is just its quantity that is low. Types II, III and IV are usually, but not always, related to a deficiency of type I collagen. One possible deficiency arises from an amino acid substitution of glycine to a bulkier amino acid, such as alanine, in the collagen protein's triple helix structure. The larger amino acid side-chains lead to steric effects that creates a bulge in the collagen complex, which in turn influences both the molecular nanomechanics and the interaction between molecules, which are both compromised. Depending on both the location of the substitution and the amino acid being used instead, different effects are seen which account for the type diversity in OI despite the same two collagen genes being responsible for most cases. Replacements of glycine with serine or cysteine are seen less often in fatal type II OI, while replacements with valine, aspartic acid, glutamic acid, or arginine are seen more often. At a larger scale, the relationship between the collagen fibrils and hydroxyapatite crystals to form bone is altered, causing brittleness. Bone fractures occur because the stress state within collagen fibrils is altered at the locations of mutations, where locally larger shear forces lead to rapid failure of fibrils even at moderate loads because the homogeneous stress state normally found in healthy collagen fibrils is lost. OI is therefore a multi-scale phenomenon, where defects at the smallest levels of tissues (genetic, nano, micro) domino to affect the macro level of tissues. Diagnosis Diagnosis is typically based on medical imaging, including plain X-rays, and symptoms. In severe OI, signs on medical imaging include abnormalities in all extremities and in the spine. As X-rays are often insensitive to the comparatively smaller bone density loss associated with type I OI, DEXA scans may be needed. An OI diagnosis can be confirmed through DNA or collagen protein analysis, but in many cases, the occurrence of bone fractures with little trauma and the presence of other clinical features such as blue sclerae are sufficient for a diagnosis. A skin biopsy can be performed to determine the structure and quantity of type I collagen. While DNA testing can confirm the diagnosis, it cannot absolutely exclude it because not all mutations causing OI are yet known and/or tested for. OI type II is often diagnosed by ultrasound during pregnancy, where already multiple fractures and other characteristic features may be visible. Relative to control, OI cortical