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Research article

Development and validation of a skin fibroblast biomarker profile for schizophrenic patients

  • Gene expression profiles of non-neural tissues through microarray technology could be used in schizophrenia studies, adding more information to the results from similar studies on postmortem brain tissue. The ultimate goal of such studies is to develop accessible biomarkers. Supervised machine learning methodologies were used, in order to examine if the gene expression from skin fibroblast cells could be exploited for the classification of schizophrenic subjects. A dataset of skin fibroblasts gene expression of schizophrenia patients was obtained from Gene Expression Omnibus database. After applying statistical criteria, we concluded to genes that present a differential expression between the schizophrenic patients and the healthy controls. Based on those genes, functional profiling was performed with the BioInfoMiner web tool. After the statistical analysis, 63 genes were identified as differentially expressed. The functional profiling revealed interesting terms and pathways, such as mitogen activated protein kinase and cyclic adenosine monophosphate signaling pathways, as well as immune-related mechanisms. A subset of 16 differentially expressed genes from fibroblast gene expression profiling that occurred after Support Vector Machines Recursive Feature Elimination could efficiently separate schizophrenic from healthy controls subjects. These findings suggest that through the analysis of fibroblast based gene expression signature and with the application of machine learning methodologies we might conclude to a diagnostic classification model in schizophrenia.

    Citation: Marianthi Logotheti, Eleftherios Pilalis, Nikolaos Venizelos, Fragiskos Kolisis, Aristotelis Chatziioannou. Development and validation of a skin fibroblast biomarker profile for schizophrenic patients[J]. AIMS Bioengineering, 2016, 3(4): 552-565. doi: 10.3934/bioeng.2016.4.552

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    [10] Marianthi Logotheti, Eleftherios Pilalis, Nikolaos Venizelos, Fragiskos Kolisis, Aristotelis Chatziioannou . Development and validation of a skin fibroblast biomarker profile for schizophrenic patients. AIMS Bioengineering, 2016, 3(4): 552-565. doi: 10.3934/bioeng.2016.4.552
  • Gene expression profiles of non-neural tissues through microarray technology could be used in schizophrenia studies, adding more information to the results from similar studies on postmortem brain tissue. The ultimate goal of such studies is to develop accessible biomarkers. Supervised machine learning methodologies were used, in order to examine if the gene expression from skin fibroblast cells could be exploited for the classification of schizophrenic subjects. A dataset of skin fibroblasts gene expression of schizophrenia patients was obtained from Gene Expression Omnibus database. After applying statistical criteria, we concluded to genes that present a differential expression between the schizophrenic patients and the healthy controls. Based on those genes, functional profiling was performed with the BioInfoMiner web tool. After the statistical analysis, 63 genes were identified as differentially expressed. The functional profiling revealed interesting terms and pathways, such as mitogen activated protein kinase and cyclic adenosine monophosphate signaling pathways, as well as immune-related mechanisms. A subset of 16 differentially expressed genes from fibroblast gene expression profiling that occurred after Support Vector Machines Recursive Feature Elimination could efficiently separate schizophrenic from healthy controls subjects. These findings suggest that through the analysis of fibroblast based gene expression signature and with the application of machine learning methodologies we might conclude to a diagnostic classification model in schizophrenia.


    1. Introduction

    The following postulates and notation are used throughout:

    • KRn (Euclidean n-space) is a solid order cone: a closed convex cone that has nonempty interior IntK and contains no affine line.

    • Rn has the (partial) order determined by K:

    yxyxK,

    referred to as the K-order.

    • XRn is a nonempty set whose Int X is connected and dense in X.

    • T: XX is homeomorphism that is monotone for the K-order:

    xyTxTy.

    A point xX has period k provided k is a positive integer and Tkx=x. The set of such points is Pk=Pk(T), and the set of periodic points is P=P(T)=kPk. T is periodic if X=Pk, and pointwise periodic if X=P.

    Our main concern is the following speculation:

    Conjecture. If P is dense in X, then T is periodic.

    The assumptions on X show that T is periodic iff T|IntX is periodic. Therefore we assume henceforth:

    •  X is connected and open Rn.

    We prove the conjecture under the additional assumption that K is a polyhedron, the intersection of finitely many closed affine halfspaces of Rn:

    Theorem 1 (Main). Assume K is a polyhedron, T: XX is monotone for the K-order, and P is dense in X. Then T is periodic.

    For analytic maps there is an interesting contrapositive:

    Theorem 2. Assume K is a polyhedron and T: XX is monotone for the K-order. If T is analytic but not periodic, P is nowhere dense.

    Proof. As X is open and connected but not contained in any of the closed sets Pk, analyticity implies each Pk is nowhere dense. Since P=k=1Pk, a well known theorem of Baire [1] implies P is nowhere dense.

    The following result of D. Montgomery [4]*is crucial for the proof of the Main Theorem:

    *See also S. Kaul [3].

    Theorem 3 (Montgomery). Every pointwise periodic homeomorphism of a connected manifold is periodic.

    Notation

    i,j,k,l denote positive integers. Points of Rn are denoted by a,b,p,q,u,v,w,x,y,z.

    xy is a synonym for yx. If xy and xy we write x or yx.

    The relations xy and yx mean yxIntK.

    A set S is totally ordered if x,ySxy or xy.

    If xy, the order interval [x,y] is {z:xzy}=KxKy.

    The translation of K by xRn is Kx:={w+x,wK.}

    The image of a set or point ξ under a map H is denoted by Hξ or H(ξ). A set S is positively invariant under H if HSS, invariant if Hξ=ξ, and periodically invariant if Hkξ=ξ.


    2. Proof of the Main Theorem

    The following four topological consequences of the standing assumptions are valid even if K is not polyhedral.

    Proposition 4. Assune p,qPk are such that

    pq,p,qPk.[p,q]X.

    Then Tk([p,q]=[p,q].

    proof. It suffices to take k=1. Evidently TP=P, and T[p,q][p,q] because T is monotone, whence Int[p,q]P is positively invariant under T. The conclusion follows because Int[p,q]P is dense in [p,q] and T is continuous.

    Proposition 5. Assume a,bPk,ab, and [a,b]X. There is a compact arc JPk[a,b] that joins a to b, and is totally ordered by .

    proof. An application of Zorn's Lemma yields a maximal set J[a,b]P such that: J is totally ordered by , a=maxJ, b=minJ. Maximality implies J is compact and connected and a,bJ, so J is an arc (Wilder [7], Theorem I.11.23).

    Proposition 6. Let MX be a homeomorphically embedded topological manifold of dimension n1, with empty boundary.

    (i) P is dense in M.

    (ii) If M is periodically invariant, it has a neighborhood base B of periodically invariant open sets.

    proof. (i) M locally separates X, by Lefschetz duality [5] (or dimension theory [6]. Therefore we can choose a family V of nonempty open sets in X that the family of sets VM:={VM:VV) satisfies:

    •  VM is a neighborhood basis of M,

    •  each set VM separates V.

    By Proposition 5, for each VV there is a compact arc JVPV whose endpoints aV,bv lie in different components of V\M. Since JV is connected, it contains a point in VMP. This proves (i).

    (ii) With notation as above, let BV:=[aV,bV]\[aV,bV]. The desired neighborhood basis is B:={BV:VV}.

    From Propositions 4 and 6 we infer:

    Proposition 7. Suppose p,qP, pq and [p,q]X. Then P is dense in [p,q].

    Let T(m) stand for the statement of Theorem 1 for the case n=m. Then T(0) is trivial, and we use the following inductive hypothesis:

    Hypothesis (Induction). n1 and T(n1) holds.

    Let QRn be a compact n-dimensional polyhedron. Its boundary Q is the union of finitely many convex compact (n1)-cells, the faces of Q. Each face F is the intersection of [p,q] with a unique affine hyperplane En1. The corresponding open face F:=F\F is an open (n1)-cell in En1. Distinct open faces are disjoint, and their union is dense and open in Q.

    Proposition 8. Assume p,qPk, pq, [p,q]X. Then T|[p,q] is periodic.

    8224; This result is adapted from Hirsch & Smith [2],Theorems 5,11 & 5,15.

    proof. [p,q] is a compact, convex n-dimensional polyhedron, invariant under Tk (Proposition 4). By Proposition 6 applied to M:=[p,q], there is a neighborhood base B for [p,q] composed of periodically invariant open sets. Therefore if F[p,q] is an open face of [p,q], the family of sets

    BF:={WB:WF}

    is a neighborhood base for F, and each WBF is a periodically invariant open set in which P is dense.

    For every face F of [p,q] the Induction Hypothesis shows that FP. Therefore Montgomery's Theorem implies T|F is periodic, so T|F is periodic by continuity. Since [p,q] is the union of the finitely many faces, it follows that T|[p,q] is periodic.

    To complete the inductive proof of the Main Theorem, it suffices by Montgomery's theorem to prove that an arbitrary xX is periodic. As X is open in Rn and P is dense in X, there is an order interval [a,b]X such that

    axb,a,bPk.

    By Proposition 5, a and b are the endpoints of a compact arc JPk[a,b], totally ordered by . Define p,qJ:

    p:=sup{yJ:yx},q:=inf{yJ:yx}.

    If p=q=x then xPk. Otherwise pq, implying x[p,q], whence xP by Proposition 8


    Conflict of Interest

    The author declares no conflicts of interest in this paper.


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