeletal and soft tissue differences between centers. This cohort also contributed 26 facial photographs (14 male, 12 female). The distribution of left-sided to right-sided clefts was 12:14. The mean age at photographs was 9.9 years. A modification of the McNeil approach was utilized. Surgical repair of the lip (3 months), hard palate and soft palate (12-14 months) were performed by 4 surgeons.

The fifth sample (referred to as “Center 5”) did not contribute any dental casts or

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cephalometric radiographs. A total of 27 facial photographs were used, (19 male, 8 female). The distribution of left-sided to right-sided clefts was 24:3. All of the profile images available from this center were of the right side of the patient, irrespective of the side on which the cleft occurred. Since the cleft-side profile view for patients with left-sided clefts was unavailable, it was decided to exclude the Nasal Profile data from this center from the analysis. The mean age at photographs was 8.10 years. The Traditional Infant Orthopedic appliance was utilized. Surgical repair of the lip (3 months), hard palate and soft palate (12 months) were performed by 4 surgeons.

The sample distributions and protocol details for all cohorts used can be found on Tables 1 and 2.

Sample Total

M/F L/R Mean Age

Center 1 – No IO

Goslon Photographs Radiographs

38 23/15 23/15 8y9m 36 21/15 21/15 8y10m 40 24/16 24/16 8y7m

Center 2 - Latham


17 10/7 11/6 9y2m 34 23/11 24/10 8y7m 30 21/9 20/10 8y8m

Center 3 - Latham


19 14/5 14/5 9y0m 19 14/5 14/5 9y1m 18 13/5 6/12 10y2m

Center 4-(NAM)

Goslon

28 23/5 21/7 7y10m

28

Photographs Radiographs

38 30/8 30/8 7y5m 17 14/3 13/4 8y9m

Center 4- (IO)


36 24/12 22/14 10y3m 26 14/12 12/14 9y9m 19 11/8 10/9 9y6m

Center 5 – (TIO)


N/A N/A N/A N/A 27 19/8 24/3 8y10m N/A N/A N/A N/A

Table 1: Demographics of Centers

Table 2: Treatment protocols of centers

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5 Methods 5.1 Evaluation of Dental Arch Relationship The standards for preparation of the models followed those set forth in the original Goslon study (Mars et al., 1992). The entire set of models from all the centers was rated twice, on separate days, by six experienced and trained raters. The models were numbered and randomized in their order of presentation. Thus, each set of models received 12 total scores that were averaged to give a mean score for each patient. Each rater had the opportunity to compare any set of models to be rated with the displayed reference models of the Yardstick. The reference Yardstick consists of a set of calibrated dental casts that were established in the original Goslon study to indicate discrete examples of each of the 5 points of the scale (Figure 9). For the second rating, the models were re-numbered and again randomized in order of presentation.

The application of the Yardstick has three variables that influence the score assigned to each model (1 = excellent to 5 = very poor). The anteroposterior assessment (overjet) has the greatest influence on the Goslon score. If there are dental compensations present in the inclination of the maxillary or mandibular incisors, the score may shift to the next higher or lower score, depending on the magnitude of the compensation. The second determinant is the vertical dimension. A deep overbite is preferable to an open bite. Finally, third in order of importance is the transverse relationship between the dental arches. This determinant infrequently influences the Goslon score and is weighted less, based on the assumption that many transverse relationships may be treated with orthodontic therapy alone. Severe collapse of the arch, however, may increase the score. The weighting of these three determinants emphasizes the need to use the reference yardstick models during rating sessions (Figure. 9).

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�

The following is adapted from the Americleft Study Guide:

Score 1:

o Class I or Class II apical base relationship

o Positive overjet and overbite (no open bite)

o No crossbite

o Good arch form

Score 2:

o Class I or Class II apical base relationship

o Corrected incisors would be in positive overjet and overbite (or minimal open bite)

o May have crossbites or minor deviation in arch form

Figure 9: Goslon Yardstick Reference Chart

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o If severe deviation in arch form or severe open bite: Score 3

Score 3:

o Edge to edge apical base relationship

o Corrected incisors would be edge to edge

o May have crossbites or major deviation in arch form

Score 4:

o Class III apical base relationship

o Corrected incisors would not be edge-to edge

o May have crossbites or major deviation in arch form

Score 5:

o Class III apical base relationship

o Corrected incisors would no touch lower incisors

o May have crossbite or poor arch form

The method of model preparation was similar from all centers including the process of duplication, the type of stone and trimming. The models were all cast in a vacuum-mixed white stone and trimmed with a fine wheel to the standard heights and angles. They were also trimmed with heels parallel so that when models are placed on their heels, teeth are in centric occlusion. The casts were all finished with light sanding, but not soaped.

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5.2 Evaluation of Craniofacial Form (Cephalometrics) The inclusion of a cephalometric comparison offers an additional dimension in the evaluation of the long-term effects of infant orthopedics. As per the original Eurocleft study (Shaw et al., 1992), the following descriptive data were recorded for each subject who contributed a cephalometric radiograph to this investigation.

1. Date of birth 2. Sex 3. Side of cleft 4. Whether or not IO was performed 5. Date of lateral cephalogram 6. Age at lateral cephalogram 7. Age and date of alveolar bone graft procedure (ABG), if performed 8. Any other surgical procedures performed and at what age

A single lateral cephalometric radiograph was furnished for each subject, all prior to secondary bone grafting, and between the ages of 6-13 years. The images from a cohort of one of the centers, were conventional radiographs printed on x-ray film. An Epson Expression scanner (model #1680) was used to convert the hardcopy radiographs (analog image) into JPEG format (digital image). The radiographic images from the remaining centers were already in digital format. These lateral cephalograms were then imported directly into the cephalometric software for further analysis (see below). The raw data was then exported from Dolphin Imaging into Microsoft Excel, where they were organized into spreadsheets according to center.

Since the lateral cephalograms from each center were produced using diverse radiographic equipment possessing different enlargement factors, an adjustment had to be made to control for radiographic magnification. The magnification factor was calculated proportionally by using the reference ruler that was contained in each cephalogram. (figure 10).

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Dolphin imaging software (version 11.7) was used for all cephalometric analysis. Forty-eight landmarks per radiograph were digitally plotted to generate a cephalometric tracing. Based on these landmarks, 17 hard tissue and 10 soft-tissue cephalometric measurements were generated (Table 3, 4). The measurements were based on those employed in the original Eurocleft study (Mølsted et al., 1992), with some modifications. The digital images were visually enhanced on the computer monitor using the magnification, brightness and contrast adjustment functions offered by the software, as necessary to facilitate landmark identification.

All cephalograms were digitally traced on the same computer monitor by the principal investigator. Each tracing was subsequently reviewed by a professional digitizer with 35 years of experience in the interpretation of patients’ with CLP, in order to verify accurate landmark identification. If there was a discrepancy in the identification of a landmark by the two independent examiners, the professional digitizer was taken as correct. Both the principal investigator and the professional digitizer were blinded to all descriptive patient data (including the origin of the cephalograms), as each patient from their respective center was assigned a unique identification code, assuring anonymity. The cephalometric evaluation was performed at the Department of Orthodontics, Faculty of Dentistry, University of Toronto, Ontario, Canada.

Figure 10: Cephalometric Hard and Soft Tissue Landmarks Used in this Study

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Hard-Tissue Cephalometric Measurements

Ba-N (mm)

SNA (°)

SNB (°)

ANB (°)

N-A-PG (°)

Wits appraisal (A⊥OP:B⊥OP) (mm)

Mandibular Length (Co-Gn) (mm)

SN-GoGn (°)

Upper Face Height (n-ANS) (mm)

Lower Face Height (ANS-Me) (mm)

Anterior Face Height (NaMe) (mm)

ANS-Me/Na-Me (%)

U1-Palatal Plane (°)

L1-GoGn (°)

Ba-N-ANS

ANS-N-Pg

Ba-N-Co-Gn

Ba-N-Pg

Table 3: Hard-issue landmarks used in this study

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Soft-Tissue Cephalometric Measurements

A’-N’-B’ (°)

Nasolabial Angle (Col-Sn-UL) (°)

Facial Convexity (G’-Sn-Po’) (°)

G’-Pn-Pog’ (°)

Nose Prominence (N’-Pn-Sn) (°)

N’-Sn’ (mm)

Sn’-Me’ (mm)

N’-Sn’:Sn’-Me’ (%)

Sella-N’-UNT

Table 4: Soft-tissue landmarks in this study

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5.3 Evaluation of Nasolabial Esthetics There is no universally accepted standard rating method to assess facial esthetics in patients with CLP at this time. However, a method that has become quite popular recently is an index developed by Asher-McDade et al., (1991). The Asher-McDade method utilizes a five-point ordinal scale in which four features of the nose and lip including nasolabial profile, nasal symmetry, nasal form and vermillion border are assessed separately and by a panel of judges (1 = very good appearance, 2 = good appearance, 3 = fair appearance, 4 = poor appearance and 5 = very poor appearance). The method requires standardization and cropping of facial photographs to display only the nasolabial region in order to reduce the influence of the surrounding facial features, since it has been shown that judges are influenced by general facial attractiveness.

The photographs from the two SickKids samples were available in either digital or photographic slide format depending on the year of photo acquisition. Photographic slides were scanned at the highest possible resolution and converted to digital images. All images (including other centers) were imported into Adobe Photoshop 6.0 and saved in JPEG format for preparation by the primary investigator as outlined below.

i. Frontal Images:

• The images were oriented with the inter-pupillary line parallel to the floor to correct for posturing errors.

• The photos were cropped with a trapezoidal outline to expose only the nasolabial area including the inner canthi region, nasal bridge, nostrils, alar regions, philtrum and upper lip.

ii. Profile Images*:

• The photos were cropped to create an outline extending superiorly from glabella, anteriorly to a point just past the nasal tip, inferiorly to stomion and angled posterior with a line from glabella tangent to the medial aspect of the eye to intersect the inferior line passing through stomion.

• The backgrounds of the profile images, that varied by center, were replaced with a

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uniform background colour to blind for center identification.

* In patients with UCLP the cleft-side and non-cleft-side profiles often yield different ratings. This was recognized in the days of Eurocleft when it was determined that the cleft-side profile photograph should be used for this assessment. In the present study (and within Americleft in general) to ensure uniformity and standardization of the images for ratings, all profile views were displayed as right-sided profiles. This conforms with conventional North American orthodontic record standards. In the case of a patient with a left-sided cleft where the cleft-side profile photograph was available, the photograph was flipped so that the cleft would appear on the right-sided profile. . If the cleft-side photograph was unavailable, the non-cleft right side profile image was still rated. This was done to ensure blinding during rating, as examiners may potentially have known which orthodontic records are standard at each center. The ratings of the non-cleft-side profiles were not used in the analysis of the data.

After cropping, each subject’s frontal and profile photographs were inserted into a PowerPoint slide. The master list of subject research numbers from all samples was randomized and subsequently an unidentifiable case number was assigned to each slide (subject) to be used for rating. An example of a coded slide is depicted below (Figure 11).

Figure 11: Example of Coded Nasolabial (Vermillion Border) Yardstick

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The complete set of 180 photographs was rated by six orthodontists with experience in treating subjects with cleft lip and palate. Two complete sets of ratings were performed on separate days. Inter- and intra-rater reliabilities were calculated using weighted kappa statistics.

5.3.1 Americleft “Q-Sort” Modification of Asher-McDade Method Despite the recent popularity of the Asher-McDade method for analysis of nasolabial appearance in patients with cleft lip and palate, it was found that the inter-rater reliabilities when rating the photographs of a previous study were only moderate-to-good. It was felt that the previous format, in which ratings were completed using a PowerPoint presentation attended by the entire group at the same time provided limited period for viewing and rating of each slide, potentially allowing for internal creep by the examiner as later subjects might be rated more favourably or harshly than earlier subjects with similar outcomes after viewing more of the subjects in the sample. While, in theory, appropriate calibration of the examiners prior to rating should minimize this effect, this was viewed by the collective group of raters to be a flaw in the original method and a limitation in attempting to apply objective measurements to a subjective assessment of nasolabial appearance.

A modification of the Asher-McDade method that might better allow for relative assessment was proposed and utilized for the ratings in this particular study. The modification, known as the Q-sort method, was originally proposed in 1953 by Stephenson and has been used in the orthodontic literature in the assessment of smile aesthetics (Schabel et al., 2009). The Q-sort method uses a progressive forced choice narrowing of the sample to create a more normal distribution for rating subjects on an aesthetic scale from least to most pleasing. In this study the Q-sort method was employed by printing the PowerPoint slides onto standard 4 x 6 inch index cards and laminating them for distribution of a set of photos to each rater. The raters were then given as much time as needed to divide and rearrange the cards into five piles based on the standard Asher-McDade five-point scale described above. When the rater was satisfied with his or her ratings, the case numbers corresponding to each pile were recorded on a standard data form and entered into an Excel spreadsheet. This distribution was repeated for each

39

variable investigated. It was collectively decided for the purpose of this study to group the previously used separate categories “nasal form” and “nasal symmetry” into a single category termed “nasolabial frontal”.

In addition, to aid in inter-rater reliability, the raters were given a visual yardstick and a written outline of the criteria for each number in the five-point scale. The visual yardstick was an 8.5 x 11 inch laminated print-out of four to five examples of what constitutes a “1”, “2”, “3”, etc. for each of the three variables. The yardstick was derived from the examples given in the original Asher-McDade study and by selecting photographs that were rated uniformly by all raters during a previous study (Mercado et al., 2011) involving the same group of raters utilizing this rating method.

5.4 Statistical Analysis The Kruskal-Wallis test with a correction for pairwise comparisons was used to compare the non-parametric categorical data (Goslon scores and nasolabial ratings). For the radiographic assessment, the center/group means of the numerical outcomes per cephalometric measurement were compared using analysis of variance (ANOVA). Pairwise comparisons of means were performed using the Tukey-Kramer method (Kramer, 1956). In addition, power analysis calculations for the cephalometric comparison were performed with the type I error rate (α) set at 0.05 and the statistical power (1-β) set at 0.80 – in order to detect a reasonable departure from the null hypothesis.

40

6 Results 6.1 Dental Arch Relationship (Goslon Yardstick)

6.1.1 Intra-Rater and Inter-Rater Reliabilities Table 5 summarizes the weighted kappa values for the evaluation of intra- and inter-examiner reliabilities for the dental arch relationship ratings averaged among six raters using the Goslon Yardstick method.

Rater 1 Rater 2 Rater 3 Rater 4 Rater 5 Rater 6 Overall

Intra-

rater

0.878 0.852 0.832 0.908 0.925 0.887 0.88

Inter-

rater

0.865 0.862 0.843 0.872 0.875 0.880 0.866

Table 5: Intra- and Inter- Rater Reliability Scores for the Dental Arch Relationship Evaluation

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1


Intra-rater

Inter-rater

Very Good

Good

Moderate

Fair

Figure 12: Inter- and Intra- Rater Reliability Scores for the Dental Arch Relationship

Evaluation

41

Overall, substantial inter- and intra-rater agreement was observed for the Goslon Yardstick comparison. According to the Classification of Landis and Koch (1977) (Table 6) the inter-rater reliability in this study was found to be good-to-very good across the six raters, whereas the intra-rater reliability was in the moderate-to-good range. The intra-rater and inter-rater reliabilities in this study are comparable to others reported in the literature (Sinko et al., 2008; Nollet et al., 2005; Fudalej et al., 2009). This can be due to the fact that with examples against which to compare a case being scored, the raters have a greater likelihood of finding similar-appearing reference cases to match the one being scored

Agreement Categories From Kappa Calculation (Landis and Koch, 1977)

Value of Kappa Strength of Agreement

<.20 Poor

.21-.40 Fair

.41-.60 Moderate

.61-.80 Good

.81-1.00 Very Good

1.00 Perfect agreement

Table 6: Agreement Categories (Landis and Koch, 1977)

6.1.2 Goslon Scores The final sample consisted of 135 patients between the ages of 6 and 13 years. There were no statistically significant differences in distribution of age, gender, type of cleft, and side of cleft, although males and left-sided clefts did make up the majority.

Significant differences were found between the centers that incorporated infant orthopedic treatment (Centers 2, 3 and 4) compared to the center that did not (center 1). The two centers (2 and 3) using the Latham appliance showed significantly higher Goslon scores (mean score 3.93 and 3.94), indicating a more severe dental arch discrepancy than the remaining centers (p<.01). Significantly higher Goslon scores were also seen in center 4(NAM) (mean 3.32) and center 4(TIO) (mean 3.33), compared to the center where no

42

infant orthopedics was employed (mean 2.49; p<.01). The distributions of the Goslon scores for each center are shown in figure 13 and a comparison chart in figure 14.

Figure 13: Goslon Rating Percentages

0%10%20%30%40%50%60%70%80%90%

100%

Ctr 1-No IO Ctr 2-Latham Ctr 3-Latham Ctr 4 - NAM Ctr 4 -TIO

12345

Figure 14: Kruskal-Wallis Goslon Distribution (The graph on the right side depicts a pairwise

comparison between centers, starting with center 1 on the top, then center 2, etc. When looking at the top

portion of the graph comparing center 1 to the remaining centers it is evident that the blue horizontal lines

cross the red dotted line on the right side, demonstrating a significantly less favorable dental arch

relationships of centers 2, 3, 4NAM and 4IO as compared to center 1. In contrast, the blue horizontal lines

in the remainder of the graph do not cross the red dotted lines on either side, indicating no significant

differences between centers in the remaining pairwise comparisons.

43

Sample sizes Mean Goslon scores, per Center (p<.01)

Center Sample Size Mean Goslon Score

1 38 2.49

2 17 3.93

3 19 3.94

4- NAM 27 3.32

4-TIO 34 3.33

Table 7: Sample Sizes and Mean Goslon Scores by Center

44

6.2 Craniofacial form 6.2.1 Intra-Rater Reliability The Intra-class correlation coefficients (ICC) for the soft and hard tissue cephalometric measurements were also found to be very good (table 8).

Intra-Class Correlation Coefficient for Hard and Soft Tissue Cephalometric Measurements

Soft tissue 0.82

Hard tissue 0.93

Table 8: Averaged Intra-Class Correlation Coefficients for Hard and Soft Tissue Cephalometric

Measurements

6.2.2 Craniofacial Form Scores Twenty cephalograms from each Center were randomly selected for the calculation of reliability of the method ("error study"). All cephalograms were re-digitized on the same computer monitor by the principal investigator and subsequently reviewed by the same professional digitizer. The raw data were exported from Dolphin Imaging into Microsoft Excel, where they were organized into spreadsheets according to center. This data set was then compared to the corresponding data set generated when the cephalograms were initially digitized, and an intra-class correlation coefficient (ICC) was calculated to assess the intra-examiner repeatability of hard-tissue and soft-tissue cephalometric measurements.

Significant differences were found in the sagittal maxillary prominence among the four centers. The most significant differences were seen in the mean SNA angle between Centers 1 (largest maxillary prominence) and 2 (lowest maxillary prominence) (p<0.05).

45

This was corroborated by the angle Ba-N-A, which also showed a significantly more favorable maxillary position in center 1 compared to centers 2 and 3. Center 4NAM and 4IO also showed a more favorable maxillary relationship compared to center 2 (figure 15). When using the Ba-N as a reference line representing the cranial base (angle Ba-N-ANS) the anterior nasal spine (ANS) in center 1 was found to be significantly more prominent than in center 2 (p<0.05). Significant differences were also seen in the mean ANB angle between center 1 and centers 3 and 4(NAM), as well as between centers 1 and 2, where center 1 consistently demonstrated the most favorable intermaxillary relationship (p<0.05) (figure 16). The same held true for the Wits appraisal, which was significantly higher in center 1 than in center 2 (p<0.05) (figure 17).

Center 1 also showed significantly higher mean NAPg (angle of convexity) than both centers 2 and 3 (p<0.05) (figure 17). Statistically greater soft tissue convexity (angle G'SnPo') was found in center 1 as compared to center 4(IO) (p<0.05) (figure 18).

4IO SNA - 4N SNA

4IO SNA - 3 SNA

4N SNA - 3 SNA

4IO SNA - 2 SNA

4N SNA - 2 SNA

3 SNA - 2 SNA

4IO SNA - 1 SNA

4N SNA - 1 SNA

3 SNA - 1 SNA

2 SNA - 1 SNA

50-5-10

If an interval does not contain zero, the corresponding means are significantly different.

Tukey Simultaneous 95% CIsDifference of Means for 1 SNA, 2 SNA, ...

Figure 15: Tukey Pairwise Comparison for SNA (left) and Ba-N-A (right) measurements

Figure 16: Tukey Pairwise Comparison Graph for Ba-N-ANS (left) and ANB (right)

4IIO ANB - 4N ANB

4IIO ANB - 3 ANB

4N ANB - 3 ANB

4IIO ANB - 2 ANB

4N ANB - 2 ANB

3 ANB - 2 ANB

4IIO ANB - 1 ANB

4N ANB - 1 ANB

3 ANB - 1 ANB

2 ANB - 1 ANB

5.02.50.0-2.5-5.0-7.5


Tukey Simultaneous 95% CIsDifference of Means for 1 ANB, 2 ANB, ...

4IO BaNA - 4N BaNA

4IO BaNA - 3 BaNA

4N BaNA - 3 BaNA

4IO BaNA - 2 BaNA

4N BaNA - 2 BaNA

3 BaNA - 2 BaNA

4IO BaNA - 1 BaNA

4N BaNA - 1 BaNA

3 BaNA - 1 BaNA

2 BaNA - 1 BaNA

50-5-10


Tukey Simultaneous 95% CIsDifference of Means for 1 BaNA, 2 BaNA, ...

4IO BaNaANS - 4N BaNaANS

4IO BaNaANS - 3 BaNaANS

4N BaNaANS - 3 BaNaANS



3 BaNaANS - 2 BaNaANS





5.02.50.0-2.5-5.0-7.5


Tukey Simultaneous 95% CIsDifference of Means for 1 BaNaANS, 2 BaNaANS, ...

46

Mandibular length (Co-Gn), was significantly larger in centers 3 and 4(IO) as compared to center 1. In addition, center 4 (IO) showed a significantly longer mandible than both centers 4(NAM) and 2 (p<0.05) (figure 18).

In the vertical dimension, significant differences were observed between center 4(IO) and centers 1, 2, and 4 (NAM), where 4(IO) showed significantly larger mean measurements of N-ANS, ANS-Me and N-Me (figure 19 and 20). The ratio between these two measurements however (proportional anterior facial height), was not significantly different between centers (p<0.05). In the soft tissue vertical dimension, center 4(IO) showed a significantly longer lower face height (as assessed by Sn-Me) compared to centers 1, 2, 3 and 4(NAM) (p<0.05) (figure 20).

4IO NAPg - 4N NAPg

4IO NAPg - 3 NAPg

4N NAPg - 3 NAPg

4IO NAPg - 2 NAPg

4N NAPg - 2 NAPg

3 NAPg - 2 NAPg

4IO NAPg - 1 NAPg

4N NAPg - 1 NAPg

3 NAPg - 1 NAPg

2 NAPg - 1 NAPg

1050-5-10-15


Tukey Simultaneous 95% CIsDifference of Means for 1 NAPg, 2 NAPg, ...

4IO Wits - 4N Wits

4IO Wits - 3 Wits

4N Wits - 3 Wits

4IO Wits - 2 Wits

4N Wits - 2 Wits

3 Wits - 2 Wits

4IO Wits - 1 Wits

4N Wits - 1 Wits

3 Wits - 1 Wits

2 Wits - 1 Wits

5.02.50.0-2.5-5.0


Tukey Simultaneous 95% CIsDifference of Means for 1 Wits, 2 Wits, ...

Figure 17: Tukey Pairwise Comparison Graph for Na-Pg (left) and Wits (right)

Figure 18: Tukey Pairwise Comparison Graph for G-Sn-Po (left) and Co-Gn (right)

4IO CoGn - 4N CoGn

4IO CoGn - 3 CoGn

4N CoGn - 3 CoGn

4IO CoGn - 2 CoGn

4N CoGn - 2 CoGn

3 CoGn - 2 CoGn

4IO CoGn - 1 CoGn

4N CoGn - 1 CoGn

3 CoGn - 1 CoGn

2 CoGn - 1 CoGn

20100-10-20


Tukey Simultaneous 95% CIsDifference of Means for 1 CoGn, 2 CoGn, ...

4IO GSnPo - 4N GSnPo

4IO GSnPo - 3 GSnPo

4N GSnPo - 3 GSnPo

4IO GSnPo - 2 GSnPo

4N GSnPo - 2 GSnPo

3 GSnPo - 2 GSnPo

4IO GSnPo - 1 GSnPo

4N GSnPo - 1 GSnPo

3 GSnPo - 1 GSnPo

2 GSnPo - 1 GSnPo

7.55.02.50.0-2.5-5.0


Tukey Simultaneous 95% CIsDifference of Means for 1 GSnPo, 2 GSnPo, ...

47

Similar differences were seen at the soft tissue level, with center 1 showing a significantly more favorable ANB’ angle as compared to centers 2, 3, 4(IO) and 4(NAM) (p<0.05). Significant differences were also shown between center 2 and 4(IO) in the nasolabial angle measurement, where center 2 demonstrated a more obtuse nasolabial angle (p<0.05) (Figure 21). The measurement of N’-Pn-Sn in center 1 was also significantly smaller than centers 2, 4(NAM) and 4(IO) (p<0.05) (figure 21).

Figure 19: Tukey Pairwise Comparison Graph for N-ANS (left) and ANS-Me (right)

Figure 20: Tukey Pairwise Comparison Graph for N-Me (left) and Sn-Me (right)

4IO ANS-Me - 4N ANS Me

4IO ANS-Me - 3 ANS-Me

4N ANS Me - 3 ANS-Me



3 ANS-Me - 2 ANS-Me



3 ANS-Me - 1 ANS-Me

2 ANS-Me - 1 ANS-Me

151050-5-10


Tukey Simultaneous 95% CIsDifference of Means for 1 ANS-Me, 2 ANS-Me, ...

4IO N-ANS - 4N N-ANS

4IO N-ANS - 3 N-ANS

4N N-ANS - 3 N-ANS

4IO N-ANS - 2 N-ANS

4N N-ANS - 2 N-ANS

3 N-ANS - 2 N-ANS

4IO N-ANS - 1 N-ANS

4N N-ANS - 1 N-ANS

3 N-ANS - 1 N-ANS

2 N-ANS - 1 N-ANS

1050-5


Tukey Simultaneous 95% CIsDifference of Means for 1 N-ANS, 2 N-ANS, ...

4IO N-Me - 4N N-Me

4IO N-Me - 3 N-Me

4N N-Me - 3 N-Me

4IO N-Me - 2 N-Me

4N N-Me - 2 N-Me

3 N-Me - 2 N-Me

4IO N-Me - 1 N-Me

4N N-Me - 1 N-Me

3 N-Me - 1 N-Me

2 N-Me - 1 N-Me

2520151050-5-10-15


Tukey Simultaneous 95% CIsDifference of Means for 1 N-Me, 2 N-Me, ...

4IO Sn-Me - 4N Sn-Me

4IO Sn-Me - 3 Sn-Me

4N Sn-Me - 3 Sn-Me

4IO Sn-Me - 2 Sn-Me

4N Sn-Me - 2 Sn-Me

3 Sn-Me - 2 Sn-Me

4IO Sn-Me - 1 Sn-Me

4N Sn-Me - 1 Sn-Me

3 Sn-Me - 1 Sn-Me

2 Sn-Me - 1 Sn-Me

20151050-5-10


Tukey Simultaneous 95% CIsDifference of Means for 1 Sn-Me, 2 Sn-Me, ...

48

4IO ANB(s) - 4N ANB(s)

4IO ANB(s) - 3 ANB(s)

4N ANB(s) - 3 ANB(s)



3 ANB(s) - 2 ANB(s)



3 ANB(s) - 1 ANB(s)

2 ANB(s) - 1 ANB(s)

3210-1-2-3-4-5-6


Tukey Simultaneous 95% CIsDifference of Means for 1 ANB(s), 2 ANB(s), ...

Figure 21: Tukey Pairwise Comparison Graph for ANB' (left) and Nasolabial Angle (right)

Figure 22: Tukey Pairwise Comparison Graph for N’-Pn-Sn

4IO NL Ang - 4N NL Ang

4IO NL Ang - 3 NL Ang

4N NL Ang - 3 NL Ang



3 NL Ang - 2 NL Ang



3 NL Ang - 1 NL Ang

2 NL Ang - 1 NL Ang

20100-10-20


Tukey Simultaneous 95% CIsDifference of Means for 1 NL Ang, 2 NL Ang, ...

4IO PnNSn - 4N PnNSn

4IO PnNSn - 3 PnNSn

4N PnNSn - 3 PnNSn

4IO PnNSn - 2 PnNSn

4N PnNSn - 2 PnNSn

3 PnNSn - 2 PnNSn

4IO PnNSn - 1 PnNSn

4N PnNSn - 1 PnNSn

3 PnNSn - 1 PnNSn

2 PnNSn - 1 PnNSn

7.55.02.50.0-2.5-5.0


Tukey Simultaneous 95% CIsDifference of Means for 1 PnNSn, 2 PnNSn, ...

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6.3 Nasolabial Esthetics 6.3.1 Intra-Rater and Inter-Rater Reliabilities

Table 9 summarizes the weighted kappa values for the evaluation of intra- and inter-examiner reliabilities for the nasolabial ratings averaged among six raters. The overall nasolabial reliability scores for this were found to be good-to-very good. The reliabilities of the nasolabial ratings are usually reported to be lower than those for the dental arch relationship evaluation (Landis and Koch, 1977)


Intra-rater 0.840 0.801 0.762 0.826 0.776 0.797 0.800

Inter-rater 0.623 0.650 0.659 0.630 0.600 0.657 0.622

Table 9: Kappa values by Rater for the Cumulative Nasolabial Scores

Figure 23: Inter- and Intra- Rater Reliability Scores for the Cumulative Nasolabial Scores

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


Intra-rater Inter-rater

Very Good

Good

Moderate

Fair

50

6.2.3 Nasolabial Esthetics Scores This evaluation was based on photographs of a total of 180 children across the five cleft centers. The frequency distributions of each score from 1 to 5 in each sample are shown in Figures (24, 26 and 28)) for the three categories of nasolabial aesthetics.

A. Nasofrontal Significant differences in nasal form and symmetry from the anterior view were found among centers (p=0.009), with the most favorable scores obtained at centers

using Latham or NAM (median scores 2.79 and 2.83, respectively) (figure 24-25). Follow-up tests were conducted to evaluate pairwise differences among the samples, controlling for Type I error across tests using the Bonferroni correction.

0%10%20%30%40%50%60%70%80%90%

100%

12345

1 – None 2 – Latham 3 – Latham 4 – NAM 4 – TIO 5 – TIO

Figure 24: Nasofrontal Score Distribution

51

B. Nasal Profile

Appearance of the nasal profile was also found to be significantly different among centers (p<0.001), with scores at centers using the Latham device being more favorable than those at centers using NAM (p<0.001), modified McNeil (p=0.015), and no infant orthopedics (p<0.001) (figure 26-27). Center 5 was only included in the comparison of nasofrontal and vermillion border, as the Profile photographs from center 5 were only of the right side of the patients (not necessarily of the affected side), so this center was excluded from the nasal profile assessment.

Figure 25: Kruskal-Wallis Nasofrontal Graph (Significantly lower scores for the nasal

assessment from the frontal view were identified in centers 2 and and 4NAM compared to center 1

(as indicated by the respective blue lines crossing past the left vertical dotted red line in the top

graph on the right hand side. Similarly when looking at the middle and lower portions of the same

graph, center 5 yielded significantly higher nasofrontal scores than both centers 2 and 4NAM.

52

Follow-up tests were conducted to evaluate pairwise differences among the five samples, controlling for Type I error across tests using the Bonferroni correction.

0%10%20%30%40%50%60%70%80%90%

100%

12345

1 – None 2 – Latham 3 – Latham 4 – NAM 4 – TIO

Figure 26: Nasal Profile Score Distribution

Figure 27: Kruskal-Wallis Nasal Profile Graph (Statistical significance is

demonstrated by the blue horizontal line crossing the vertical dotted red lines)

53

C. Vermillion Border

Significant differences in vermillion border alignment were present among centers (p=0.007), with the most favorable scores obtained at the center using NAM (median score 2.63) (figure 28). Follow-up tests were conducted to evaluate pairwise differences among the six samples, controlling for Type I error across tests using the Bonferroni correction (Figure 29).

0%10%20%30%40%50%60%70%80%90%

100%

1 2

3 4

5

1 – None 2 – Latham 3 – Latham 4 – NAM 4 – TIO 5 – TIO

Figure 28: Vermillion Border Score Distribution

54

The median values for each sample across the esthetic categories and the results of the Kruskal Wallis multiple and pairwise comparisons are summarized on Table 10.

Vermillion Border Nasolabial Frontal Nasolabial Profile Cumulative Score

Center 1 3.50 3.42 3.42 3.42

Center 2 3.21 2.92 2.50 2.83

Center 3 3.08 3.17 3.00 3.08

Center 4-NAM 2.63 2.83 3.00 2.83

Center 4-IO 3.29 3.38 2.83 3.25

Center 5 3.42 3.42 N/A N/A

Table 10: Median Values of Nasolabial Esthetic Ratings Using the Modified Asher-McDade Method

Figure 29: Kruskal-Wallis Vermillion Border Graph (Looking at the right hand graph,

statistical significance is seen when the blue horizontal line crosses the vertical dotted red

lines. Center 1, 2, 4IO and 5 show significantly less favorable vermillion border esthetics

than center 4NAM)

55

7 Discussion 7.1 Interpretation of Results When analyzing the results of the dental arch relationships, significant differences were shown between the center that did not incorporate IO and those that did. Centers 2 and 3 were found to have Goslon scores of 4 or 5 in more than 50% of their cohorts, whereas in center 1 the corresponding portion was lower than 20%. This difference may be due to the use of the Latham appliance itself. The activation of the screw mechanism in an infant can lead to the generation of high forces that could potentially impair subsequent maxillary growth. Henkel and Gundlach (1997) theorized that such impairment may result from an “unphysiologic movement in the premaxillary-vomerine suture” from activation of the appliance. However, for the reasons explained in the previous chapter direct inferences cannot be made to specific treatment modalities or protocols, as there is a large number of variables that may have been responsible for these findings.

In particular, the protocol involving the Latham appliance in conjunction with GPP showed a significantly poorer Goslon score and therefore a more severe antero-posterior inter-arch discrepancy. Techniques of alveolar repair performed in infancy, including GPP, have been introduced to obtain early union of the dentoalveolar arch and potentially obviate the need for secondary grafting procedures. However, surgery at the alveolar cleft at infancy may carry a greater risk of disturbing subsequent midfacial growth and development. Factors that may be involved in this include devascularization, periosteal disruption, and/or scar tissue formation. Previously published cephalometric assessments of midfacial growth following the Millard technique have been inconclusive, largely because of limitations in sample size. Berkowitz et al., (2004) reported a longitudinal study in patients with unilateral and bilateral cleft lip and palate treated with the Latham device and GPP compared to patients treated with lip adhesion and no infant orthopedics or GPP. They found a higher frequency of anterior and posterior crossbites in the presurgical orthopedics group at 6, 9 and 12 years of age. On the other hand, Grayson and colleagues have claimed that NAM treatment can overcome many of the limitations posed by the earlier Millard-Latham technique. The NAM approach, when followed by a GPP is claimed to decrease the need for secondary alveolar bone grafting (Santiago et al., 1998; Grayson et

56

al., 1998; Grayson et al., 2001) while minimizing maxillary growth restriction. From the results of the study, and for many of the reasons outlined in the previous chapter, it is certainly impossible to determine what particular element of the protocol (i.e the use of the Latham appliance per se, or the GPP) was responsible for the presumed inhibition of maxillary growth. It would have been perhaps beneficial to make a sample of patients at a comparable age, treated with GPP and NAM, or no IO so as to isolate the effects. Unfortunately such a sample was not available.

The hard- and soft-tissue cephalometric findings parallel those of the dental arch relationship. An interesting finding in craniofacial comparison of hard tissues was the significantly higher mean SNA in center 1 (mean 79.9°) as compared to center 2 (mean 74.8°). The cohort from Center 1 was also found to have a more favorable ANB angle compared to centers 2, 3 and 4(NAM), indicating a greater maxillary prominence. Similar trends were seen in the soft tissue cephalometric values. Center 3, which used Latham and GPP, had the lowest mean maxillary prominence (mean BaNA of 56.3°) demonstrating a possible contribution. When further assessing maxillo-mandibular relationships, center 1 (mean 8.9°) showed a significantly higher mean convexity angle (NAPg) compared to center 2 (mean -1.67°) and 3 (mean 0.11°) indicating a more favorable inter-maxillary relationship. The mean NAPg values for centers 1 (mean 8.9°), 4(NAM) (mean 3.87°) and 4(IO) (mean 4.55°) were surprisingly in the normal range for non-cleft patients of approximately 4 degrees as derived from the Burlington growth study (Thompson and Popovich, 1977). The more favorable arch relationship and maxillary prominence seen in center 1, which does not use IO, raises questions concerning the usefulness of this service in improving long-term treatment outcomes. This is also summated by the results of the Eurocleft study that found centers with the least amount of intervention to be associated with the most favorable outcomes (Shaw et al., 1992b). The prospective RCT by Dutchcleft, as previously stated, also found no real effect of IO on maxillary arch dimension, which caused the elimination of IO from cleft center protocols in the Netherlands (Prahl et al.,

2001; Prahl et al., 2006; Bongaarts et al., 2006). There were no significant differences seen in the mandibular antero-posterior dimension with respect to the cranial base between centers, however, some significant differences were identified when considering the overall mandibular length (Co-Gn). Center 4(IO) (mean 111.76) demonstrated the largest

57

average mandibular length as compared to center 1 (mean 97.8), 2 (mean 101.12) and 4(NAM) (mean 99.25) as well as center 3 (mean 106.32). Vertically, the cohort that used TIO showed a significantly larger anterior face height both in hard and soft tissue as compared to center 1, 2 and 4(NAM). As previously mentioned, this center also demonstrated the longest mandibles, which can indicate an overall difference in patients of this cohort, associated with a downward and backward rotation of the mandible and a longer vertical facial dimension.

Turning our attention to the nose itself, the significantly decreased nasolabial angle in center 4IO (mean 105.13°) as compared to center 4NAM (mean 118.27°) is of interest. A plausible explanation could be that the nasal portion of the NAM device allowed for a more upturned or a less depressed nasal tip than the TIO. However, the projection of the nasal tip as described by G-Pn-Pg, was not significantly different between the centers. An alternate measurement for nasal tip protrusion (N-Pn-Sn) however, did differ significantly between center 1 (mean 18.06), center 2 (mean 21.92), center 4IO (mean 22.07) and center 4NAM (mean 21.09) where center 1 has the most unfavorable angle. Center 4NAM however, did not demonstrate the largest mean angle of nasal projection as would have been anticipated had the former hypothesis been correct. In contrast, it was center 4IO, the center with the most acute nasolabial angle, that did not perform any specific manipulations to the nose, that showed the most favorable N-Pn-Sn. It would therefore appear more plausible to attribute these discrepancies to differences in surgical technique and skill, as these repairs were done by different surgeons or surgical teams.

The overall esthetics of the lip and nose were analyzed in this study because of the deep impact they have on the patient in everyday social settings. Esthetics has been described as a sensory perception that is multifactorial in nature and reflects one’s genetic, environmental, and cultural background (Naini et al., 2006). The challenge remains to identify whether there are specific nasolabial morphologic characteristics that substantially influence esthetic judgment. The notion of symmetry having a positive influence on esthetics has both been supported (Mealey et al., 1999; Faure et al., 2002; Ramsey et al., 2004) and disputed (Laitung et al., 1993; Sarver and Johnston, 1993; Perrett et al., 1994; Kowner, 1998) in the literature, depending on the study.

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When comparing the nasolabial esthetics in the groups of subjects in this study who underwent IO during infancy to the group that performed surgical repair of the cleft without IO, significant differences in scores for the categories of vermillion border, nasolabial frontal and overall nasolabial aesthetics were identified. The analysis demonstrated more favorable outcomes in the groups of subjects that underwent either NAM or the Latham technique. In the nasal frontal dimension, the centers using the Latham appliance (centers 2 and 3) and NAM demonstrated better esthetic scores than the centers with TIO and the center that did not use any IO. For the cohort from Center 4NAM this result is perhaps to be expected, as the NAM appliance incorporates a nasal stent that is meant to improve the nasal symmetry and tip projection. However, the superior performance of the cohorts from the two centers using the Latham appliance may appear somewhat surprising, as the Latham appliance does not have a specific nasal component. This may perhaps be explained by the fact that both centers 2 and 3 perform a primary nasal repair as part of their protocol in addition to the Latham IO. This may also account for the favorable nasal profile scores of latter two centers. Conversely, when vermillion borders were considered, the cohort from center 4NAM fared significantly better, which is probably a reflection of surgical skill rather than type of appliance used.

The reports in the published literature on the effects of NAM range from shortly after the end of the intervention to around the age of 12-18 months (Shetty et al., 2012, Ezzat et al.,

2007). Certainly when it comes to NAM treatment there is no published evaluation of the long-term effects of its use. In this investigation we attempted an assessment of nasolabial aesthetics between the ages of 6 and 13 years in orders to evaluate the differences and similarities after a large proportion of facial growth had been completed. The intention was to gauge different protocols with respect to their "medium- to long-term” effects rather than short-term. The risk of this approach is that, because the subjects are older at the time of evaluation, they are likely to have undergone several other procedures and interventions as part of the various protocols that they were treated under, and the effects of these procedures could serve to “camouflage” or accentuate the effect of the component of the protocol of interest (in this case, the type of IO). In other words, as stated previously, any differences found could serve as indications or trends that could support or counter a

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hypothesis, but no direct inference between the type of IO and a final outcome can be made at this point.

In summary, the claimed esthetic benefits of IO must be weighed against the possible long-term negative sequelae, specifically when it comes to growth of the midfacial skeleton, the relationship between the dental arches and the nasolabial esthetics. Considering the findings of this investigation, no IO seems to be favorable for the dental arch relationship and maxillary growth, whereas IO seems to offer and improvement with respect to the appearance of the lip and nose, without disregarding the previous disclaimers and limitations of the study.

7.2 Limitations of the Study The desire to achieve optimal facial esthetics with minimal growth disturbances in the treatment of patients with CLP has brought the importance of outcome assessment to the forefront. The effect of different infant orthopedics on arch development, skeletal growth and nasolabial esthetics has remained a controversial issue and thus continues to inspire further comparative studies.

The present study has several limitations, which should be kept in perspective while interpreting the results and conclusions. The use of multiple surgeons performing the infant initial cleft repairs demonstrates one such limitation. The severity of Goslon scores among the centers using IO, specifically the Latham appliance, cannot be necessarily attributed to the particular appliance used at that center. Also, the inference that surgical scarring and Latham’s “active” nature caused the increased proportion of higher Goslon scores however, cannot be directly implied. The number of surgeons, experience and skill of the surgeons, use or non-use of a standardized protocol, and the surgical timing and sequence of procedures can all be suggested as factors that influenced the final outcomes.

Centers 2 and 3 had a less than optimal sample size with respect to dental models (17 and 19 dental casts respectively), based on a power calculation that recommended a minimum sample size of 30. The results of this center were included in the analysis. However, the relative outcomes and any conclusions regarding the impact of the treatment protocol on

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inter-arch relationship must be treated with caution. Although the results of the Goslon scores for these centers were not different from those of the two other centers, it is unknown whether the scores for this sample accurately represent the treatment outcomes or whether the limited sample is biased toward better or worse outcome results.

The variable of cleft severity poses another potential limitation that has received little attention to date. Peltomaki et al., (2001) found that patients with larger clefts and small arch circumference, arch length, or both, showed less favorable maxillary growth than those with smaller clefts. This variable was not measured so the cohort with the most unfavorable Goslon results may include a higher number of patients with more severe cleft deformities. Therefore, further randomized control studies comparing the effects of IO within different orthopedic and surgical techniques are needed for assessing long-term results.

Analysis of the skeletal changes associated with different IO protocols on cephalometric radiographs also comes with certain limitations. Inter-center studies such as Eurocleft, Americleft, and the present investigation contain the risk that any significant differences found in craniofacial form (in addition to dental arch relationships and nasolabial esthetics) may have arisen not only from differences in the treatment protocol employed by each center, but also because the populations compared were fundamentally dissimilar. Specifically, ethnic, genetic, and age differences all represent sources of variability that could contribute to the differences observed (Ross, 1987; Trenouth et al., 1999; Daskalogiannakis et al., 2006). This potential lack of baseline equivalence between cases treated at different centers is referred to as susceptibility bias (WHO, 2002). These inherent differences in craniofacial form among the participating centers patient population reduce the validity of comparisons made between them when relating variations in craniofacial morphology and treatment protocol. To minimize the confounding effect of susceptibility bias on the outcomes measured, it was agreed in advance among the representatives of all centers that only consecutively treated, non-syndromic CUCLP Caucasian subjects of a certain age range be included in this investigation.

The issue of variable magnification in the cephalometric radiographs obtained from the different centers was an important one. In the original Eurocleft study, the need for

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international standardization of the specifications of cephalometric equipment was identified (Shaw et al., 1992). In an effort to circumvent the issue of variable radiographic enlargement factors in the present investigation, the technique of size adjusting all linear distances using a proportionality derived by using the inherent ruler on the cephalogram. Unfortunately, distortion represents another inherent source of error in such studies, which cannot be controlled.

When selecting the appropriate cephalometric measurements, care was taken to avoid measurements (such as Harvold's maxillary length (Co-ANS)) that carry a high degree of error in the event of the presence of a discrepancy between centric relation and centric occlusion or habitual occlusion (i.e a functional shift). Patients with CLP tend to have a higher frequency of anterior crossbites and therefore may also present with mandibular shifts (Daskalogiannakis and Ross, 1997).

Esthetic outcome assessments inevitably also carry a high degree of subjectivity. Moreover, the use of still photographic images has many limitations (Tobiasen, 1988; Asher-McDade et al., 1992; Morrant and Shaw, 1996). While results of studies using 3-dimensional assessments are becoming rapidly available and may represent the future of cleft deformity analysis, digital 2-dimensional photographs are still the most widely available, economical and accessible clinical records for use in inter-center collaborative studies. Since this was a retrospective study, we could only use records that had been already collected for patient care in the past and were consistently available for all centers. There is still no widely accepted standard rating method to assess facial esthetics in cleft lip and palate. The index by Asher-McDade et al., (1991) as previously introduced, was used in the Eurocleft study (Asher-McDade et al., 1992), the CSAG study (Williams et al., 2001) and the Eurocleft follow-up study (Brattström et al., 2005). It was further employed, in modified form, in a Scandinavian inter-center study (Brattström et al., 1992). Although it has inherent limitations, the Asher-McDade method has been shown to be reliable and reproducible and has been used in similar multi-center assessments of nasolabial aesthetics in the past; it was therefore selected for use in this study (Williams et al., 2001; Mercado et al., 2011). Some images in this study were scanned from printed photos, others from slides and others were obtained directly from digital cameras with high resolution. While variations in image

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quality can be overcome in the gross evaluation of the continuity of the vermillion border, shape of the nose, and profile using the Asher- McDade method, evaluation of the upper lip in greater objective detail would require live subjects or highly standardized images at the same resolution (Mercado et al., 2011).

A further criticism of the method used to assess nasolabial appearance in this study is that it did not include a worm’s-eye view photograph that is thought, by some, to be the best angle to assess nostril symmetry and deviations in nasal form. On the flipslide, this angle is rarely shown in social circumstances, and may be an unrealistic measure of a reduction of visible social stigmata (Kuijpers-Jagtman et al., 2009). Regardless, one must remember that this study was based on retrospectively available records that had been taken for treatment planning as part of each center's protocol. In this context, worm’s eye views, like the affected-side profile views, were not consistently available from all centers. As in previous retrospective comparisons, certainly within the Americleft spectrum, the inconsistency in available records among centers has been a major stumbling block. Standardization among centers, both with respect to image quality and the type of records taken at each age (including views should be part of a standard photographic series) would greatly enhance our potential to detect the effects of differences in protocols.

As previously mentioned, the influence of additional variables, such as genetic variability, the type of surgical repair and the individuals delivering the protocol, were other obvious limitations of this investigation. The WHO (2004) referred to the confounding effect of discrepancies in surgical skill and technique as proficiency bias, stating that it confounds any attempt at comparisons of outcomes, except within randomized trials. Within the five samples in this study, primary repair was performed by anywhere between one and four surgeons with varying surgical experience and methods of repair. This proficiency bias makes it impossible to draw definitive conclusions regarding whether any observed differences in aesthetic outcomes truly reflect the influence of the IO procedure or are merely a reflection of the technical skills of different operators within and across samples.

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8 Conclusions

Under the conditions of this investigation the following conclusions can be drawn:

1. Two centers using Latham appliance in conjunction with gingivoperiosteoplasty (GPP) showed significantly higher Goslon scores (indicative of a more severe dental arch discrepancy) compared to the remaining centers.

2. Significantly higher Goslon scores were also seen in centers using NAM and modified McNeil compared to the center where no IO was employed.

3. Centers using Latham or NAM appliances achieved better nasolabial scores from the frontal view than centers using no IO or Modified McNeil

4. Centers using Latham appliance achieved better nasal profile scores than centers that used no IO, NAM, or Modified McNeil

5. The center using NAM achieved better vermillion border scores than centers using Latham, Modified McNeil or no IO

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9 Clinical Significance and Future Directions It is important to provide evidence-based decisions with regard to treatment protocols for patients with CLP. Changes to the facial esthetics, dental arch relationship and craniofacial form were observed in these patients using different IO appliances, however a definitive cause and effect conclusion could not be made. There exists a great need for randomized controlled trials of prospective design to further study the possible beneficial and/or negative effects of IO for the preparation of hard and soft tissues prior to primary repair.

The present investigation was conducted with the hope of raising awareness and continuing the quest of understanding both the positive and negative sequelae of the use or non-use of IO. Studies like this, much like their predecessor inter-center investigations like the Eurocleft and Americleft, are meant to raise awareness in the international CLP community about the lack of standards in recording and reporting outcomes, and the absence of quality evidence upon which centers can base their current protocols.

Continuations to this study would potentially focus on isolating those centers that perform primary nasal repair in addition to (or instead of) IO, in order to assess the effect of this variable on nasolabial esthetics or change in facial growth potential. In the instance of the primary nasal repair or surgical revisions resulting in equivalent appearance by a specific age as a type of IO or GPP, in otherwise controlled protocols, an assessment of the differences in burden of care may be important. Such an attempt was made by Singer et al., . (2012) to assess the BOC of NAM for the improvement of nasolabial esthetics in patients with CUCLP.

Given the immense variability among center protocols internationally, controlling for most or all remaining variables will be necessary if we are to ever detect a clear cause-and-effect relationship. It is hoped that results obtained from retrospective, cross-sectional comparisons such as this one can be used to design future prospective studies to assess outcomes of interventions for patients with CLP more objectively, so that clinicians may maximize treatment benefits.

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11 Appendix 1: Abbreviations/Acronyms

ACPA: American Cleft Palate Craniofacial Association BCLP: Bilateral Cleft Lip and Palate CA: Coefficient of Asymmetry CCT: Controlled Clinical Trial CDC: Center for Disease Control CLP: Cleft Lip and Palate CSAG: Clinical Standards Advisory Group CT: Computed Tomography CUCLP: Complete Unilateral Cleft Lip and Palate DMA: Dentomaxillary Alignment Appliance GPP: Gingivoperiosteoplasty IO: Infant Orthopedics JPEG: Joint Photographic Experts Group NAM: Nasoalveolar Molding PSIO: Presurgical Infant Orthopedics RCT: Randomized Controlled Trial TIO: Traditional Infant Orthopedics UCLP: Unilateral Cleft Lip and Palate WHO: World Health Organization

81

12 Appendix 2: Goslon Kruskal-Wallis Results: Multiple Comparisons

Kruskal Wallis: multiple comparisons

Kruskal-Wallis Test on the data

Group N Median Ave Rank Z

Ctr 1 38 2.333 38.1 -5.69

Ctr 2 17 4.000 98.2 3.16

Ctr 3 19 4.000 99.5 3.52

Ctr 4-NAM 28 3.333 72.0 0.38

Ctr 4-IO 36 3.667 71.3 0.32

Overall 138 69.5

H = 43.14 DF = 4 P = 0.000

H = 43.32 DF = 4 P = 0.000 (adjusted for ties)

Kruskal-Wallis: All Pairwise Comparisons

----------------------------------------

Comparisons: 10

Ties: 94

Family Alpha: 0.2

Bonferroni Individual Alpha: 0.02

Bonferroni Z-value (2-sided): 2.326

----------------------------------------

Standardized Absolute Mean Rank Differences

82

|Rbar(i)-Rbar(j)| / Stdev

Rows: Group i = 1,...,n

Columns: Group j = 1,...,n

1. Table of Z-values

Ctr 1 0.00000 * * * *

Ctr 2 5.15769 0.00000 * * *

Ctr 3 5.46637 0.09278 0.00000 * *

Ctr 4-NAM 3.41144 2.13125 2.30889 0.0000000 *

Ctr 4-IO 3.57610 2.28765 2.48333 0.0710985 0

----------------------------------------------------------

Adjusted for Ties in the Data


Ctr 1 0.00000 * * * *

Ctr 2 5.16838 0.00000 * * *

Ctr 3 5.47771 0.09297 0.00000 * *

Ctr 4-NAM 3.41851 2.13567 2.31367 0.0000000 *

Ctr 4-IO 3.58352 2.29239 2.48848 0.0712460 0

2. Table of P-values

Ctr 1 1.00000 * * * *

Ctr 2 0.00000 1.00000 * * *

Ctr 3 0.00000 0.92593 1.00000 * *

83

Ctr 4-NAM 0.00063 0.03271 0.02069 1.00000 *

Ctr 4-IO 0.00034 0.02188 0.01283 0.94320 1

----------------------------------------------------------

Sign Confidence Intervals controlled at a family error rate of 0.2

Desired Confidence: 90.003

Sign confidence interval for median

Confidence

Achieved Interval

N Median Confidence Lower Upper Position

Ctr 1 38 2.333 0.8567 2.167 2.833 15

0.9000 2.167 2.874 NLI

0.9270 2.167 2.917 14

Ctr 2 17 4.000 0.8565 3.667 4.083 6

0.9000 3.645 4.083 NLI

0.9510 3.583 4.083 5

Ctr 3 19 4.000 0.8329 3.917 4.083 7

0.9000 3.878 4.083 NLI

0.9364 3.833 4.083 6

Ctr 4-NAM 28 3.333 0.8151 3.083 3.667 11

0.9000 3.018 3.798 NLI

0.9128 3.000 3.833 10

Ctr 4-IO 36 3.667 0.8675 3.000 3.917 14

0.9000 3.000 3.917 NLI

84

0.9348 3.000 3.917 13

Kruskal-Wallis: Conclusions

The following groups showed significant differences (adjusted for ties):

Groups Z vs. Critical value P-value

Ctr 1 vs. Ctr 3 5.47771 >= 2.326 0.0000

Ctr 1 vs. Ctr 2 5.16838 >= 2.326 0.0000

Ctr 1 vs. Ctr 4-IO 3.58352 >= 2.326 0.0003

Ctr 1 vs. Ctr 4-NAM 3.41851 >= 2.326 0.0006

Ctr 3 vs. Ctr 4-IO 2.48848 >= 2.326 0.0128

85

13 Appendix 3: Hard Tissue Cephalometric Landmark Definitions

Hard Tissue Landmarks

A-Point The deepest point on the anterior contour of the maxillary alveolar process

ANS The tip of the bony anterior nasal spine at the inferior margin of the piriform

aperature, in the midsagittal plane

ANS’ The deepest point on the concavity of the anterior surface of the maxilla in the

midline, within 3mm of the floor of the nose

B-Point The deepest point on the anterior contour of the mandibular alveolar process

Ba Basion: the most anteroinferior point on the margin of the foramen magnum

Co Condylion: the most posterosuperior point on the head of the mandibular

condyle

Gn Gnathion: the most anteroinferior point on the outline of the chin

Go Gonion: the most posteroinferior point on the angle of the mandible

LIA Lower incisor apex: the apex of the most labially placed mandibular central

incisor

LIT Lower incisor tip: the incisal tip of the most labially placed mandibular

incisor

Me Menton: the most inferior point on the outline of the chin

N Nasion: the most anterior point of the frontonasal suture

Pg Pogonion: the most anterior point on the outline of the chin

PNS Point of intersection of a vertical line projected down from PTM

86

(perpendicular to a plane contructed 7 ° up from SN) and the palatal plane

S Sella: the geometric center of sella turcica

UIA Upper incisor apex: the apex of the most labially placed maxillary central

incisor

UIT Upper incisor tip: the incisal tip of the most labially placed maxillary central

incisor

87

14 Appendix 4: Soft- Tissue Cephalometric Landmark Definitions

Soft Tissue Landmarks

A’ Soft-tissue subspinale: the point of greatest concavity or convexity in the

midline of the upper lip

B’ Soft-tissue supramentale: the point of greatest concavity in the midline of the

lower lip

CT Columella tangent: the point of intersection with the nasal outline of a tangent

to the columella from Sn

G’ Soft-tissue glabella: the most prominent point on the soft tissue drape of the

forehead

LI Labrale inferius: the most prominent point on the vermillion border of the

lower lip

LS Labrale superius: the most prominent point on the vermillion border of the

upper lip

Me’ Soft-tissue menton: the soft tissue point overlying menton

N’ Soft-tissue nasion: the deepest point of the frontonasal curvature

P Pronasale: the most prominent point on the apex of the nose

Pg’ Soft-tissue pogonion: the most anterior point on the soft tissue outline of the

chin

Sn Subnasale: the point where the base of the columella of the nose meets the

upper lip

UNT Upper nasal tangent point from N’

88

15 Appendix 5: ANOVA and Tukey Pairwise Comparison for Cephalometric Measurements

One-way ANOVA: 1 N-Ba, 2 N-Ba, 3 N-Ba, 4N Na, 4IO N-Ba

Method

Null hypothesis All means are equal

Alternative hypothesis At least one mean is different

Significance level α = 0.05

Equal variances were assumed for the analysis.

Factor Information

Factor Levels Values

Factor 5 1 N-Ba, 2 N-Ba, 3 N-Ba, 4N Na, 4IO N-Ba

Analysis of Variance

Source DF Adj SS Adj MS F-Value P-Value

Factor 4 1181 295.32 4.73 0.001

Error 119 7423 62.38

Total 123 8604

Model Summary

89

S R-sq R-sq(adj) R-sq(pred)

7.89782 13.73% 10.83% 4.57%

Means

Factor N Mean StDev 95% CI

1 N-Ba 40 93.097 5.454 (90.625, 95.570)

2 N-Ba 30 95.08 6.12 ( 92.22, 97.93)

3 N-Ba 18 97.65 8.66 ( 93.96, 101.34)

4N Na 17 92.89 14.76 ( 89.10, 96.69)

4IO N-Ba 19 101.77 4.82 ( 98.18, 105.36)

Pooled StDev = 7.89782

Tukey Pairwise Comparisons

Grouping Information Using the Tukey Method and 95% Confidence

Factor N Mean Grouping

4IO N-Ba 19 101.77 A

3 N-Ba 18 97.65 A B

2 N-Ba 30 95.08 B

1 N-Ba 40 93.097 B

4N Na 17 92.89 B

Means that do not share a letter are significantly different.

90

One-way ANOVA: 1 SNA, 2 SNA, 3 SNA, 4N SNA, 4IO SNA

Method





Factor Information


Factor 5 1 SNA, 2 SNA, 3 SNA, 4N SNA, 4IO SNA



Factor 4 463.0 115.75 5.67 0.000

Error 119 2428.0 20.40

Total 123 2891.0

Model Summary

91


4.51701 16.01% 13.19% 8.59%

Means


1 SNA 40 79.985 4.057 (78.571, 81.399)

2 SNA 30 74.810 4.804 (73.177, 76.443)

3 SNA 18 77.51 5.32 ( 75.40, 79.61)

4N SNA 17 77.476 3.801 (75.307, 79.646)

4IO SNA 19 78.04 4.74 ( 75.98, 80.09)





1 SNA 40 79.985 A

4IO SNA 19 78.04 A B

3 SNA 18 77.51 A B

4N SNA 17 77.476 A B

2 SNA 30 74.810 B


92

One-way ANOVA: 1 SNB, 2 SNB, 3 SNB, 4N SNB, 4IO SNB

Method





Factor Information


Factor 5 1 SNB, 2 SNB, 3 SNB, 4N SNB, 4IO SNB



Factor 4 46.28 11.57 0.59 0.669

Error 119 2325.52 19.54

Total 123 2371.80

Model Summary

93


4.42066 1.95% 0.00% 0.00%

Means


1 SNB 40 74.852 3.660 (73.468, 76.237)

2 SNB 30 74.633 4.970 (73.035, 76.231)

3 SNB 18 76.51 4.83 ( 74.45, 78.57)

4N SNB 17 74.971 4.057 (72.848, 77.094)

4IO SNB 19 75.36 4.87 ( 73.36, 77.37)





3 SNB 18 76.51 A

4IO SNB 19 75.36 A

4N SNB 17 74.971 A

1 SNB 40 74.852 A

2 SNB 30 74.633 A


94

One-way ANOVA: 1 BaNA, 2 BaNA, 3 BaNA, 4N BaNA, 4IO BaNA

Method





Factor Information


Factor 5 1 BaNA, 2 BaNA, 3 BaNA, 4N BaNA, 4IO BaNA



Factor 4 514.1 128.53 9.29 0.000

Error 119 1647.0 13.84

Total 123 2161.1

Model Summary

95


3.72029 23.79% 21.23% 17.17%

Means


1 BaNA 40 61.758 3.334 (60.593, 62.922)

2 BaNA 30 56.353 4.126 (55.008, 57.698)

3 BaNA 18 58.839 3.899 (57.103, 60.575)

4N BaNA 17 60.006 2.821 (58.219, 61.793)

4IO BaNA 19 59.737 4.309 (58.047, 61.427)





1 BaNA 40 61.758 A

4N BaNA 17 60.006 A

4IO BaNA 19 59.737 A

3 BaNA 18 58.839 A B

2 BaNA 30 56.353 B


96

One-way ANOVA: 1 NAPg, 2 NAPg, 3 NAPg, 4N NAPg, 4IO NAPg

Method





Factor Information


Factor 5 1 NAPg, 2 NAPg, 3 NAPg, 4N NAPg, 4IO NAPg



Factor 4 2218 554.61 9.50 0.000

Error 119 6944 58.36

Total 123 9163

Model Summary

97


7.63911 24.21% 21.66% 17.21%

Means


1 NAPg 40 8.957 6.288 (6.566, 11.349)

2 NAPg 30 -1.67 7.97 (-4.43, 1.09)

3 NAPg 18 0.11 7.94 (-3.46, 3.67)

4N NAPg 17 3.87 8.73 ( 0.20, 7.54)

4IO NAPg 19 4.55 8.41 ( 1.08, 8.02)





1 NAPg 40 8.957 A

4IO NAPg 19 4.55 A B

4N NAPg 17 3.87 A B C

3 NAPg 18 0.11 B C

2 NAPg 30 -1.67 C


98

One-way ANOVA: 1 Wits, 2 Wits, 3 Wits, 4N Wits, 4IO Wits

Method





Factor Information


Factor 5 1 Wits, 2 Wits, 3 Wits, 4N Wits, 4IO Wits



Factor 4 190.2 47.54 3.18 0.016

Error 119 1776.4 14.93

Total 123 1966.6

Model Summary

99


3.86363 9.67% 6.63% 1.37%

Means


1 Wits 40 1.165 3.148 (-0.045, 2.375)

2 Wits 30 -1.570 4.090 (-2.967, -0.173)

3 Wits 18 -1.60 4.94 ( -3.40, 0.20)

4N Wits 17 -1.094 3.558 (-2.950, 0.761)

4IO Wits 19 -1.495 4.000 (-3.250, 0.260)





1 Wits 40 1.165 A

4N Wits 17 -1.094 A B

4IO Wits 19 -1.495 A B

2 Wits 30 -1.570 B

3 Wits 18 -1.60 A B


100

One-way ANOVA: 1 CoGn, 2 CoGn, 3 CoGn, 4N CoGn, 4IO CoGn

Method





Factor Information


Factor 5 1 CoGn, 2 CoGn, 3 CoGn, 4N CoGn, 4IO CoGn



Factor 4 2999 749.84 8.85 0.000

Error 119 10079 84.69

Total 123 13078

Model Summary

101


9.20294 22.93% 20.34% 14.89%

Means


1 CoGn 40 97.800 6.023 (94.919, 100.681)

2 CoGn 30 101.12 8.06 ( 97.79, 104.44)

3 CoGn 18 106.32 10.08 (102.03, 110.62)

4N CoGn 17 99.25 15.98 ( 94.83, 103.67)

4IO CoGn 19 111.76 7.33 (107.58, 115.94)





4IO CoGn 19 111.76 A

3 CoGn 18 106.32 A B

2 CoGn 30 101.12 B C

4N CoGn 17 99.25 B C

1 CoGn 40 97.800 C


102

One-way ANOVA: 1 SNGoGn, 2 SNGoGn, 3 SNGoGn, 4N SNGoGn, 4IO SNGoGn

Method





Factor Information


Factor 5 1 SNGoGn, 2 SNGoGn, 3 SNGoGn, 4N SNGoGn, 4IO SNGoGn



Factor 4 157.0 39.24 1.24 0.298

Error 119 3764.7 31.64

Total 123 3921.7

Model Summary

103


5.62461 4.00% 0.78% 0.00%

Means


1 SNGoGn 40 34.577 5.015 (32.817, 36.338)

2 SNGoGn 30 34.33 5.73 ( 32.29, 36.36)

3 SNGoGn 18 31.86 6.86 ( 29.24, 34.49)

4N SNGoGn 17 35.14 6.08 ( 32.44, 37.84)

4IO SNGoGn 19 35.66 4.94 ( 33.11, 38.22)





4IO SNGoGn 19 35.66 A

4N SNGoGn 17 35.14 A

1 SNGoGn 40 34.577 A

2 SNGoGn 30 34.33 A

3 SNGoGn 18 31.86 A


104

One-way ANOVA: 1 N-ANS, 2 N-ANS, 3 N-ANS, 4N N-ANS, 4IO N-ANS

Method





Factor Information


Factor 5 1 N-ANS, 2 N-ANS, 3 N-ANS, 4N N-ANS, 4IO N-ANS



Factor 4 559.1 139.79 6.93 0.000

Error 119 2399.6 20.16

Total 123 2958.7

Model Summary

105


4.49049 18.90% 16.17% 10.15%

Means


1 N-ANS 40 43.737 2.300 (42.332, 45.143)

2 N-ANS 30 43.890 4.007 (42.267, 45.513)

3 N-ANS 18 46.66 5.14 ( 44.57, 48.76)

4N N-ANS 17 43.62 8.03 ( 41.46, 45.77)

4IO N-ANS 19 49.453 3.710 (47.413, 51.493)





4IO N-ANS 19 49.453 A

3 N-ANS 18 46.66 A B

2 N-ANS 30 43.890 B

1 N-ANS 40 43.737 B

4N N-ANS 17 43.62 B


106

One-way ANOVA: 1 ANS-Me, 2 ANS-Me, 3 ANS-Me, 4N ANS Me, 4IO ANS-Me

Method





Factor Information


Factor 5 1 ANS-Me, 2 ANS-Me, 3 ANS-Me, 4N ANS Me, 4IO ANS-Me



Factor 4 729.7 182.42 5.48 0.000

Error 119 3960.2 33.28

Total 123 4689.9

Model Summary

107


5.76883 15.56% 12.72% 7.54%

Means


1 ANS-Me 40 59.080 4.859 (57.274, 60.886)

2 ANS-Me 30 58.140 5.447 (56.054, 60.226)

3 ANS-Me 18 59.74 7.77 ( 57.05, 62.44)

4N ANS Me 17 56.86 7.17 ( 54.09, 59.63)

4IO ANS-Me 19 64.868 4.281 (62.248, 67.489)





4IO ANS-Me 19 64.868 A

3 ANS-Me 18 59.74 A B

1 ANS-Me 40 59.080 B

2 ANS-Me 30 58.140 B

4N ANS Me 17 56.86 B


108

One-way ANOVA: 1 N-Me, 2 N-Me, 3 N-Me, 4N N-Me, 4IO N-Me

Method





Factor Information


Factor 5 1 N-Me, 2 N-Me, 3 N-Me, 4N N-Me, 4IO N-Me



Factor 4 2428 607.04 7.88 0.000

Error 119 9167 77.04

Total 123 11595

Model Summary

109


8.77704 20.94% 18.28% 12.74%

Means


1 N-Me 40 100.707 5.874 (97.960, 103.455)

2 N-Me 30 101.03 7.84 ( 97.86, 104.21)

3 N-Me 18 105.19 11.14 (101.10, 109.29)

4N N-Me 17 98.96 14.76 ( 94.74, 103.17)

4IO N-Me 19 112.56 4.97 (108.58, 116.55)





4IO N-Me 19 112.56 A

3 N-Me 18 105.19 A B

2 N-Me 30 101.03 B

1 N-Me 40 100.707 B

4N N-Me 17 98.96 B


110

One-way ANOVA: 1 ANS-Me/N-Me, 2 ANS-Me/N-Me, 3 ANS-Me/N-Me, 4N ANS-Me/N-Me, 4IO ANS-Me/N-Me

Method





Factor Information


Factor 5 1 ANS-Me/N-Me, 2 ANS-Me/N-Me, 3 ANS-Me/N-Me, 4N ANS-Me/N-Me, 4IO ANS-Me/N-Me



Factor 4 50.21 12.554 1.90 0.115

Error 119 786.04 6.605

Total 123 836.25

Model Summary

111


2.57009 6.00% 2.85% 0.00%

Means


1 ANS-Me/N-Me 40 58.620 2.132 (57.815, 59.425)

2 ANS-Me/N-Me 30 57.520 2.618 (56.591, 58.449)

3 ANS-Me/N-Me 18 56.744 3.137 (55.545, 57.944)

4N ANS-Me/N-Me 17 57.694 2.638 (56.460, 58.928)

4IO ANS-Me/N-Me 19 57.605 2.702 (56.438, 58.773)





1 ANS-Me/N-Me 40 58.620 A

4N ANS-Me/N-Me 17 57.694 A

4IO ANS-Me/N-Me 19 57.605 A

2 ANS-Me/N-Me 30 57.520 A

3 ANS-Me/N-Me 18 56.744 A


112

One-way ANOVA: 1 U1-PP, 2 U1-PP, 3 U1-PP, 4N U1-PP, 4IO U1-PP

Method





Factor Information


Factor 5 1 U1-PP, 2 U1-PP, 3 U1-PP, 4N U1-PP, 4IO U1-PP



Factor 4 437.9 109.5 1.06 0.381

Error 119 12322.0 103.5

Total 123 12759.9

Model Summary


113

10.1758 3.43% 0.19% 0.00%

Means


1 U1-PP 40 100.97 9.40 (97.78, 104.15)

2 U1-PP 30 97.01 10.93 (93.33, 100.69)

3 U1-PP 18 96.69 9.71 (91.94, 101.44)

4N U1-PP 17 97.76 11.43 (92.88, 102.65)

4IO U1-PP 19 100.52 9.77 (95.90, 105.14)





1 U1-PP 40 100.97 A

4IO U1-PP 19 100.52 A

4N U1-PP 17 97.76 A

2 U1-PP 30 97.01 A

3 U1-PP 18 96.69 A


114

One-way ANOVA: 1 L1-GoGn, 2 L1-GoGn, 3 L1-GoGn, 4N L1-GoGn, 4IO L1-GoGn

Method





Factor Information


Factor 5 1 L1-GoGn, 2 L1-GoGn, 3 L1-GoGn, 4N L1-GoGn, 4IO L1-GoGn



Factor 4 166.1 41.54 0.96 0.433

Error 119 5157.7 43.34

Total 123 5323.9

Model Summary

115


6.58348 3.12% 0.00% 0.00%

Means


1 L1-GoGn 40 90.81 7.00 ( 88.75, 92.87)

2 L1-GoGn 30 88.190 4.523 (85.810, 90.570)

3 L1-GoGn 18 89.30 6.79 ( 86.23, 92.37)

4N L1-GoGn 17 89.84 8.33 ( 86.68, 93.00)

4IO L1-GoGn 19 91.33 6.50 ( 88.34, 94.32)





4IO L1-GoGn 19 91.33 A

1 L1-GoGn 40 90.81 A

4N L1-GoGn 17 89.84 A

3 L1-GoGn 18 89.30 A

2 L1-GoGn 30 88.190 A

Means

116

16 Appendix 6: Nasolabial Kruskal-Wallis Results: Multiple Comparisons

16.1 Nasofrontal Ratings Kruskal-Wallis: Multiple Comparisons



Ctr 1 13 3.417 102.7 1.96

Ctr 2 34 2.792 64.9 -2.04

Ctr 3 19 3.167 77.6 -0.14

Ctr 4-NAM 38 2.833 65.1 -2.17

Ctr 4-IO 26 3.375 90.3 1.39

Ctr 5 27 3.417 94.9 2.00

Overall 157 79.0

H = 15.30 DF = 5 P = 0.009



----------------------------------------

Comparisons: 15

Ties: 113

Family Alpha: 0.2



----------------------------------------

117






Ctr 1 0.00000 * * * * *

Ctr 2 2.54726 0.00000 * * * *

Ctr 3 1.53298 0.97357 0.00000 * * *

Ctr 4-NAM 2.57384 0.01543 0.97951 0.00000 * *

Ctr 4-IO 0.79941 2.14602 0.92847 2.18239 0.000000 *

Ctr 5 0.50480 2.56124 1.27356 2.60860 0.368078 0

----------------------------------------------------------



Ctr 1 0.00000 * * * * *

Ctr 2 2.54877 0.00000 * * * *

Ctr 3 1.53388 0.97415 0.00000 * * *

Ctr 4-NAM 2.57536 0.01544 0.98009 0.00000 * *

Ctr 4-IO 0.79988 2.14728 0.92902 2.18368 0.000000 *

Ctr 5 0.50510 2.56275 1.27432 2.61014 0.368295 0


118

Ctr 1 1.00000 * * * * *

Ctr 2 0.01081 1.00000 * * * *

Ctr 3 0.12506 0.32998 1.00000 * * *

Ctr 4-NAM 0.01001 0.98768 0.32704 1.00000 * *

Ctr 4-IO 0.42378 0.03177 0.35288 0.02899 1.00000 *

Ctr 5 0.61349 0.01038 0.20255 0.00905 0.71265 1

----------------------------------------------------------




Confidence

Achieved Interval


Ctr 1 13 3.417 0.9077 3.250 3.833 4

0.9199 3.240 3.853 NLI

0.9775 3.083 4.167 3

Ctr 2 34 2.792 0.8786 2.583 3.083 13

0.9199 2.542 3.125 NLI

0.9424 2.500 3.167 12

Ctr 3 19 3.167 0.8329 2.750 3.500 7

0.9199 2.514 3.500 NLI

119

0.9364 2.417 3.500 6

Ctr 4-NAM 38 2.833 0.8567 2.667 2.917 15

0.9199 2.597 2.986 NLI

0.9270 2.583 3.000 14

Ctr 4-IO 26 3.375 0.8314 3.167 3.583 10

0.9199 3.167 3.583 NLI

0.9245 3.167 3.583 9

Ctr 5 27 3.417 0.8779 3.333 3.833 10

0.9199 3.226 3.869 NLI

0.9478 3.083 3.917 9




Ctr 4-NAM vs. Ctr 5 2.61014 >= 2.475 0.0091

Ctr 1 vs. Ctr 4-NAM 2.57536 >= 2.475 0.0100

Ctr 2 vs. Ctr 5 2.56275 >= 2.475 0.0104

Ctr 1 vs. Ctr 2 2.54877 >= 2.475 0.0108

16.2 Vermillion Border ratings Kruskal-Wallis: Multiple Comparisons



Ctr 1 13 3.500 90.0 0.91

120

Ctr 2 34 3.208 85.6 0.96

Ctr 3 19 3.083 83.2 0.43

Ctr 4-NAM 38 2.625 53.6 -3.96

Ctr 4-IO 26 3.292 90.8 1.45

Ctr 5 27 3.417 86.8 0.98

Overall 157 79.0

H = 16.06 DF = 5 P = 0.007



----------------------------------------

Comparisons: 15

Ties: 115

Family Alpha: 0.2



----------------------------------------






Ctr 1 0.00000 * * * * *

121

Ctr 2 0.29818 0.00000 * * * *

Ctr 3 0.41723 0.18484 0.00000 * * *

Ctr 4-NAM 2.49485 2.98383 2.31849 0.00000 * *

Ctr 4-IO 0.04856 0.43654 0.55223 3.21441 0.000000 *

Ctr 5 0.21124 0.10057 0.26337 2.90150 0.319559 0

----------------------------------------------------------



Ctr 1 0.00000 * * * * *

Ctr 2 0.29845 0.00000 * * * *

Ctr 3 0.41761 0.18500 0.00000 * * *

Ctr 4-NAM 2.49710 2.98652 2.32058 0.00000 * *

Ctr 4-IO 0.04861 0.43693 0.55273 3.21731 0.000000 *

Ctr 5 0.21143 0.10066 0.26361 2.90412 0.319848 0


Ctr 1 1.00000 * * * * *

Ctr 2 0.76536 1.00000 * * * *

Ctr 3 0.67623 0.85323 1.00000 * * *

Ctr 4-NAM 0.01252 0.00282 0.02031 1.00000 * *

Ctr 4-IO 0.96123 0.66216 0.58045 0.00129 1.00000 *

Ctr 5 0.83255 0.91982 0.79208 0.00368 0.74908 1

----------------------------------------------------------

122




Confidence

Achieved Interval


Ctr 1 13 3.500 0.9077 3.000 3.750 4

0.9199 2.955 3.755 NLI

0.9775 2.250 3.833 3

Ctr 2 34 3.208 0.8786 3.000 3.417 13

0.9199 3.000 3.417 NLI

0.9424 3.000 3.417 12

Ctr 3 19 3.083 0.8329 2.667 3.500 7

0.9199 2.667 3.559 NLI

0.9364 2.667 3.583 6

Ctr 4-NAM 38 2.625 0.8567 2.500 2.917 15

0.9199 2.291 2.986 NLI

0.9270 2.250 3.000 14

Ctr 4-IO 26 3.292 0.8314 3.083 3.417 10

0.9199 3.007 3.417 NLI

0.9245 3.000 3.417 9

Ctr 5 27 3.417 0.8779 3.000 3.667 10

0.9199 3.000 3.702 NLI

0.9478 3.000 3.750 9

123




Ctr 4-NAM vs. Ctr 4-IO 3.21731 >= 2.475 0.0013

Ctr 2 vs. Ctr 4-NAM 2.98652 >= 2.475 0.0028

Ctr 4-NAM vs. Ctr 5 2.90412 >= 2.475 0.0037

Ctr 1 vs. Ctr 4-NAM 2.49710 >= 2.475 0.0125

16.3 Nasal Profile Ratings Kruskal-Wallis: Multiple Comparisons



Ctr 1 13 3.417 92.4 2.72

Ctr 2 34 2.500 44.1 -3.85

Ctr 3 19 3.000 62.7 -0.36

Ctr 4-NAM 38 3.000 75.1 1.87

Ctr 4-IO 26 2.833 68.1 0.39

Overall 130 65.5

H = 20.30 DF = 4 P = 0.000



----------------------------------------

124

Comparisons: 10

Ties: 91

Family Alpha: 0.2



----------------------------------------






Ctr 1 0.00000 * * * *

Ctr 2 3.93345 0.00000 * * *

Ctr 3 2.19516 1.71958 0.00000 * *

Ctr 4-NAM 1.43181 3.48464 1.17472 0.000000 *

Ctr 4-IO 1.90257 2.44272 0.47661 0.731662 0

----------------------------------------------------------



Ctr 1 0.00000 * * * *

Ctr 2 3.93645 0.00000 * * *

125

Ctr 3 2.19683 1.72089 0.00000 * *

Ctr 4-NAM 1.43290 3.48730 1.17561 0.000000 *

Ctr 4-IO 1.90402 2.44459 0.47697 0.732221 0


Ctr 1 1.00000 * * * *

Ctr 2 0.00008 1.00000 * * *

Ctr 3 0.02803 0.08527 1.00000 * *

Ctr 4-NAM 0.15189 0.00049 0.23975 1.00000 *

Ctr 4-IO 0.05691 0.01450 0.63338 0.46403 1

----------------------------------------------------------




Confidence

Achieved Interval


Ctr 1 13 3.417 0.7332 3.000 4.083 5

0.9000 2.924 4.159 NLI

0.9077 2.917 4.167 4

Ctr 2 34 2.500 0.8786 2.333 2.583 13

126

0.9000 2.315 2.601 NLI

0.9424 2.250 2.667 12

Ctr 3 19 3.000 0.8329 2.417 3.167 7

0.9000 2.340 3.167 NLI

0.9364 2.250 3.167 6

Ctr 4-NAM 38 3.000 0.8567 2.833 3.250 15

0.9000 2.833 3.250 NLI

0.9270 2.833 3.250 14

Ctr 4-IO 26 2.833 0.8314 2.667 3.250 10

0.9000 2.667 3.300 NLI

0.9245 2.667 3.333 9




Ctr 1 vs. Ctr 2 3.93645 >= 2.326 0.0001

Ctr 2 vs. Ctr 4-NAM 3.48730 >= 2.326 0.0005

Ctr 2 vs. Ctr 4-IO 2.44459 >= 2.326 0.0145

an inter-center comparison of dental arch relationships ... · born with a cleft. in fact, there is...

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