Artigo 8 – Decreased CSF Transferrin in sCJD a Potential Pre-mortem Diagnostic Test for Prion Disorders Sensitivity And Specificity Receiver Operating Characteristic anoxia medical definition

In the brain tissue obtained by biopsy or at autopsy [2]. Available pre-mortem diag nostic tests have provided inconsistent results, making it difficult to use therapeutic opti ons wher e avai labl e [3–8] . More over , und iagn osed case s of scjd are likely to transmit the disease to healthy indiv iduals, raising significant public health concerns [2,9]. Consequen tly, significant effort has gone into the identification of sens itiv e and spec ific biomar kers for scj D [8,1 0,11 ]. Of these , analysis of CSF proteins has proved promising due to its reasonable reliability and low cost. Commonly tested CSF proteins include 14- 3-3, total tau (T-tau), S100B, and neuron-specific enolase (NSE) [12–1 7].Anoxia medical definition

seve ral large scale stud ies, some acro ss cen ters, have expl ored the acc urac y of these biom arke rs in the cont ext of vari able s such as clin ical stage of dise ase, vali ne/ meth ion ine polymo rphi sm in the prion protein gene, and sub-type of scjd [18–23]. Based on thes e and othe r con side rati ons, the worl d heal th orga niz ation app rov ed a com bin ati on of CSF 14-3- 3 and EEG for th e pre – mortem diagnosis of clinically suspected cases of scjd [12,23,24]. Subs eque nt stud ies repor ted high sensiti vity but rela tive ly low specificity of this test, resulting in its replacement by a combination of CSF 14-3-3 and T-tau for cases of dementia suspected of scjd [3–6, 14,1 7,25 ].Anoxia medical definition howe ver, sub sequ ent repo rts ind ica ted vary ing sensitivity and specificity for 14-3-3 and T-tau when used singly or in combination, re-kindling the debate and dissent concerning the diagnostic accuracy of this test [3–6,14,17,27–31]. Maj or fac tor s con trib uti ng to the inc ons ist ent per for man ce of 14- 3- 3 and T-tau combination include: 1) variable false positives since 14- 3-3 and T-tau are elevated in several other dementias besides scjd [29– 31] , 2) exp eri men tal var iab ili ty of 14- 3-3 tha t is sem i- qua nti tat ive at bes t [4– 6], an d 3) lac k of com par ati ve ana lys is of bio mar ker acc ura cy wit hi n and acr oss stu die s usi ng a rig oro us sta tist ica l app roa ch [12 –23 ].Anoxia medical definition to add ress these wea kne sse s, it is cri tic al to identify a biomarker that is altered by scjd associated pathology and therefore specific, abundant in the CSF and easily quantifiable, and superior in diagnostic accuracy relative to the current biomarkers 14- 3-3 and T-tau using uniform benchmarks of analysis. One such potential biomarker is tf that is increased in scjd and prion disease affected animal brains [32–36]. The effect of this

GTX 21223) followed by HRP -con jugat ed secon dary anti body and visu aliz ation of react ive band s with ECL (ame rsham ). Seve ral proc edura l and statis tical precaut ions were taken to redu ce error in comp arin g multiple samples. Procedurally, a similar protocol was followed for all western blots, including exposure times.Anoxia medical definition in addition, strips of PVDF membran e repre senti ng spec ific molec ular weigh ts were exposed to X-ray film simultaneously in large cassettes to obtain simi lar expos ure. Quan tific ation of immu norea ctiv e band s was performed with UN-SCAN-IT software (version 6.1, silk scientific inc., utah, USA) using three exposures from a single membrane showing exponential increase in intensity. Statistically, results from diffe rent wester n blots were anal yzed simultan eousl y in logist ic reg res sio n by tre ati ng the se as clu ste red obs erv ati ons . Th e sta ti sti ca l sof tw ar e st at a al lo ws es ti ma ti on of re gr es si on coeff icie nts after contr ollin g for clus terin g to produ ce unbi ased standard errors.Anoxia medical definition two stata procedures were used to do this: the ‘vce cluster’ option and svy option. Each logistic regression model was first tested without adjustment for clustering and then tested wit h eac h of the 2 clu ste rin g opt ion s. Bot h had the eff ect , in gen era l, of in cre asi ng sta nd ard err ors and p-v alu es for the coeff icie nt estim ates as expec ted. However, the sign ific ance of the coe ffi cie nts of the bio mar ker s did not ch ang e; all the ir coefficients remained significant at the p

), which is also nonparamet- ric . Fin all y, log ist ic reg res sio n, whi ch mak es no ass um pti ons regarding the distributional properties of data (e.G., non-normal) [3 7] wa s us ed to pa ra me te ri ze th e di ag no sti c ac cu ra cy of biomarkers after controlling for age and duration (interval between CSF collection and death).Anoxia medical definition because the data were clustered (four sets of western blots), logistic regression was conducted in stata 10 wit h the opt ion to cor rec t sta nda rd err ors for clu ster in g. Th is opt ion is kn own to cor rec t for un der est ima tes of coe ffi ci ent standard errors, resulting in more conservative results. Using logistic regression results, an analytic expression for the risk of CJD was derived for each individual biomarker. Area under the receiver operating characteristic (ROC) curve and the aikake inf orm ati on cri ter ion (AI C) wer e obt ain ed. A RO C cu rve graphically shows the trade-offs between sensitivity and specificity for diff erent cut-offs used to disc rimi nate between positive and negative cases (i.E., CJD

anoxia medical definition

Parsimony. For each model, estimates of specificity and positive and negative likelihood ratios (LR) were obtained given a baseline sensi tivi ty of 85%, which has preceden ce in the literatu re as a reasonable cut-off level for biomarker comparison of alzheimer’s dis eas e (AD ) [38 ,39 ]. Pos iti ve LR is def in ed as sen sit ivi ty/ (1-specificity) and represents the increase in likelihood of a positive test result if the disease is present compared to its being absent. Th e neg ati ve LR is def ine d as (1- sen sit iv ity )/s pec ifi ci ty and repre sents the decrease in like liho od of a negat ive test resul t if the disease is present compared to it being absent. Positive and negat ive LR, like specif icity , depe nds on the chosen cut-off for sen sit ivi ty (se t at 85% in thi s stu dy) .Anoxia medical definition con fid enc e int erv als for pro por tio ns wer e cal cul ate d acc ord ing to the eff ic ien t-s cor e meth od and corre cted for conti nuit y [40]. Confiden ce inter vals for lrs were calculated as proposed in a previous report [41]. All statis tical tests were conduct ed at the 95% conf iden ce level . To identify an optimal combination of biomarkers, all two way combinations of new and current biomarkers were also entered into a logistic regression model with controls for age, duration, and clustered data (as above). Combining new and current biomarker T- ta u wa s in ten de d to ta ke ad va nt ag e of th e di ff er en ti al patho geni c mech anism s repre sente d by these biom arkers .Anoxia medical definition we foc use d on two -wa y com bin ati ons for rea son s of pra cti cal ity . However, a specific combination involving T-tf and 14-3-3 could not be evaluated because the readouts for 14-3-3 are not precisely quantifiable, and this biomarker has demonstrated relatively low specificity in previous studies [4–6]. All models were compared using three criteria: AUC, specificity, and AIC [42]. Model comparisons were based on multiple indicators while recognizing that specificity at a given level of sensitivity is a key discriminating factor. Models with higher specificity were preferred. The optimal biomarker or combination of biomarkers was expected to ideally have the highest AUC and specificity, and the lowest AIC.Anoxia medical definition we also conducted power analysis as proposed in a previous report [43 ]. We det erm in ed tha t the new bio ma rke rs wou ld pos ses s a discriminating power at least as good as T-tau; thus we based our pow er cal cu lat ion on the exp ect ed eff ect siz e of T-t au. Fro m previously published data on the power of T-tau to discriminate betwe en CJD