Bayesian Hierarchical Models for Detecting Safety Signals in 检测安全信号的贝叶斯层次模型

1、Bayesian Hierarchical Models for Detecting Safety Signals in Clinical TrialsH. Amy Xia and Haijun MaAmgen, Inc.MBSW 2009, Muncie, INMarch 20, 2009Disclaimer: The views expressed in this presentation represent personal views and do not necessarily represent the views or practices of Amgen.Outline Int

2、roduction A motivating example Bayesian Hierarchical Models Meta analysis of Adverse Events data from multiple studies incorporating MedDRA structure Incorporate patient level data Effective graphics Closing RemarksThree-Tier System for Analyzing Adverse Events in Clinical Trials Tier 1: Pre-specifi

3、ed Detailed Analysis and Hypothesis Testing Tier 1 AEs are events for which a hypothesis has been defined Tier 2: Signal Detection among Common Events Tier 2 AEs are those that are not pre-specified and “common” Tier 3: Descriptive Analysis of Infrequent AEs Tier 3 AEs are those that are not pre-spe

4、cified and infrequentGould 2002 & Mehrotra 2004SPERT White Paper 2008Multiplicity Issue in Detecting Signals Is Challenging Detection of safety signals from routinely collected, not pre-specified AE data in clinical trials is a critical task in drug development Multiplicity issue in such a setti

5、ng is a challenging statistical problem Without multiplicity considerations, there is a potential for an excess of false positive signals Traditional ways of adjusting for multiplicity such as Bonferroni may lead to an excessive rate of false negatives The challenge is to develop a procedure for fla

6、gging safety signals which provides a proper balance between no adjustment versus too much adjustmentConsiderations Regarding Whether Flagging an Event Actual significance levels Total number of types of AEs Rates for those AEs not considered for flagging Biologic relationships among various AEs1st

7、two are standard considerations in the frequentist approach. The 2nd two are not, but relevant in the Bayesian approach- Berry and Berry, 2004Bayesian Work in Signal Detection Spontaneous adverse drug reaction reports Gamma Poisson Shrinker (GPS) on FDA AERS database (DuMouchel,1999) Bayesian Confid

8、ence Propagation Neural Network (BCPNN) on WHO database (Bate, et al. 1998) Clinical trial safety (AE) data Bayesian hierarchical mixture modeling (Berry and Berry, 2004)Meta Analysis Glass (1976)Meta-analysis refers to a statistical analysis that combines the results of some collection of related s

9、tudies to arrive a single conclusion to the question at hand Meta-analysis based on aggregate patient data (APD meta-analysis) Individual patient data (IPD) meta-analysis Bayesian modeling is a natural choice to incorporate the complex hierarchical structure of the dataGeorge Chi, H.M. James Hung, R

10、obert ONeill (FDA CDER)“Safety assessment is one area where frequentist strategies have been less applicable. Perhaps Bayesian approaches in this area have more promise.” (Pharmaceutical Report, 2002)An Example Data from four double-blind placebo-controlled studies on drug X. Study populations are s

11、imilar. Sample sizes: After converting all AEs into same MedDRA version, reported AEs are coded to 464 PTs under 23 SOCs and 233 HLTsStudyDrug XNDrug XSubj-yrPlaceboNPlaceboSubj-yrStudy A5728.255519.02Study B486104.7516634.93Study C39085.4419340.97Study D31268.7830665.91N_0: sample size in placebo a

12、rm; N_1: sample size in treatment armn_0: # subject with AE in placebo arm; n_1: # subject with AE in treatment armrt_0: subject incidence in placebo arm; rt_1: subject incidence in treatment armProposed Bayesian Approach Hierarchical mixture models for aggregated binary responses was constructed ba

13、sed on the work by Berry & Berry(2004) Explore impact of using different MedDRA hierarchy Inclusion of study effects Further extended to a hierarchical Poisson mixture model, to account for different exposure/follow-up times between patients Individual patient level models are discussed Implemen

14、ted the above models with available software WinBUGS for model implementation S-Plus graphics for inferenceMedDRA MedDRA (the Medical Dictionary for Regulatory Activities Terminology) is a controlled vocabulary widely used as a medical coding scheme. MedDRA Definition (MSSO): MedDRA is a clinically-

15、validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry. The terminology is used through the entire regulatory process, from pre-marketing to post-marketing, and for data entry, retrieval, evaluation, and presentation.https:/eudract.eme

16、a.europa.eu/docs/medDRA/Introduction_To_MedDRA.ppt MSSO: Introduction to MedDRA/cder/present/dia-699/dia628/index.htmMedDRA and Pharmacovigilance - The Way Forward, 7/8/99/cder/present/dia-699/dia628/index.htmMedDRA and Pharmacovigilance - The Way Forward, 7/8/99SOC

17、 = Respiratory, thoracic and mediastinal disordersHLGT = Respiratory tract infectionsHLT =Viral upper respiratorytract infectionsHLT = Influenza viral infectionsHLGT = Viral infectious disordersSOC = Infections and infestationsPT = Influenza Example of MedDRA Hierarchyhttps:/eudract.emea.europa.eu/d

18、ocs/medDRA/Introduction_To_MedDRA.ppt MSSO: Introduction to MedDRAHierarchical Structure of MedDRA Bayesian hierarchical models allow for explicitly modeling AEs with the existing coding structure AEs in the same SOC more likely to be similar within than across SOCs. Allow for this possibility, but

19、does not impose it, depending on the actual data SOC tends to be too broad. HLT is more closely related to medical concepts. In fact, clinical and safety people would (informally) consider the similarity of the AEs, say, within SOCs when they review AE tables For example, if differences in several C

20、V events were observed, then each would be more likely to be causal than if differences came from medically unrelated areas (eg, skin, neurological, thrombosis, cancer) Bayesian hierarchical modeling allows a scientific, explicit, and more formal way to take it into consideration Notations Study i=1

21、,I, SOC b=1,B and PT j=1,kb Data: For AEibj Treatment group: Yibj incident events observed in Nit patients with Tibj subjects exposure Control group: Xibj incident events observed in Nic patients with Cibj subjects exposureBayesian Meta Analysis Hierarchical Logistic Regressionly.respective groups,

22、control and treatmentin the AEfor ratesevent are and where,BinomialBinomialibjibjibjibj,icibjibj,itibj ct) c(N ), X t(N Y) 1()exp();1()exp( :prior 3 Stage);,(:prior 2 Stage);,()1 ()0( :prior 1 Stage:OR-logeffect ent for treatmPrior Mixture),N( , ),N( )logit(t ,)logit(c2bj2bbbj2bj,bjibjbjibjibjibj ib

23、jppppppbbbbbIIBetaNCommon treatment effect for same PT across studiesBayesian Meta Analysis Hierarchical Logistic Regression (Cont.) Treatment effect with additive study effects: A random treatment effect/multiplicative model:),()1 ()0(, ),N(),N( , ),N( )logit(t ,)logit(c2bj2bjbjibj2bbbj2bj,bjibjibj

24、ibjibjibj ibjbbbbN)01. 0 , 0(),()1 ()0(),N( , ),N( )logit(t ,)logit(c2bj2bbbj2bj,bjibjibjibjibjibj ibjNNStudyibbbbiBayesian Meta Analysis Hierarchical Logistic Regression (Cont.) Other priors Stage 1 bj N(b , 2b ); Stage 2 bN(0, 20 ); 2b IG(, ); b N(0, 20 ); 2b IG(, )- Stage 3 0N(00 , 200 ); 20 IG(0

25、0, 00) 0N(00 , 200 ); 20 IG(00, 00)Hyperparameters 00, 200, 00, 00, 00, 200, 00, 00, , , , are fixed constantsInference AEbj is flagged if Pr( bj d*| Data) p, where bj is log-OR in Binomial models and log-RR in Poisson models. d* and p are all prespecified constants. Graphs are useful tools in decip

26、hering data and presenting results Model Selection Deviance Information Criteria (DIC) was used to compare models with same data Limited sensitivity analyses were done to check the robustness of the models Different levels of MedDRA structures were used SOC/PT, HLT/PT and SOC/HLT/PT Treatment effect

27、 with additive study effects model using SOC/PT structure was chosenBayesian Meta Analysis Hierarchical Log-linear Regression Poisson models Adjust for different exposures in treatment and control Assume constant hazard over time Unless AEs are fairly common or follow up of studies are quite unbalan

28、ced between treatment arms, usually are not very different from Binomial modelsYibjPois(tibj Tibj ); XbjPois(cibj Cibj)where tibj and cibj are event rates, and Tibj and Cibj for AEibj are total exposure times in the treatment and control groups, respectivelylog(cibj )=ibj; log(tibj )=ibj + bj , Note

29、 that bj =log(RRbj)Fishers Exact Test 2-sided P-valuesRaw Risk Difference(%), Treatment - Placebo - log10 (Fisher exact p-value)-0.010.00.010.020.00.51.01.52.02.5 ECCHYMOSIS EXCORIATION FATIGUE HERPES SIMPLEX SINUSITISGASTROINTESTINAL DISORDER.INFECTIONS AND INFESTATIO.SKIN AND SUBCUTANEOUS TIS.NEOP

30、LASMS BENIGN, MALIGNA.GENERAL DISORDERS AND ADM.PSYCHIATRIC DISORDERSINJURY, POISONING AND PRO.RESPIRATORY, THORACIC AND.CARDIAC DISORDERSMUSCULOSKELETAL AND CONNE.REPRODUCTIVE SYSTEM AND B.RENAL AND URINARY DISORDE.EYE DISORDERSINVESTIGATIONSNERVOUS SYSTEM DISORDERSMETABOLISM AND NUTRITION .IMMUNE

31、SYSTEM DISORDERSEAR AND LABYRINTH DISORDE.SURGICAL AND MEDICAL PROC.VASCULAR DISORDERSENDOCRINE DISORDERSHEPATOBILIARY DISORDERSBLOOD AND LYMPHATIC SYSTE.0123log Odds RatioGASTROENTERITIS VIRALINFLUENZABRONCHITISDIZZINESSTENSION HEADACHEBASAL CELL CARCINOMAURTICARIAEXCORIATIONHEADACHEINJECTION SITE

32、BRUISINGDYSPEPSIAHERPES SIMPLEXFATIGUESINUSITISECCHYMOSISPetos Method0123log Odds RatioTENSION HEADACHEUPPER RESPIRATORY TRACT INFECTIONPHARYNGITISURTICARIABRONCHITISDIZZINESSNASOPHARYNGITISINFLUENZADYSPEPSIAINJECTION SITE BRUISINGHEADACHEECCHYMOSISHERPES SIMPLEXSINUSITISFATIGUEM-H TA CC Methodlog-O

33、R posterior meansP(OR 1|Data)-3-2-10120.00.81.0 ECCHYMOSISBLOOD AND LYMPHATIC SYSTE.CARDIAC DISORDERSEAR AND LABYRINTH DISORDE.ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER.GENERAL DISORDERS AND ADM.HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO.INJURY,

34、POISONING AND PRO.INVESTIGATIONSMETABOLISM AND NUTRITION .MUSCULOSKELETAL AND CONNE.NEOPLASMS BENIGN, MALIGNA.NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE.REPRODUCTIVE SYSTEM AND B.RESPIRATORY, THORACIC AND.SKIN AND SUBCUTANEOUS TIS.SURGICAL AND MEDICAL PROC.VASCULAR DISORD

35、ERSlog-OR posterior meansP(OR 1|Data)-3-2-10120.00.81.0 ECCHYMOSISBLOOD AND LYMPHATIC SYSTE.CARDIAC DISORDERSEAR AND LABYRINTH DISORDE.ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER.GENERAL DISORDERS AND ADM.HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO.

36、INJURY, POISONING AND PRO.INVESTIGATIONSMETABOLISM AND NUTRITION .MUSCULOSKELETAL AND CONNE.NEOPLASMS BENIGN, MALIGNA.NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE.REPRODUCTIVE SYSTEM AND B.RESPIRATORY, THORACIC AND.SKIN AND SUBCUTANEOUS TIS.SURGICAL AND MEDICAL PROC.VASCULA

37、R DISORDERSlog-OR posterior meansP(OR 1|Data)-3-2-10120.00.81.0 ARRHYTHMIA ARTERIOSCLEROSIS CORONARY ARTERY BUNDLE BRANCH BLOCK LEFT EAR DISCOMFORT TINNITUS VERTIGO VERTIGO POSITIONAL CATARACT CONJUNCTIVAL HAEMORRHAGE CONJUNCTIVITIS DIPLOPIA DRY EYE EYE INFLAMMATION EYE PRURITUS EYELID OEDE

38、MA ABDOMINAL DISTENSION ABDOMINAL PAIN ABDOMINAL PAIN UPPER ABDOMINAL TENDERNESS DIARRHOEA DRY MOUTH DYSPEPSIA FLATULENCE FOOD POISONING GASTROINTESTINAL HYPERMOTILITY GASTROINTESTINAL INFLAMMATION GASTROOESOPHAGEAL REFLUX DISEASE GINGIVAL BLEEDING NAUSEA STOMACH DISCOMFORT TOOTH DISORDER TOOTHACHE

39、FATIGUE INJECTION SITE BRUISING INJECTION SITE HAEMATOMA IRRITABILITY MALAISE LIVER DISORDER HYPERSENSITIVITY SEASONAL ALLERGY ABDOMINAL INFECTION ACUTE SINUSITIS APPENDICITIS BRONCHITIS BRONCHITIS CHRONIC CANDIDIASIS CAT SCRATCH DISEASE CELLULITIS STAPHYLOCOCCAL CERVICITIS CONDYLOMA ACUMINATUM CYST

40、ITIS DIVERTICULITIS EAR INFECTION ERYSIPELAS EYELID INFECTION FOLLICULITIS FUNGAL INFECTION FURUNCLE GASTROENTERITIS VIRAL GENITAL INFECTION FEMALE GINGIVAL INFECTION HERPES SIMPLEX HERPES VIRUS INFECTION INFECTED INSECT BITE INFECTED SEBACEOUS CYST INFECTIOUS MONONUCLEOSIS INFLUENZA LABYRINTHITIS L

41、ARYNGITIS LOWER RESPIRATORY TRACT INFECTION MASTITIS NASOPHARYNGITIS ONYCHOMYCOSIS ORAL PUSTULE OTITIS EXTERNA OTITIS MEDIA PHARYNGITIS PNEUMONIA POSTOPERATIVE WOUND INFECTION PULPITIS DENTAL PUNCTURE SITE INFECTION RASH PUSTULAR RHINITIS SIALOADENITIS SINUSITIS SKIN INFECTION SUBCUTANEOUS ABSCESS T

42、INEA CRURIS TINEA INFECTION TINEA VERSICOLOUR TONSILLITIS TOOTH ABSCESS TOOTH INFECTION VAGINAL CANDIDIASIS VAGINAL INFECTION VIRAL INFECTION VIRAL UPPER RESPIRATORY TRACT INFECTION ANIMAL BITE CONTUSION EXCORIATION FALL FOOT FRACTURE HAND FRACTURE HEAT STROKE POST-TRAUMATIC PAIN ROAD TRAFFIC ACCIDE

43、NT SCAPULA FRACTURE TENDON INJURY THERMAL BURN TOOTH FRACTURE TOOTH INJURY WOUND BLOOD CHOLESTEROL INCREASED BLOOD GLUCOSE INCREASED BLOOD PRESSURE INCREASED BODY TEMPERATURE INCREASED WEIGHT DECREASED WEIGHT INCREASED HYPERCHOLESTEROLAEMIA BACK PAIN INTERVERTEBRAL DISC DEGENERATION JOINT EFFUSION M

44、YALGIA SHOULDER PAIN TENDONITIS BASAL CELL CARCINOMA FIBROUS HISTIOCYTOMA LIPOMA PROSTATE CANCER SEBORRHOEIC KERATOSIS SKIN PAPILLOMA SQUAMOUS CELL CARCINOMA OF SKIN BURNING SENSATION CAROTID ARTERY STENOSIS CARPAL TUNNEL SYNDROME CEREBROVASCULAR ACCIDENT CEREBROVASCULAR INSUFFICIENCY DISTURBANCE IN

45、 ATTENTION DIZZINESS DIZZINESS POSTURAL DYSGEUSIA FACIAL PALSY HEADACHE HYPERSOMNIA HYPERTONIA HYPOAESTHESIA LETHARGY MEMORY IMPAIRMENT MIGRAINE NERVE COMPRESSION NEURALGIA PARAESTHESIA RESTLESS LEGS SYNDROME SCIATICA SENSORY DISTURBANCE SINUS HEADACHE SOMNOLENCE SYNCOPE SYNCOPE VASOVAGAL TENSION HE

46、ADACHE AGITATION ALCOHOLISM ANXIETY ATTENTION DEFICIT/HYPERACTIVITY DISORDER BIPOLAR I DISORDER DEPRESSION DYSPHORIA INSOMNIA LIBIDO DECREASED NERVOUSNESS PREMATURE EJACULATION STRESS CALCULUS BLADDER HAEMATURIA NEPHROLITHIASIS POLLAKIURIA STRESS INCONTINENCE TRIGONITIS URINARY INCONTINENCE URINARY

47、RETENTION BENIGN PROSTATIC HYPERPLASIA CERVICAL DYSPLASIA ERECTILE DYSFUNCTION OVARIAN CYST RUPTURED VAGINAL LACERATION VULVOVAGINAL DRYNESS ALLERGIC COUGH DYSPHONIA DYSPNOEA DYSPNOEA EXERTIONAL EPISTAXIS HYPERVENTILATION NASAL CONGESTION RHINITIS ALLERGIC RHINORRHOEA RHONCHI SINUS CONGESTION SLEEP

48、APNOEA SYNDROME SNEEZING SNORING THROAT IRRITATION ACNE ACTINIC KERATOSIS DERMAL CYST DERMATITIS CONTACT ECCHYMOSIS ECZEMA GUTTATE PSORIASIS INGROWING NAIL INTERTRIGO NIGHT SWEATS ONYCHOMADESIS SKIN HAEMORRHAGE SKIN LESION URTICARIA ENDODONTIC PROCEDURE FLUSHING HOT FLUSH HYPERTENSION LYMPHOEDEMABLO

49、OD AND LYMPHATIC SYSTE.CARDIAC DISORDERSEAR AND LABYRINTH DISORDE.ENDOCRINE DISORDERSEYE DISORDERSGASTROINTESTINAL DISORDER.GENERAL DISORDERS AND ADM.HEPATOBILIARY DISORDERSIMMUNE SYSTEM DISORDERSINFECTIONS AND INFESTATIO.INJURY, POISONING AND PRO.INVESTIGATIONSMETABOLISM AND NUTRITION .MUSCULOSKELE

50、TAL AND CONNE.NEOPLASMS BENIGN, MALIGNA.NERVOUS SYSTEM DISORDERSPSYCHIATRIC DISORDERSRENAL AND URINARY DISORDE.REPRODUCTIVE SYSTEM AND B.RESPIRATORY, THORACIC AND.SKIN AND SUBCUTANEOUS TIS.SURGICAL AND MEDICAL PROC.VASCULAR DISORDERSlog-OR posterior meansP(OR 1|Data)-3-2-10120.00.81.0 ARRHY

51、THMIA ARTERIOSCLEROSIS CORONARY ARTERY BUNDLE BRANCH BLOCK LEFT EAR DISCOMFORT TINNITUS VERTIGO VERTIGO POSITIONAL CATARACT CONJUNCTIVAL HAEMORRHAGE CONJUNCTIVITIS DIPLOPIA DRY EYE EYE INFLAMMATION EYE PRURITUS EYELID OEDEMA ABDOMINAL DISTENSION ABDOMINAL PAIN ABDOMINAL PAIN UPPER ABDOMINAL TENDERNE

52、SS DIARRHOEA DRY MOUTH DYSPEPSIA FLATULENCE FOOD POISONING GASTROINTESTINAL HYPERMOTILITY GASTROINTESTINAL INFLAMMATION GASTROOESOPHAGEAL REFLUX DISEASE GINGIVAL BLEEDING NAUSEA STOMACH DISCOMFORT TOOTH DISORDER TOOTHACHE FATIGUE INJECTION SITE BRUISING INJECTION SITE HAEMATOMA IRRITABILITY MALAISE

53、LIVER DISORDER HYPERSENSITIVITY SEASONAL ALLERGY ABDOMINAL INFECTION ACUTE SINUSITIS APPENDICITIS BRONCHITIS BRONCHITIS CHRONIC CANDIDIASIS CAT SCRATCH DISEASE CELLULITIS STAPHYLOCOCCAL CERVICITIS CONDYLOMA ACUMINATUM CYSTITIS DIVERTICULITIS EAR INFECTION ERYSIPELAS EYELID INFECTION FOLLICULITIS FUN

54、GAL INFECTION FURUNCLE GASTROENTERITIS VIRAL GENITAL INFECTION FEMALE GINGIVAL INFECTION HERPES SIMPLEX HERPES VIRUS INFECTION INFECTED INSECT BITE INFECTED SEBACEOUS CYST INFECTIOUS MONONUCLEOSIS INFLUENZA LABYRINTHITIS LARYNGITIS LOWER RESPIRATORY TRACT INFECTION MASTITIS NASOPHARYNGITIS ONYCHOMYC

55、OSIS ORAL PUSTULE OTITIS EXTERNA OTITIS MEDIA PHARYNGITIS PNEUMONIA POSTOPERATIVE WOUND INFECTION PULPITIS DENTAL PUNCTURE SITE INFECTION RASH PUSTULAR RHINITIS SIALOADENITIS SINUSITIS SKIN INFECTION SUBCUTANEOUS ABSCESS TINEA CRURIS TINEA INFECTION TINEA VERSICOLOUR TONSILLITIS TOOTH ABSCESS TOOTH

56、INFECTION VAGINAL CANDIDIASIS VAGINAL INFECTION VIRAL INFECTION VIRAL UPPER RESPIRATORY TRACT INFECTION ANIMAL BITE CONTUSION EXCORIATION FALL FOOT FRACTURE HAND FRACTURE HEAT STROKE POST-TRAUMATIC PAIN ROAD TRAFFIC ACCIDENT SCAPULA FRACTURE TENDON INJURY THERMAL BURN TOOTH FRACTURE TOOTH INJURY WOU

57、ND BLOOD CHOLESTEROL INCREASED BLOOD GLUCOSE INCREASED BLOOD PRESSURE INCREASED BODY TEMPERATURE INCREASED WEIGHT DECREASED WEIGHT INCREASED HYPERCHOLESTEROLAEMIA BACK PAIN INTERVERTEBRAL DISC DEGENERATION JOINT EFFUSION MYALGIA SHOULDER PAIN TENDONITIS BASAL CELL CARCINOMA FIBROUS HISTIOCYTOMA LIPO

58、MA PROSTATE CANCER SEBORRHOEIC KERATOSIS SKIN PAPILLOMA SQUAMOUS CELL CARCINOMA OF SKIN BURNING SENSATION CAROTID ARTERY STENOSIS CARPAL TUNNEL SYNDROME CEREBROVASCULAR ACCIDENT CEREBROVASCULAR INSUFFICIENCY DISTURBANCE IN ATTENTION DIZZINESS DIZZINESS POSTURAL DYSGEUSIA FACIAL PALSY HEADACHE HYPERS

59、OMNIA HYPERTONIA HYPOAESTHESIA LETHARGY MEMORY IMPAIRMENT MIGRAINE NERVE COMPRESSION NEURALGIA PARAESTHESIA RESTLESS LEGS SYNDROME SCIATICA SENSORY DISTURBANCE SINUS HEADACHE SOMNOLENCE SYNCOPE SYNCOPE VASOVAGAL TENSION HEADACHE AGITATION ALCOHOLISM ANXIETY ATTENTION DEFICIT/HYPERACTIVITY DISORDER B

60、IPOLAR I DISORDER DEPRESSION DYSPHORIA INSOMNIA LIBIDO DECREASED NERVOUSNESS PREMATURE EJACULATION STRESS CALCULUS BLADDER HAEMATURIA NEPHROLITHIASIS POLLAKIURIA STRESS INCONTINENCE TRIGONITIS URINARY INCONTINENCE URINARY RETENTION BENIGN PROSTATIC HYPERPLASIA CERVICAL DYSPLASIA ERECTILE DYSFUNCTION OVARIAN